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The Benefits of Exercise on Structural and Functional Plasticity in the Rodent Hippocampus of Different Disease Models

Abstract

In this review, the benefits of physical exercise on structural and functional plasticity in the hippocampus are discussed. The evidence is clear that voluntary exercise in rats and mice can lead to increases in hippocampal neurogenesis and enhanced synaptic plasticity which ultimately result in improved performance in hippocampal-dependent tasks. Furthermore, in models of neurological disorders, including fetal alcohol spectrum disorders, traumatic brain injury, stroke, and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease exercise can also elicit beneficial effects on hippocampal function. Ultimately this review highlights the multiple benefits of exercise on hippocampal function in both the healthy and the diseased brain.

ABBREVIATIONS

AD

Alzheimer’s disease

BDNF

brain derived neurotrophic factor

CA

Cornu Ammonis

CFC

contextual fear conditioning

DGC

dentate granule cell

DG

dentate gyrus

EC

entorhinal cortex

fMRI

functional magnetic resonance imaging

GABA

gamma amino butyric acid

GCL

granule cell layer

HD

Huntington disease

LPP

lateral perforant path

LTD

long-term depression

LTP

long-term potentiation

MPP

medial perforant path

MWM

Morris water maze

NMDA

N-methyl D-aspartate

PD

Parkinson’s disease

PND

postnatal day

RAM

radial arm maze

TBI

traumatic brain injury

INTRODUCTION

The hippocampus is a bilateral structure that is found in the medial temporal lobe of the mammalian brain and is considered part of the limbic system. The hippocampus consists of the dentate gyrus (DG), the Cornu Ammonis (CA) 1 and CA3 regions (also known as the hippocampus proper) and the subiculum (reviewed by [1]). The hippocampus has been the focus of intensive research due to its important role in learning and memory, particularly that associated with declarative (i.e., explicit) and spatial memory [1].

The hippocampus displays both structural and functional plasticity into adulthood. This plasticity can be positively manipulated by interventions such as physical exercise. In this review we summarize the benefits of voluntary physical exercise on hippocampal neurogenesis (which is referred to structural plasticity in this review), and function (which is referred to synaptic plasticity and behavioral improvement in this review) in rodents. We also review the potential benefits of physical exercise on hippocampal plasticity in rodent models of neurological disorders, including traumatic brain injury, stroke and neurodevelopmental and neurodegenerative disorders. For purposes of simplicity, we have focused on studies utilizing rats and mice and where voluntary physical exercise paradigms have been employed. Finally, we have limited our review to studies examining adult animals, except for the section on neurodegenerative diseases. While exercise has also been shown to be beneficial in juvenile and aging animals [2–7], these studies are outside the scope of this review.

The hippocampus

Information flow in the hippocampus

Information flow in the hippocampus is generally unidirectional and is known as the trisynaptic circuit [8] (Fig. 1). The first connection in the trisynaptic circuit originates from Layer II of the entorhinal cortex (EC) and projects to the DG via a group of fibres known as the perforant path. The fibres synapse on the dendrites of the dentate granule cells (DGCs) located in the molecular cell layer. There are two subdivisions of the perforant path: medial (MPP) and lateral (LPP). The MPP originates in the medial EC and projects to the middle one-third of the molecular cell layer, whereas the LPP originates in the lateral EC and projects to the outermost third of the molecular cell layer. Both the MPP and LPP provide excitatory input onto the DGCs but are physiologically distinct and have different short-term and long-term plasticity properties [9–11]. The MPP and LPP are the major inputs of cortical information into the hippocampus and the DGCs play an important role in processing and filtering information before it is sent to other regions of the hippocampus via the trisynaptic circuit [8]. From the DG, DGC axons project onto pyramidal cells in the CA3 region of the hippocampus (Fig. 1). This pathway is unique in that the bundles of axons are unmyelinated and are therefore known as the mossy fibres. The third component of the trisynaptic circuit is the CA3 to CA1 projection known as the Schaffer Collaterals. Pyramidal cells of the CA3 send axons into the stratum radiatum and stratum oriens of the CA1 and innervate apical and basal dendrites of the CA1 pyramidal cells [1]. The CA1 then projects information to the subiculum and both the CA1 and the subiculum project fibres back to Layers V and VI of the EC to complete the cortical information loop (Fig. 1). It should be noted that the CA1 also receives projections from the EC and this pathway is known as the temporoammonic pathway [1]. These projections arise from layers III and V of the EC. This pathway may play a more prominent role in stress and anxiety related behaviours as opposed to spatial memory [12] (which is discussed below (Section 1.1.2)).

The role of the hippocampus in spatial memory

In the 1950 s, Dr. William Scoville performed a bilateral limbic surgery on patient Henry Molasion (commonly known as H.M.), giving the first real insight into the function of the hippocampus [13]. In order to treat H.M.’s recurrent seizures, the hippocampus, amygdala, collateral sulcus, perihinal cortex, EC and the medial mammillary nucleus, were removed [14]. Following surgery, H.M was afflicted with severe memory deficits; he lacked the ability to form and retain long-term memories of new facts (semantic memory) and events (episodic memory). This was the first case where a strong link was made between the hippocampus and explicit (i.e. intentional and conscious) memory.

Numerous studies have now refined the role of the hippocampus in the formation and maintenance of explicit spatial memory [15, 16]. In the 1980’s, Dr Richard Morris created the Morris water maze (MWM) test with the purpose of training rodents to learn the spatial location of a hidden platform submerged in cloudy water as a test for hippocampal function [17]. He observed that hippocampal lesions significantly impaired performance in this task [17].

Other studies have identified place cells in the hippocampus, which has led to the cognitive map theory of hippocampal function [18, 19]. These are cells that become active when a rodent is in a specific location in a specific environment [18] and such cells have also been detected in humans [20]. The presence of place cells within the hippocampus provides evidence that this structure organizes and stores stimuli with respect to a spatial framework (i.e. a cognitive map) and may be used for spatial navigation [21, 22]. Indeed, recent studies have suggested that the hippocampal formation acts as a network that encodes events and their contexts, with each distinct region playing a specific but complementary role in the processing of spatial information.

Within this scenario, the DG is believed to play a unique role in spatial pattern separation (reviewed by [23]). Spatial pattern separation is the enhancement of contrast between two similar spatial patterns or events. At the neuronal level this is thought to occur either through change in neuronal firing rate or through the firing of different neuronal sets [24, 25]. The DGCs display sparse firing characteristics and there are very few connections between DGCs and CA3 pyramidal cells [26], which make the DG optimally structured for spatial pattern separation. Furthermore, the existence of populations of DGCs that fire only when a rodent is in a given environment indicate that the DG contains place fields that are important for pattern separation [27–29].

The CA3 region has been implicated in spatial pattern completion – the capacity to retrieve previously stored information when presented with partial or incomplete inputs [30]. Evidence for this comes from studies where mice that lacked N-methyl-D-aspartate (NMDA) receptor expression in the CA3 were trained on the MWM. While these mice were able to perform the task as well as control mice, if the external environment was altered by removing a subset of the external cues so the mice only had an incomplete set of visual cues to recall the location of the platform, deficits in performance were observed [31]. These results indicate that the ability to use partial/incomplete spatial input was compromised and implicate the CA3 in spatial pattern completion.

The CA1 region of the hippocampus has been implicated in the processing of the temporal order of spatial patterns or events. This function is important to ensure that spatial events separated by time are encoded with minimum overlap [32]. The CA1 region also plays a major role in spatial memory (see Section 3.2.1) and contextual fear conditioning (see Section 3.2.2) and is the most widely studied area of the hippocampus [1]. Ablating or impairing the function of the CA1 region leads to deficits in delayed spatial discrimination [33], Morris Water Maze performance [34], temporal ordering tasks [35], and contextual fear conditioning [36] in rodents and spatial memory impairments in monkeys [37].

Together, the three major regions of the hippocampus – the DG, CA3 and CA1 encode spatial memory, but each region has its own distinct role within this function. The DG is associated with pattern separation, the CA3 with spatial pattern completion, and the CA1 with temporal order processing. The three regions work in concert to encode spatial memory.

Structural and functional plasticity in the hippocampus

The hippocampus is a dynamic structure that displays both structural and functional plasticity. Structural plasticity can occur through the process of adult hippocampal neurogenesis which occurs only in the DG sub-region of the hippocampus [38, 39]. Through this process new neurons are produced and integrated into existing CNS circuitry throughout the life span. Progenitor cells create neuroblasts in the subgranular zone of the DG that migrate into the granule cell layer (GCL) and differentiate into DGCs (reviewed by [40]). These new neurons incorporate themselves into existing neuronal circuits and display action potentials and functional synaptic inputs similar to DG granule cells formed during the developmental period (reviewed by [41]).

Functional, or synaptic, plasticity in the hippocampus is the process by which neurons alter their ability to communicate with one another. Enhancing synaptic efficacy, also known as long-term potentiation (LTP), is largely dependent upon kinase activation and protein synthesis, and serves as the primary biological mechanism for understanding how learning and memory processes operate in the brain [42, 43]. Long-term depression (LTD) is the opposite of LTP and is characterized by a decrease in synaptic efficacy [43, 44]. This process has been linked to forgetting.

PHYSICAL EXERCISE-INDUCED ENHANCEMENTS IN STRUCTURAL PLASTICITY IN THE HIPPOCAMPUS

The beneficial effects of physical exercise on adult hippocampal neurogenesis were first reported by van Praag et al., (1999) showing that voluntary wheel running promotes hippocampal neurogenesis in adult mice [45]. A positive correlation between running distance and levels of hippocampal neurogenesis has been repeatedly demonstrated in mice [46–48]. Notably, enhancement of neurogenesis by running can be affected by variables including genetic background [48, 49], age [4, 50], form of running (forced vs. voluntary; 39, 45–47), housing environment (single or group housing; [54], and duration (days to months) of exercise training [7, 47, 55]. Despite the variability among different studies, exercise-induced enhancements in hippocampal neurogenesis have been consistently reported in mice and rats in the literature [4, 5, 45–49, 52, 56–58, 54, 59] (Table 1).

The pioneer study by van Praag and colleagues (1999) indicated that long-term voluntary wheel running for 2 to 4 months significantly increased the process of neuronal survival in female adult C57 mice and concurrently enhanced synaptic plasticity and learning and memory performance in the MWM [45]. Further studies by this group have also found significant increases in neuronal differentiation and survival following 45 days voluntary wheel running in both young and aged C57B/L male mice [5].

Recent studies have revealed that physical exercise exerts its promoting effects on cells at different stages of neurogenesis. In adult male and female C57B/L mice, voluntary running increases the number of proliferating cells with a peak occurring after 3-days of short-term running, followed by a return to basal levels after 32 [60] or 35 days of running [61]. Conversely, significant increases in differentiating neuronal cells can only be observed after 10 days of running [7]. These data indicate that voluntary running-induced cell proliferation occurs only in the initial period of running, and longer periods of running mainly promote neuronal differentiation and survival rate of newborn neurons.

Adult neurogenesis is derived from self-renewing neural stem cells (type-1 cells, radial glial-like stem cells: nestin and GFAP positive), which can give rise to intermediate progenitor cells (type-2a cells: nestin positive, GFAP negative) that undergo amplification and acquire neural cell fate to neural progenitors (type 2b cells: nestin and doublecortin positive). These neural progenitors will then differentiate into migrating neuroblasts (type-3 cells: nestin negative, doublecortin positive) that exit cell cycle to become post-mitotic neurons (reviewed by [62]). It is elusive whether running induces adult neurogenesis by influencing proliferation or survival of distinct populations of precursor cells or both. Suh and colleagues (2007) reported that voluntary wheel running activated proliferation of early lineage radial glial-like stem cells [63], which is echoed by the findings of Bednarczyk et al., [64] showing an increase in the number of early lineage stems cells which are Ki67 (a endogenous marker for proliferating cells) and GFAP positive. Similar results were also reported by Lugert et al., (2010) who showed that running activates quiescent radial precursor cells to enter into the cell cycle [65]. In female adult C57BL/1 mice, voluntary wheel running for 7 days induces a transient increase in proliferative precursor cells as well as a reduced portion of DCX positive type-2b/3 cells that re-entered S-phase [61], suggesting that running induces neurogenesis not only by enhancing cell proliferation, but also by promoting cell cycle exit of progenitor cells. Farioli-Vecchioli and colleagues have shown that 12-days of running shortens the cell cycle of NeuroD1-positive progenitor cells (type-2b and -3) in wild-type mice, and also appears to shorten the length of the S-phase as well as the length of the whole cell cycle of both GFAP and Sox2 positive neural stem cells and NeuroD1-positive progenitors in Btg1-null mice that lack the anti-proliferative gene Btg1 [66]. Conversely, Fischer and colleagues only observed a trend towards a shorter cell cycle length in mice showing increased cell proliferation following 5- days of running, and concluded that the effect of running on progenitor cell proliferation was not caused by shortening of cell cycle length [67]. The contradictory results reported by Fischer et al., [67] and Farioli-Vecchioliet al., [66] may be due to the fact that the cell cycle length was examined on the entire proliferating population vs. specific progenitor cell populations. Furthermore, the duration of running (5 days vs 12 days) could have impacted these results. Taken together, running may exert its pro-neurogenic effect by cell cycle shortening on specific subpopulations of neural stem cells and its effect may depend on duration of running.

Prolonged wheel running also increases the number of neuroblasts and mature neurons in the DG [64]. Of note, the presence of a running wheel itself is a form of environmental enrichment which can promote the processes of adult neurogenesis, because both locked wheel and running wheel mice show increases in proliferating cells as indicated by significant increases in co-labeled Ki67 and GFAP positive cells [68]. Importantly, Bednarczyk and colleagues reported that increased number of neuroblasts (DCX positive cells) and newborn neurons (co-labeled with BrdU and NeuN) were only observed in running mice, but not in the mice with locked wheels, indicating that running is needed to increase maturation and survival of post-mitotic neuroblasts. Taken together, there appear to be running-independent and -dependent stages of adult hippocampal neurogenesis [68].

Environmental enrichment that includes supplying cages with toys, tunnels and running wheels induces robust increases in cell proliferation and neurogenesis [69]. However, a recent study has indicated that the running wheel is the critical stimulus for inducing neurogenesis in an enriched environment [70]. When mice are exposed sequentially to the running and then the environment enrichment, there is an additive increase in neurogenesis [71]. Increasing the pool of proliferating precursor cells by running together with an appropriate survival-promoting stimulus such as environmental enrichment follows the idea that the combination of exercise and environmental enrichment may potentially lead to more adult neurogenesis which may benefit hippocampal function.

PHYSICAL EXERCISE-INDUCED ENHANCEMENTS IN FUNCTIONAL PLASTICITY IN THE HIPPOCAMPUS

Synaptic plasticity

Synaptic plasticity refers to changes in neural communication as a result of experience, and can be measured throughout the brain. Two forms of synaptic plasticity have been assessed in the hippocampus, LTP, commonly associated with memory formation, and LTD, which has more recently been associated with memory clearance or forgetting.

The effects of exercise on synaptic plasticity in the hippocampus have been understudied (reviewed by [72]) despite the fact that exercise can reliably enhance performance on a range of hippocampal behaviors (see Section 3.2). The effects of exercise on in vitro hippocampal synaptic plasticity were first shown in female mice in 1999 [45], where one week of voluntary wheel running resulted in greater LTP in the DG. These findings were replicated both in vivo and in vitro in male rats where voluntary and forced running enhanced LTP in the DG [59, 73, 74] and CA3 [75]. In the DG, exercise may enhance LTP by lowering the induction threshold for LTP, though the mechanism for this change in induction threshold is unknown [73].

Interestingly, in van Praag’s seminal study of female mice, there was no effect of wheel running on CA1 LTP [45]. Conversely, forced exercise in sleep-deprived rats overcame impairments in in vivo late-phase LTP in the CA1 to the level of non-sleep deprived rats [76]. Interestingly, in this study forced exercise had no effect on CA1 LTP in healthy rats, suggesting that exercise-mediated enhancements of LTP in the CA1 are only evident in models where CA1 LTP is already depleted such as in sleep deprivation, aging and neurodegenerative disease [76–78] (see section 4.4). While these regional differences between DG and CA1 LTP were originally thought to be a direct result of increased neurogenesis following exercise, this group later showed that new neurons display enhanced LTP induction and only develop normal synaptic responses when they are 4-5 weeks old [79].

Bidirectional plasticity

More recently, studies of the effects of exercise on bidirectional plasticity have emerged. Vasuta et al., [80] studied exercise-induced changes in in vitro synaptic plasticity in the mouse DG, and the contributions of different NMDAR-subunits on these physiological changes. The effects of voluntary wheel running on DG LTP were replicated, however wheel running had no effect on DG LTD. LTP in the DG is generally NMDAR-dependent [73], however until 2007, the physiological contributions of the different NMDAR subunits on exercise-mediated plasticity were unknown. In this study, selective NR2A or NR2B blockade abolished DG LTP in non-exercised mice. In exercised animals, however, only NR2A blockade abolished DG LTP, and NR2B blockade significantly reduced, but did not block DG LTP. Conversely, neither exercise nor selective blockade of NR2A or NR2B subunits had an effect on DG LTD in sedentary animals, but NR2A blockade abolished LTD while NR2B blockade left LTD intact in exercised mice. Interestingly, while exercise increases NR2B mRNA specifically in the DG region, it does not affect NR1 or NR2A subunit mRNA nor either of these subunits in the CA1 region [73]. Together, these data indicate a unique role for the NR2A subunit in both LTP and LTD in the DG that emerges following exercise.

A great disparity exists in the study of hippocampal physiology following exercise in non-diseased animals. The exercise-induced changes in NMDAR-subunit composition in the hippocampus discussed here are likely just one component of the benefits of exercise, as others have reported increases in dendritic complexity [81] and neurotrophic factors [82] to name a few, which all have implications on synaptic plasticity in the hippocampus [83, 84]. Indeed, there are many mechanisms that may underlie the exercise-induced changes (or lack thereof) in synaptic plasticity in different sub-regions of the hippocampus (many of which are reviewed in this issue) however more work must be done in order to fully understand how each of these putative mechanisms contributes to exercise-induced hippocampal plasticity.

Behavioral plasticity

The effect of voluntary wheel running on hippocampal-dependent behaviors has been extensively studied in both healthy and diseased rodents. Here, we will summarize the most commonly used behaviors in the study of exercise in healthy animals.

Morris water maze

The Morris water maze task (MWM) is a classic hippocampal behavioral task that has been modified in order to assess different aspects and types of memory such as working memory, long-term memory acquisition, and retrieval. Fundamentally, in this task, animals are placed in a pool of opaque water, and must use distal visual cues in order to locate a hidden platform where they may escape the water. Following multiple learning trials over multiple days, the swim path or latency to reach the platform can be measured as an indication of spatial memory acquisition. The platform can be removed for a probe trial where the time spent searching the trained platform location can be assessed to measure reference memory.

The MWM is the most studied behavioral task in exercise literature. Runners acquire the MWM task more readily than non-runners, where by the third day of training, runners take a more direct path and take less time to reach the platform than non-runners [45]. At the time of the probe trial, runners spend a significantly greater proportion of time in the correct quadrant, than incorrect quadrants, and the improvements in performance in runners were paralleled by increases in hippocampal neurogenesis. The rapid acquisition of the MWM task by runners has been extensively replicated [46, 85], and this acquisition by runners may be more rapid than mice housed in enriched environments [70], though together, environmental enrichment and exercise might have additive effects on behavioral improvement in the MWM [71]. Curiously, when hippocampal neurogenesis is disrupted by irradiation, running-induced improvements in performance in the MWM are no longer evident [86].

Fear conditioning

In contextual fear conditioning (CFC) tasks, an animal is conditioned to fear a context by providing a tone followed by a footshock. After a pre-determined delay, the animal is returned to the fearful context without the footshock, and the freezing response to either the context or the tone in that context is measured. This behavioral task requires the activity of the amygdala, hippocampus, as well as frontal and cingulate cortices (reviewed by [87]).

CFC has been commonly used to assess learning and memory improvements following exercise. Following 30 days of voluntary wheel running, male rats exhibited more freezing in the fearful context when returned to that context 24 hours after footshock training [88]. This evidence of increased freezing to the fearful context has been reported in other groups following exercise [89, 90]. In a study by Burghardt et al., [89] male rats that ran voluntarily froze more than rats that were in the locked control condition, indicating that the voluntary aspect of exercise plays a role in this type of learning. There also appears to be a sensitive period during which voluntary exercise has an effect on this fear conditioning, where running between footshock training and testing has no effect on freezing times, while running before training results in increased freezing to the fearful context [90]. Unlike spatial memories in the MWM, the exercise-mediated behavioral improvements in CFC are not dependent on intact hippocampal neurogenesis [86].

Arm mazes

The radial arm maze (RAM) is a spatial memory task that is sensitive to hippocampal damage. This task can be modified for a multitude of memory types and has classically been used to assess working memory. For this version of the task, the animal can exit a central zone and visit a multitude of arms (from 8–48) in order to collect a food or water reward located at the end of each rewarded arm. The animal must remember which arms it has already visited in order to not visit the same arm again.

Female rats that underwent voluntary wheel running required fewer trials to reach criterion than their non-runner counterparts [91]. Similarly, in male rats, runners made fewer reference errors and more correct choices than non-runners [92].

The Y maze is another spatial memory task where animals must make a choice to pick either the left or right arm in order to receive a reward at the end of one arm, which is hidden from the view of the animal. As in the MWM, runner mice showed rapid acquisition of the Y-maze task, reaching over 80% correct arm choices by the second trial during the first training session [93]. Once non-runners had learned the Y-maze task, and were allowed 14 days of voluntary running, they had better memory retention than mice that did not run at all. In this same task, when, after the 14-day running (or non-running) delay, the reward location was reversed, those mice that ran acquired the reversal learning task more rapidly [93].

Novel object recognition

Novel object recognition is another classic hippocampal-dependent task (reviewed by [94]), which has been used to study different types of memory. In its most simple version, animals are allowed to freely explore an environment containing two identical objects followed by a pre-determined interval before being returned to the environment for a test phase. In the test phase, one of the familiar objects is replaced with a novel object, which the animal will spend more time investigating if it remembers the familiar object. This task is known to require the intact function of both the hippocampus and the perirhinal cortex in rats [95, 96].

Voluntary wheel running also has been shown to improve novel object recognition in mice [97] and rats [77, 98] where improved performance was correlated with increases in BDNF expression in the perirhinal cortex [98]. There also appears to be a temporal relationship between the time that exercise stops and the behavioral test begins, where testing immediately after exercise produces the greatest improvements in object recognition and BDNF expression in the hippocampus and perirhinal cortex [99].

Learning and forgetting of hippocampus-dependent memories

New avenues of study have sought to understand the relationship between neurogenesis and forgetting (see [100] for a review). Feng et al., (2001) demonstrated that impaired neurogenesis causes increased memory retention in the CFC task, suggesting that hippocampal neurogenesis may play a role in memory clearance [101]. Similarly, when hippocampal neurogenesis is ablated, working memory was improved in the RAM [102]. This ablation of hippocampal neurogenesis slows the decay of the hippocampal dependency of remote CFC memories, whereas in controls, remote CFC memories become less hippocampal dependent over time. Running increases the rate at which these CFC memories become hippocampal independent without affecting the expression of the memory, an effect that is blocked by irradiation [103]. Most recently Akers et al., (2014) have shown a clear link between neurogenesis and forgetting where running induced forgetting of a CFC task in adult mice. Using guinea pigs and degus, species that both have low levels of postnatal neurogenesis, they showed intact memory retention except when neurogenesis was stimulated by memantine [104]. Together these studies begin to suggest a role for neurogenesis and memory retention and clearance in the hippocampus.

EFFECTS OF EXERCISE IN NEUROLOGICAL DISORDERS

Fetal alcohol spectrum disorders

Ethanol can cause significant damage to the fetus [105, 106] and can result in fetal alcohol spectrum disorders (FASD) with the extent of damage caused by ethanol varying due to the timing, frequency and volume of ethanol consumed, as well as the genetics and metabolism of the mother.

FASD can be modelled in rodents using a variety of methodologies which are outlined in recent reviews from our laboratory [107, 108]. The most commonly used methods are the liquid diet model where a pregnant dam receives a liquid diet containing 36% (v/v) ethanol throughout pregnancy, and the gavage model where ethanol is administered via oralintubation.

FASD and structural plasticity

FASD can lead to a variety of structural deficits in the hippocampus including decreases in adult hippocampal neurogenesis [109–113]. The effect of exercise has been examined in a variety of models of FASD to determine whether beneficial effects on neurogenesis and neuron structure occur [111, 114, 115].

Redila et al., (2006) were the first to show that decreases in cell proliferation that occur with prenatal ethanol exposure can be rescued in rats with one week of exercise [115]. Using a different model of FASD, where animals were exposed to ethanol during the third trimester equivalent (corresponding to PND1-10 in the rat), Helfer et al., (2009) found that 12 days of voluntary running wheel exercise during adolescence increased proliferation of cells in the DG, but long-term survival of these neurons was not increased [111]. It is important to note that in this study, baseline levels of proliferation and neurogenesis were comparable between the control and the ethanol-exposed animals, which differs from the study byRedila et al. (2006).

The effect of exercise on neurogenesis was also examined using the gavage model where ethanol was administered throughout all three trimester equivalents [114]. Ethanol exposure reduced cell proliferation and increased early neuronal maturation, but did not affect cell survival [114]. When ethanol exposed animals were given access to voluntary running wheels for 12 days beginning at PND 48, increases in cell proliferation and maturation were observed which indicates that despite deficits caused by ethanol exposure, the brain still has the capacity to respond to the beneficial effects of exercise [114]. Remarkably, increases in the proliferation marker Ki67 were actually much greater in ethanol exposed animals than in control animals following exercise. This may be linked to the fact that ethanol exposed animals ran significantly more than controls, which could indicate a hyperactive phenotype in these animals [114].

These varied results between studies are probably due to the different models of ethanol exposure employed. However, results from Helfer et al., (2009) and Boehme et al., (2011) suggest that while exercise may be able to stimulate proliferation and differentiation, additional therapies may need to be utilized to ensure that the new neurons are able to survive and integrate into functional networks of the hippocampus. For example, Hamilton et al., (2014) combined exercise followed by environmental enrichment. Using BrdU labeling, the authors found that ethanol-exposed animals had lower rates of cell survival than control animals. However, in ethanol-exposed animals who were given voluntary access to a running wheel (started at PND 30 for 12 days) followed by access to an enriched environment (from PND 42 – 72), the levels of cell survival were comparable to those of control animals [110]. These results indicate that both exercise and enrichment may be needed in order to enhance cell proliferation as well as cellsurvival.

FASD and synaptic plasticity

Ethanol exposure causes long lasting deficits in synaptic plasticity in the DG – in particular, LTP is decreased in adolescent and adult male offspring [116–121]. Interestingly, in females, LTP in the DG is increased in adolescent animals, and there are no differences in LTP between control and ethanol-exposed offspring in adulthood [117,121–123]. Only one study has examined the effect of exercise on synaptic plasticity in the DG of animals exposed to ethanol during development. Only males were examined in this study, but the results clearly indicate that access to a running wheel from PND 28 – 60 (32 days), was enough to completely reverse the deficits in LTP observed in the ethanol-exposed offspring [118].

FASD and behaviour

Learning and memory and executive function are impaired in individuals with FASD [124–127]. Functional brain abnormalities can be examined in human populations using functional MRI (fMRI) technology. fMRI has been used to examine spatial working memory in adults and children with FASD, and impairments compared to control subjects are commonly observed [128, 129]. fMRI has also indicated that subjects with FASD exhibit abnormal patterns of brain activation during tasks involving verbal learning [130], verbal working memory [131], and visual working memory [132].

There is a multitude of data indicating that learning and memory, particularly spatial, reference, and working memory, are impaired in animals that were exposed to ethanol during development. Deficits in the MWM where animals show impairments in spatial acquisition, reference and place memory are observed in animals when ethanol exposure occurs both in the prenatal [118, 133–141] and postnatal [142–148] periods.

Only two studies to date have examined the effects of exercise on behaviour in the MWM in animals with FASD. Christie et al., (2005) examined the effects of voluntary wheel running from PND 54 – 64 in animals where the liquid diet model of ethanol administration was used. In this study, the two trial version of the MWM was conducted over a five day period, and both reference and working memory were assessed. Animals exposed to ethanol displayed significant deficits in both reference and working memory when compared to control groups; however, this deficit was completely reversed in the animals that were allowed access to a running wheel [118]. Similar findings were obtained by Thomas et al., (2008) using the postnatal gavage model of ethanol exposure (3rd trimester equivalent). In this study, animals were allowed access to a running wheel from PND 21 – 51 and then from PND 52 – 57 they were tested in the MWM (4 trials a day, plus a probe trial on the final day). Ethanol-exposed animals that did not exercise had significant deficits in performance, however, these deficits were greatly reduced in the animals allowed access to a running wheel [147]. Performance in the probe trial was not affected by ethanol-exposure; however, exercise also increased performance in this task in both ethanol-exposed and control animals.

The effect of exercise on other hippocampal behaviours has also been examined using the gavage model of FASD. Schreiber et al., (2012) have shown that neonatal ethanol exposure causes significant deficits in CFC tasks [149]. Interestingly, if ethanol-exposed animals were given access to a running wheel from PND 30 – 42 and then environmental enrichment from PND 42 – 72, these deficits in behaviour were not overcome [149]. In contrast, a similar study from the same laboratory showed that exercise could benefit other forms of contextual fear conditioning [110]. Ethanol-exposure causes deficits in trace eyeblink conditioning [150] and a variant of contextual fear conditioning called the context pre-exposure facilitation effect [112, 151]. Hamilton et al., (2014) examined the effects of exercise (PND 30 – 42) followed by environmental enrichment (PND 42 – 72) on these behaviours following ethanol-exposure from PND 4 – 9. They determined that the combination of exercise and enrichment was able to overcome the deficits induced by neonatal ethanol exposure [110].

Other behavioural phenotypes which may be mediated through the hippocampus and are common with FASD include increased depression and anxiety [152–155]. Brocardo et al., (2012) showed that animals exposed to ethanol throughout all three trimester equivalents (i.e. GD 1–21 plus PND 4–10) using the gavage model have increased depression-like and anxiety-like behaviours. These effects were present in both male and female offspring. A cohort of ethanol-exposed animals was given access to a running wheel for 12 days from PND 48 – 60 and at PND 60 was tested for anxiety and depression-like behaviours. Exercise did not rescue anxiety-like behaviours measured using the elevated plus maze in male or female offspring [156]. Ethanol-exposed females showed increased depressive-like behaviour in the forced swim test when compared to control groups. This effect was not rescued by exercise [156]. In males, a similar increase in depression-like behaviours was observed following ethanol-exposure, however, unlike in females, this effect could be rescued by exercise [156]. This study suggests that gender may play a role in response to exercise-elicited antidepressant effect in ethanol-exposed rats.

Summary

FASD causes a variety of perturbations in hippocampal structure and function which translate into deficits in hippocampal behaviour. Reductions in neurogenesis are commonly observed which may underlie the deficits in synaptic plasticity and hippocampal behaviour.

Although limited, there are a handful of studies which have examined the benefits of exercise in FASD and the results from these studies provide evidence that exercise may be able to overcome these structural and functional deficits in the hippocampus, to a point where ethanol-exposed animals can no longer be distinguished from control animals. These improvements also appear to translate into positive behavioural changes suggesting that exercise may be beneficial in overcoming some of the learning and memory deficits associated with FASD. However, it is important to note that exercise may not be beneficial for all behavioural phenotypes exhibited in animals exposed to ethanol during the perinatal period [149, 156]. Furthermore, studies like those of Brocardo et al., (2012) emphasize the importance of examining both males and females, because sex-specific differences in the effects of ethanol, and the benefits of exercise, may be observed.

Traumatic brain injury

Traumatic brain injury (TBI) can occur when the head hits, or is hit by an object. Up to 1.7 million incident or recurrent TBIs occur annually in the US, most commonly caused by falls, vehicular accidents, assault, and sports injuries [157]. Direct mechanical insult to brain tissue caused by the initial impact, skull fracture, or penetrating injury, along with the stretching and shearing of cell processes and vasculature, result in a cascade of pathophysiological processes throughout the brain that can cause immediate and persistent symptoms. Impaired learning and memory are common symptoms of TBI, regardless of the type or severity of injury. Despite its central, and therefore relatively protected location, changes in hippocampal volume have been reported in humans and rodents after TBI [158–161], suggesting it is susceptible to damage by secondary injury mechanisms, which likely contribute to persistent learning and memory impairment resulting from TBI (reviewed by [162]). It is an important goal of experimental animal models of TBI to identify mechanisms underlying TBI symptoms like learning and memory impairment, and to identify interventions that can treat them (for a review of animal models of TBI see [163]). Owing to the heterogeneity of this type of injury, there has been great difficulty in finding effective treatments. The potential to promote structural and functional plasticity in the hippocampus makes exercise an attractive means of rescuing cognitive deficits arising from TBI.

Structural and functional plasticity in TBI

There is a paucity of information available on how exercise directly affects hippocampal structure and functional plasticity following TBI; however emerging evidence shows that initiating moderate exercise after a short recovery period may elevate levels of plasticity-promoting proteins and reduce cognitive deficits after experimental TBI in rodents. These effects are consistently mediated by elevations in the neurotrophin BDNF.

An important focus of this research is to establish a timeline to determine when exercise becomes restorative after TBI, as there is evidence that intense physical and cognitive exertion in the acute recovery phase may exacerbate TBI pathology and increase symptom severity [164]. Due to the heterogeneity in exercise paradigms between studies there is controversy over the optimal time to initiate an exercise intervention, but the majority of literature suggests that delaying the onset of exercise is beneficial. In a mouse model of TBI, MWM performance impairments were rescued, CREB and BDNF expression were elevated, and hippocampal neurogenesis was increased by seven days of voluntary wheel running initiated 5 weeks, but not 1 week post-injury [165]. In rats, however, seven days of voluntary wheel running initiated three days after TBI elevated hippocampal BDNF levels, and ameliorated the TBI-induced increase in hippocampal myelin-associated glycoprotein (MAG) and Nogo-A, which are proteins that inhibit axonal growth [166]. Another group found that adult male rats showed reduced deficits in acquisition of spatial reference memory the MWM and elevated hippocampal BDNF when given access to a running wheel 14–20 days after mild TBI [167, 168]. However, when running wheel access was provided 0–6 days post-injury MWM impairments were increased, and BDNF levels were not changed [168]. In these paradigms, administration of a BDNF inactivator prior to exercise attenuated enhancements in MWM performance [167] and elevations in plasticity related proteins [166].

Injury severity may dictate when it is best to begin an exercise intervention after TBI. In adult male rats, exercise-induced elevations in BDNF were seen when running wheel access was provided at 14–20 days after a mild TBI, but when a moderate TBI was induced, BDNF was only elevated when access to the running wheel was withheld until 30–36 days post-injury [169]. Interestingly, the same group also found that hippocampal BDNF was elevated after voluntary running 0–7 days after moderate TBI, though they noted that injured animals ran significantly less than controls [170]. This highlights an important challenge in this area of research, as injured animals are more likely to abstain from voluntary running, making it difficult to control for exercise duration and exertion. It is possible that in paradigms where voluntary exercise is initiated immediately after TBI, injured rats abstained from exercise during the initial period where they were more vulnerable to sustain further damage.

Summary

The available literature collectively suggests that delayed exercise after TBI can reduce learning and memory impairment, and elevate plasticity-related proteins in the hippocampus. However, there is a paucity of information on precisely how elevated neurotrophins affect structural plasticity and improve behavioural recovery after brain injury. Insight in this matter could be gained through histological and electrophysiological analysis of hippocampal tissue in order to determine whether these exercise-mediate changes correlate with changes in structural and functional plasticity.

Stroke

Ischemic and hemorrhagic stroke occur when blood circulation to a certain area of the brain is restricted due to vessel blockade or rupture, respectively. This produces metabolic distress, tissue damage and cell death in the affected area. Stroke is an extremely prevalent condition, affecting up to 800 000 Americans annually [171]. Depending on which area of the brain is affected, symptomology can include debilitating and persistent impairment to cognitive, motor, visual, auditory, and speech function. When the affected area includes the hippocampus, learning and memory can be severely impaired (reviewed by [172]). Stroke often results in motor deficits, and the potential for exercise to induce plasticity in sensory and motor cortices, and improve functional recovery in motor tasks has been well studied [173–175]. There is evidence that exercise can augment hippocampal plasticity after stroke as well. However, the information available on the therapeutic effects of voluntary exercise is extremely limited, likely due to difficulty implementing voluntary exercise paradigms in motor-impaired animals. Where voluntary exercise paradigms have been used, outcome measures primarily focuses on exercise mediated elevation in hippocampal plasticity-related proteins, indicating there is a need for further research directly measuring how exercise affects structural and functional plasticity in the hippocampus.

Structural and functional plasticity in stroke

Motor deficits resulting from stroke complicate the application of an exercise intervention. This is an important consideration, as controls may exercise more vigorously or longer duration in voluntary exercise paradigms, but forced exercise may not produce equivalent results. For this reason, information on how voluntary exercise affects structural and functional plasticity in the hippocampus is extremely limited. In a mouse model of ischemic stroke, voluntary wheel running, but not forced swimming, rescued memory impairments in the MWM. This was accompanied by elevated CREB phosphorylation, and increased survival of adult generated neurons in the hippocampus [176]. Another mouse model found that 42 days of voluntary wheel running was sufficient to increase hippocampal neurogenesis and reduce learning impairments in the MWM after ischemia [177].

There is evidence that voluntary running elevates hippocampal BDNF after ischemic stroke, but more research is needed to determine if this effect translates into changes in hippocampal plasticity or cognitive outcome [174, 175].

Summary

Physical activity has the potential to improve stroke outcome by augmenting hippocampal plasticity, but there is a lack of information on how exercise-mediated improvements in cognition and changes in plasticity related proteins correlate with structural and functional changes in the hippocampus. Ongoing research should attempt to establish how exercise-mediated behavioral recovery and neurotrophin expression correlate with neurogenic changes and electrophysiological analysis of hippocampal tissue.

Neurodegenerative disorders

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), constitute a heterogeneous group of disorders that commonly display a characteristic progressive loss of structure and/or function of populations of neurons and glia in the CNS [178]. This neuronal degeneration primarily affects specific neuronal populations, which include cortical and hippocampal neurons in AD [179], dopaminergic neurons in PD [180], and striatal gamma-aminobutyric acid (GABA)ergic neurons in HD (reviewed by [181]). Clinically, these diseases are predominantly adult onset and show chronic progression of cognitive deficits.

Animal models of neurodegenerative diseases provide valuable tools in assessing therapeutic strategies for these disorders. Bearing in mind the well-defined benefits of physical exercise on cognitive function, it is reasonable to consider that exercise may in fact be used as a strategy to prevent or impair the cognitive decline associated with age-related neurodegenerative diseases. In this section, we review the influence of voluntary exercise on structural and functional plasticity in adult-aged rodent models of AD, PD, and HD.

Alzheimer’s disease

AD, the leading cause of dementia in the elderly, is an age-related, irreversible neurodegenerative disorder clinically characterized by progressive memory loss and multiple cognitive deficits (reviewed by [182]). Important neuropathological hallmarks of AD in the brain include the gradual accumulation of extracellular plaque depositions composed of amyloid-beta (Aβ) peptide, the formation of neurofibrillary tangles (NFT) consisting of hyperphosphorylated tau protein, and substantial neuronal death [183, 184]. The etiology of AD is not yet known, however two competing hypotheses exist. In the Amyloid hypothesis, Aβ plaques are considered to be the causal component in AD pathogenesis [185]. The second theory, the Presenilin hypothesis, is based on loss-of-function presenilin mutations that lead to neurodegeneration and memory impairment in AD [186]. Despite this controversy, the hippocampus is known to be particularly vulnerable to AD, and is one of the first regions to be affected [187].

AD and structural plasticity

Studies of adult hippocampal neurogenesis in a variety of available transgenic rodent models of AD (reviewed by [188]) have generated contradictory results [156, 189]. Decreases in neurogenesis were reported in transgenic or knock-in mice carrying the PDAPP mutation [190], the Swedish mutation in the APP gene [191–194], PS1 gene mutations [193–196], as well as in double-transgenic mice for APP and PS1 [193, 194]. APP, PS1, and tau protein triple-transgenic mice also show deficits in neurogenesis [197]. In contrast, transgenic mice that express APP with the Swedish, Dutch, and London mutations [198], or with the Swedish and Indiana mutations [199, 200] were found to have increased hippocampal neurogenesis. Discrepancies in the literature are likely based on a variety of factors such as transgenic model used, stage of disease progression, and difference in protocols used to evaluate neurogenesis.

A successful treatment for AD has yet to be developed. A putative lifestyle treatment is exercise, which has been shown to promote neurogenesis in rodent models of AD. APPswe-PS1ΔE9 mice provided 10 weeks of voluntary wheel running showed enhanced levels of hippocampal neurogenesis. Moreover, running significantly prevented neuronal cell loss in the DG and CA3 hippocampal subregions, but did not affect the CA1 [201]. In the Tg2576 AD model, voluntary runners were found to have greater hippocampal volume compared to sedentary littermates following 16 weeks of access to wheel running [202]. An age-dependent effect of voluntary wheel running was found in the APP23 AD mouse model, where 10 days of exercise induced an increase in adult hippocampal neurogenesis in 18 month-old animals, but had no effect in the 6 month-old cohort [203]. These findings suggest the ability of the AD brain to upregulate cell proliferation and neuronal differentiation in response to voluntary physical exercise.

AD and functional plasticity

García-Mesa et al. (2011) used electrophysiology to investigate synaptic function and plasticity in 3xTg-AD mice that were subjected to 6-month wheel running treatment. LTP could not be produced in the 3xTg-AD animals, while exercise was found to only weakly protect the impairment of LTP induction at the CA1-medial prefrontal cortex synapse [204]. Considering the limited evidence available that examines the role of exercise on synaptic plasticity in AD, the remainder of this section focuses primarily on hippocampal behaviour. Various transgenic mouse models of AD show deficits in several hippocampal-dependent learning and memory tasks, such as object recognition, spatial learning, and fear conditioning (reviewed by [188, 205]).

Clinical studies with AD patients indicate that physical and cognitive activities are associated with reduced risk of disease [206–208]. Similarly, rodent models of AD that undergo voluntary exercise display encouraging results. Using a Tg2576 mouse model, Yuede and colleagues (2009) found that voluntary runners (16 weeks of wheel running) displayed greater investigation latencies of novel objects in a recognition memory paradigm in comparison to sedentary controls, or forced exercise animals [202]. Transgenic animals containing the ɛ4 allele of the APOE gene exhibit cognitive impairment on the hippocampus-dependent radial-arm water maze task. Following 6 weeks of free access to wheel-running, ɛ4 mice displayed improvements in this task compared to their sedentary counterparts [209]. The TgCRND8 model of AD also benefits from voluntary exercise; 5-months of voluntary running decreased Aβ plaques in the hippocampus and enhanced hippocampal-dependent learning in the MWM [210]. Another AD model, THY-Tau22, displays progressive learning and memory alterations [211, 212]. In response to a 9-month voluntary exercise period, memory alterations were prevented in the THY-Tau22 mice as assessed by a two-trial Y-maze task in which running animals spent more time in the novel arm [213]. Cognitive deterioration as well as behavioural and psychological symptoms of dementia (BPSD)-like behaviours, such as anxiety and the startle response, were ameliorated by exercise in triple transgenic (3xTg) AD mice with access to running wheel. Of the different experimental cohorts studied, the best neuroprotection was identified in 7 month-old 3xTg-AD mice that had undergone exercise treatment for 6 months [204]. APPswe/PS1ΔE9 mice display spatial memory impairments in the MWM. In response to 10 weeks of voluntary-wheel running, this cognitive decline is significantly decreased in comparison to sedentary controls [201].

In contrast to the above-mentioned studies, TgCRND8 mice with access to running wheel for a 10 week period displayed no improvements in cognitive or neuropathological parameters in comparison to non-runner controls. Despite this, spontaneous stereotypic behaviours of TgCRND8 mice [214], such as repetitive bouts of jumping, climbing, or bar-chewing, were significantly reduced in the wheel-running transgenics [215]. Furthermore, APP23 mice that ran for 8.5 months did not show enhancements in spatial learning, or hippocampal neurogenesis. Interestingly, environmental enrichment lacking a running wheel improved MWM performance and increased hippocampal neurogenesis [216]. This is an important distinction, as other studies report enhanced cellular plasticity in TgCRND8 [217] and improved cognition in PS1/PDAPP [218] AD models in response to “enrichment” that includes running wheels.

Summary

Although voluntary exercise is the focus of the present review, AD-related exercise research is by no means limited to this paradigm. Treadmill and forced exercise experimental designs are also commonly used in this field. Similar to the majority of voluntary running studies, they show the importance of exercise in preventing the cognitive decline associated with AD [219, 220], repressing neuronal cell death [221], enhancing neurogenesis [222], improving hippocampal LTP [219], and improving cognitive function [223–226]. Trends in current literature suggest that exercise may help to prevent the cognitive decline associated with AD and delay the onset of symptoms. Interestingly, these benefits appear to require relatively long periods of exercise. While cognitive improvements in AD studies require voluntary access to running wheels for 10 weeks up to 9 months, healthy animals or FASD model animals for example, typically undergo exercise paradigms ranging from 7 days to 2 months (see previous sections).

Parkinson’s disease

PD is characterized by the progressive loss of dopamingeric neurons in the substantia nigra that projects to the striatum of the basal ganglia. Physical symptoms of this disorder including motor dysfunction such as rigidity; tremor and bradykinesina are accompanied by non-motor symptoms such as cognitive deficits and depressive disorders. Volumetric magnetic resonance imaging studies have suggested a progressive hippocampal volume loss in PD patients [227]. Intracellular accumulation of α-synuclein is the pathological feature of Parkinson’s disease and mutations in the gene encoding for this protein is known to be linked to this disease [228]. Abnormalities in hippocampal plasticity have been observed in α-synuclein-related transgenic animal models [229, 230] as well as lesion models of dopamine depletion using either the1-methyl-4-phenyl-1,2,3,6-tetrhydropyridine (MPTP) or 6-hydroxydomine (6-OHDA) [231–233], which leads to death of dopamingeric neurons and subsequent depletion of dopamine in the dorsal striatum.

PD and structural plasticity

Altered structural plasticity including cell proliferation, differentiation, and survival of adult-born neurons, as well as decreased dendritic complexity and spine formation has been related to the pathogenesis of PD (reviewed by [234]). Decreased hippocampal neurogenesis is altered in 6-OHDA and MPTP–induced animal models of PD [235, 236]. Similarly, decreased cell proliferation and neuronal survival are also found in transgenic mice expressing mutant α-synuclein [237, 238], which echo the decreased hippocampal cell proliferation observed in postmortem brain from PD patients [235].

There are currently no studies examining the effects of voluntary wheel running on structural plasticity in PD. However, in the 6-OHDA- rat model of PD, a regime of 4-weeks of treadmill exercise (30 min/day, 5 days/week) increased cell proliferation and the migration of neural stem cells towards the lesion site accompanied by up-regulated BDNF and glial cell-derived neurotrophic factor (GDNF) in the striatum [239]. Exercise training also enhances survival and integration of transplanted cells in animal model of PD (reviewed by [240]).

PD and functional plasticity

Impaired synaptic plasticity in hippocampal sub-regions has been reported in animal models of PD. Decreased LTP and enhanced LTD were found in the CA1 region in mice injected with MPTP [233], while decreased LTP and impairment of long-term recognition memory was found in the DG of mice with bilateral 6-hydroxydopamine (6-OHDA) lesions [231]. The impaired LTD in the DG may be linked to disrupted dopaminergic and noradrenergic transmission in the DG [232] and decreased NR2A/NR2B subunit ratio in NMDA receptors [241].

Although clinical studies have demonstrated that physical training improved motor function as well as cognitive performance in PD patients [242, 243], currently there are no studies reporting changes of hippocampal synaptic plasticity following physical training in animal models of PD. Thus, it is unclear whether exercise-induced beneficial effects on cognitive performance on PD patients are at least partly mediated by enhanced hippocampal neurogenesis or synaptic plasticity.

Studies examining the potential beneficial effects of physical exercise on PD are primarily focused on behavioral recovery on motor skill performance [244–248]. In the MPTP mouse model, improvement in motor function is likely linked to increased dopamine transmission, enhanced expression of dopamine receptors or increased glutamate receptor expression in the dorsal striatum following exercise [249, 250].

Summary

In summary, there are very few studies examining the benefits of voluntary wheel running on structural and functional plasticity in the hippocampus. This may be due to the etiology of the disease and the difficulties in motor function that are observed. However, evidence from human studies does suggest that voluntary exercise, potentially in pre-symptomatic patients may be beneficial for hippocampal function.

Huntington’s disease

HD is an autosomal dominant neurodegenerative disease caused by a characteristic cytosine-adenine-guanine (CAG) repeat expansion within the HD gene, which results in an expansion of poly-glutamine residues in the huntingtin protein. Under normal conditions, there are 6 – 35 CAG repeats, whereas HD patients may have up to 250 repeats [251]. As a result, mutant huntingtin aggregates into insoluble ubiquitinated neuronal intranuclear inclusions (NIIs) [252]. This mutation primarily causes neurodegeneration of medium spiny neurons in the caudate nucleus, as well as deterioration of certain populations of striatal interneurons [253] and cortical atrophy in other brain regions as the disease progresses (reviewed by [169]).

The characteristic clinical symptom of HD is progressive involuntary choreatic movements followed by later onset bradykinesia and rigidity [254]. In addition to motor disturbances, cognitive impairment and psychiatric symptoms are associated with the progression of the disease, which is invariably fatal 15 – 20 years after onset (reviewed by [242]).

HD and structural plasticity

In contrast to the contradictory results accompanying neurogenesis in AD, there is an apparent consensus that HD reduces adult hippocampal neurogenesis. Lazic and colleagues (2004) were the first to identify this using the R6/1 transgenic model of HD [256]. Additional research of R6/1 [257–259] and R6/2 mice [260–263], as well as a transgenic rat model [264] have extended upon our understanding of adult neurogenesis deficits in the hippocampus of HD rodent models.

To investigate the potential of physical exercise as therapeutic strategy in HD, various studies have analyzed the modulation of neurogenesis after voluntary running in a variety of HD models. Those that specifically investigated adult animals, show that running enhances adult hippocampal neurogenesis, but only in wildtype controls and not in R6/1 HD mice [265, 266].

HD and functional plasticity

Sedentary R6/1 HD mice develop phenotypic rear-paw clasping by 16 weeks of age. Additionally, they display abnormal rearing behavior as well as deficits in motor coordination and spatial working memory. Following 10 weeks of access to a running wheel, the rear-paw clasping onset is delayed, there are normalized levels of rearing behavior and cognitive impairments are ameliorated. Despite this, motor coordination is not rescued [267]. Voluntary exercise during a 4 week period was found to have anti-depressive effects in R6/1 transgenic mice that showed reduced immobility in forced-swim test [265].

In the current review, we focus on adult animals. However, characteristic motor dysfunction is an unavoidable confound with rodent HD models since they are known to run less than wildtype littermates. Considering the progressive nature of HD, several studies have used juvenile animals to investigate the impact of exercise prior to overt symptoms. In 5 week old R6/2 HD mice, a 4 week period of voluntary wheel-running did not rescue the observed reduction in adult hippocampal neurogenesis (60% of wildtype level) [268]. More recently, Potter and collaborators (2010) established that exercise was not beneficial in N171-82Q transgenics, and that it may in fact be detrimental to the vulnerable HD nervous system [269]. Conversely, others have reported that wheel running delays onset of motor deficits [270], improves gait, motor coordination, and slows progression of cognitive dysfunction [271] in juvenile R6/1 HD mice.

Summary

There is a paucity of data examining the effects of exercise on hippocampal plasticity in HD. Taken together, the effectiveness of exercise as an environmental therapy for HD is currently transgenic model-dependent with age-related discrepancies in the literature.

DISCUSSION AND CONCLUSIONS

There is a multitude of evidence that suggests that physical exercise can lead to significant benefits in hippocampal structure and function in rodents, which ultimately results in behavioral benefits. As highlighted in the various sections there are some gaps in the literature that need to be filled, but the majority of the evidence suggests that exercise can be beneficial not only in healthy adult animals (Table 1), but also in disease models, including developmental disorders, mood disorders, traumatic brain injury and neurodegeneration (Tables 2–4). How exercise leads to these substantial benefits in hippocampal function is still under debate. Exercise increases blood vasculature and enhances angiogenesis in the brain and boosts levels of neurotrophins, including brain derived neurotrophic factor (BDNF) [272, 273]. These increases are observed with short or long periods of running, and appear to remain upregulated for a period of time after exercise has ceased [73, 82, 272, 274]. BDNF can increase the production of cell survival genes and proteins important for synaptic plasticity and neurogenesis which may explain the benefits observed in synaptic plasticity and learning and memory [275, 276]. Other factors to consider include enhancements in dendritic complexity and spine density as well as glial cell function. The many potential mechanisms through which exercise can boost hippocampal function are discussed in great detail in recent reviews [277–279].

This review focussed primarily on rodent models of disease, but it is important to note that many of the benefits of exercise found in rodents are also observed in humans. Many human studies have found significant benefits of exercise, not only in healthy individuals but also in individuals with neuropsychiatric and neurodegenerative disorders. It is difficult to assess neurogenesis and synaptic plasticity in humans, however, there is ample evidence to suggest that exercise can enhance learning and memory and other aspects of hippocampal function (reviewed by [277]). Exercise has been shown to enhance hippocampal learning and memory tasks in children [280, 281], adolescents, [282], adults [283] and the elderly [284, 285]. In fact, many studies have investigated whether exercise can reduce or prevent age-related cognitive decline. Studies have indicated that exercise can boost gray matter volume in the hippocampus of aged individuals [286] which leads to enhanced memory [284], and may delay the onset of dementia or Alzheimer’s disease (reviewed by [287,288]).

In conclusion, exercise interventions can be extremely beneficial for hippocampal structure and function. The benefits of exercise on hippocampal neurogenesis, synaptic plasticity and behaviour have been extensively studied and have been summarized in this review. The mechanisms responsible for these beneficial effects appear to be vast and diverse, but many effects appear to converge on enhancing BDNF in the brain. Importantly, the benefits of physical exercise are also observed in humans, indicating that exercise interventions should be considered at any age in order to enhance hippocampal learning and memory and delay cognitive decline.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare regarding this manuscript.

REFERENCES

1 

Anderson P, Morris R, Amaral D, Bliss T, O’Keefe J. The Hippocampus Book [Internet]. Oxford University Press. 2007. 872 p. Available from: http://books.google.com/books/about/The_hippocampus_book.html?id=zg6oyF1DziQC

2 

Kitamura T, Mishina M, Sugiyama H. Dietary restriction increases hippocampal neurogenesis by molecular mechanisms independent of NMDA receptors. Neurosci Lett [Internet]. 2005/12/17 ed. 2006;393(2-3):94-6. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list uids=16356642

3 

Helfer JL, Goodlett CR, Greenough WT, Klintsova AY. The effects of exercise on adolescent hippocampal neurogenesis in a rat model of binge alcohol exposure during the brain growth spurt. Brain Res [Internet]. 2009/08/04 ed. 2009;1294:1-11. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list uids=19647724

4 

Marlatt MW, Potter MC, Lucassen PJ, van Praag H. Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol [Inter- net]. 2012 Jun [cited 2015 Mar 19];72(6):943-52. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3485396&tool=pmcentrez&rendertype=abstract

5 

Van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci [Internet]. 2005 Sep 21 [cited 2014 Jul 14];25(38):8680-5. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1360197&tool=pmcentrez&rendertype=abstract

6 

Kannangara TS, Lucero MJ, Gil-Mohapel J, Drapala RJ, Simpson JM, Christie BR, et al. Running reduces stress and enhances cell genesis in aged mice. Neurobiol Aging [Internet]. 2011 Dec [cited 2015 Mar 19];32(12):2279-86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20106549

7 

Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G. Physical exercise prevents agerelated decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging [Internet]. 2006 Oct [cited 2015 Mar 19];27(10):1505-13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16271278

8 

Andersen P, Bliss TVP, Skrede KK1971Lamellar organization of hippocampal excitatory pathwaysExp Brain Res13222238

9 

McNaughton BL1980Evidence for two physiologically distinct perforant pathways to the fascia dentataBrain Res199119

10 

Colino A, Malenka RC1993Mechanisms underlying induction of long-term potentiation in rat medial and lateral perforant paths in vitro J Neurophysiol6911501159

11 

Bramham CR, Milgram NW, Srebro B. Activation of AP5sensitive NMDA Receptors is Not Required to Induce LTP of Synaptic Transmission in the Lateral Perforant Path. Eur J Neurosci [Internet]. 1991;3:1300-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12106227

12 

Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci [Internet]. 2013 Oct 2 [cited 2015 Jul 7];33(40):15669-74. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3787493&tool=pmcentrez&rendertype=abstract

13 

SCOVILLEWB, MILNER B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry [Internet]. 1957 Feb;20(1):11-21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13406589

14 

Corkin S, Amaral DG, González RG, Johnson KA, Hyman BTH1997M.’s medial temporal lobe lesion: findings from magnetic resonance imagingThe Journal of neuroscience: The Official Journal of the Society for Neuroscience39643979

15 

Vargha-Khadem F1997Differential effects of early hippocampal pathology on episodic and semantic memoryScience376380

16 

O’Reilly RC, Norman KA2002Hippocampal and neocortical contributions to memory: Advances in the complementary learning systems frameworkTrends in Cognitive Sciences505510

17 

Morris RG, Garrud P, Rawlins JN, O’Keefe J1982Place navigation impaired in rats with hippocampal lesionsNature297681683

18 

O–Keefe J,Dostrovsky J. The hippocampus as a spatialmap. Preliminary evidence fromunit activity in the freely-moving rat. Brain Res [Internet]. 1971 Nov;34(1):171-5. Available http://www.ncbi.nlm.nih.gov/pubmed/5124915

19 

O’Keefe J, Conway DH1978Hippocampal place units in the freely moving rat: Why they fire where they fireExperimental Brain Research314573590

20 

Ekstrom AD, Kahana MJ, Caplan JB, Fields TA, Isham EA, Newman EL2003Cellular networks underlying human spatial navigationNature425184188

21 

Taube JS, Muller RU, Ranck JB1990Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulationsJ Neurosci10436447

22 

Fyhn M, Molden S, Witter MP, Moser EI, Moser M-B2004Spatial representation in the entorhinal cortexScience30512581264

23 

Kesner RP2013An analysis of the dentate gyrus functionBehavioural Brain Research17

24 

Leutgeb JK, Leutgeb S, Moser M-B, Moser EI2007Pattern separation in the dentate gyrus and CA3 of the hippocampusScience315961966

25 

Treves A, Tashiro A, Witter ME, Moser EI2008What is the mammalian dentate gyrus good for?Neuroscience11551172

26 

Galimberti I, Gogolla N, Alberi S, Santos AF, Muller D, Caroni P2006Long-term rearrangements of hippocampal mossy fiber terminal connectivity in the adult regulated by experienceNeuron50749763

27 

Muller RU, Kubie JL1987The effects of changes in the environment on the spatial firing of hippocampal complex-spike cellsJ Neurosci719511968

28 

Eichenbaum H, Wiener SI, Shapiro ML, Cohen NJ1989The organization of spatial coding in the hippocampus: A study of neural ensemble activityJ Neurosci927642775

29 

Jung MW, McNaughton BL1993Spatial selectivity of unit activity in the hippocampal granular layerHippocampus3165182

30 

Kesner RP. Behavioral functions of the CA3 subregion of the hippocampus. Learn Mem [Internet]. 2007 Nov [cited 2015 Mar 19];14(11):771-81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18007020

31 

Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD2002Requirement for hippocampal CA3 NMDA receptors in associative memory recallScience297211218

32 

Kesner RP, Lee I, Gilbert P2004A behavioral assessment of hippocampal function based on a subregional analysisRev Neurosci15333351

33 

Volpe BT, Davis HP, Towle A, Dunlap WPLoss of hippocampal CA1 pyramidal neurons correlates with memory impairment in rats with ischemic or neurotoxin lesions

34 

Olsen GM, Scheel-Krüger J, Møller A, Jensen LHRelation of spatial learning of rats in the Morris water maze task to the number of viable CA1 neurons following four-vessel occlusion

35 

Gilbert PE, Kesner RP, Lee I. Dissociating hippocampal subregions: Double dissociation between dentate gyrus and CA1. Hippocampus [Internet]. 2001 Jan [cited 2015 Jun 21];11(6):626-36. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11811656

36 

Lee I, Kesner RP. Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning. Hippocampus [Internet]. 2004 Jan [cited 2015 Jun 2];14(3):301-10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15132429

37 

Ridley RM, Timothy CJ, MacLean CJ, Baker HF. Conditional learning and memory impairments following neurotoxic lesion of the CA1 field of the hippocampus. Neuroscience [Internet]. 1995 Jul [cited 2015 Jun 30];67(2):263-75. Available from: http://www.sciencedirect.com/science/article/pii/030645229500063O

38 

Altman J, Das GD1967Postnatal neurogenesis in the guinea-pigNature214509310981101

39 

Ehninger D, Ehninger D, Kempermann G, Kempermann G. Neurogenesis in the adult hippocampus. Cell Tissue Res [Internet]. 2008;331(1):243-50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17938969

40 

Christie BR, Cameron HA. Neurogenesis in the adult hippocampus. Hippocampus [Internet]. 2006 Jan [cited 2013 Aug 15];16(3):199-207. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16411231

41 

Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH2002Functional neurogenesis in the adult hippocampusNature415687510301034

42 

Bliss TVP, Lomo T1973Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the preforant pathJ Physiol232331356

43 

Bliss TVP, Collingridge GL1993A synaptic model of memory: Long-term potentiation in the hippocampusNature36173139

44 

Christie BR1996Long-term depression (LTD) in the hippocampusHippocampus6112

45 

Van Praag H, Christie BR, Sejnowski TJ, Gage FH1999Running enhances neurogenesis, learning, and long-term potentiation in miceProc Natl Acad Sci96231342713431

46 

Rhodes JS, van Praag H, Jeffrey S, Girard I, Mitchell GS, Garland T2003Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel runningBehav Neurosci117510061016

47 

Holmes MM, Galea LA, Mistlberger RE, Kempermann G. Adult hippocampal neurogenesis and voluntary running activity: Circadian and dose-dependent effects. J Neurosci Res [Internet]. 2004;76(2):216-22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15048919

48 

Clark PJ, Kohman RA, Miller DS, Bhattacharya TK, Brzezinska WJ, Rhodes JS. Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains. Genes Brain Behav [Inter1561net]. 2011;10(3):345-53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21223504

49 

Merritt JR, Rhodes JS. Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze. Behav Brain Res [Internet]. 2015;280:62-71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25435316

50 

Kim YP, Kim H, Shin MS, Chang HK, Jang MH, Shin MC, et al. Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Neurosci Lett [Internet]. 2004;355(1-2):152-4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14729257

51 

Uda M, Ishido M, Kami K, Masuhara M. Effects of chronic treadmill running on neurogenesis in the dentate gyrus of the hippocampus of adult rat. Brain Res [Internet]. 2006;1104(1):64-72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16824490

52 

Leasure JL, Jones M. Forced and voluntary exercise differentially affect brain and behavior. Neuroscience [Internet]. 2008;156(3):456-65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18721864

53 

Li H, Liang A, Guan F, Fan R, Chi L, Yang B. Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress. Brain Res [Internet]. 2013;1531:1-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23916669

54 

Stranahan AM, Khalil D, Gould E. Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci [Internet]. 2006;9(4):526-33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16531997

55 

Snyder JS, Glover LR, Sanzone KM, Kamhi JF, Cameron HA. The effects of exercise and stress on the survival and maturation of adult-generated granule cells. Hippocampus [Internet]. 2009;19(10):898-906.Available from: http://www.ncbi.nlm.nih.gov/pubmed/19156854

56 

Van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adultmouse dentate gyrus. Nat Neurosci [Internet]. 1999 Mar [cited 2011 Aug 23];2(3):266-70. Available from: http://dx.doi.org/10.1038/6368

57 

Brown J, Cooper-Kuhn CM, Kempermann G, Van Praag H, Winkler J, Gage FH, et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci [Internet]. 2003;17(10):2042-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12786970

58 

Yau SY, Li A, Hoo RL, Ching YP, Christie BR, Lee TM, et al. Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc Natl Acad Sci U S A [Internet]. 2014;111(44):15810-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25331877

59 

Patten AR, Sickmann H, Hryciw BN, Kucharsky T, Parton R, Kernick A2013Long-term exercise is needed to enhance synaptic plasticity in the hippocampusLearn Mem2011642647

60 

Kronenberg G, Reuter K, Steiner B, Brandt MD, Jessberger S, Yamaguchi M, et al. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J Comp Neurol [Internet]. 2003;467(4):455-63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14624480

61 

Brandt MD, Maass A, Kempermann G, Storch A. Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neuroge nesis. Eur J Neurosci [Internet]. 2010;32(8):1256-64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20950279

62 

Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Götz M2010Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and agingCell Stem Cell65445456

63 

Suh H, Consiglio A, Ray J, Sawai T, D’Amour KA, Gage FH. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell [Internet]. 2007;1(5):515-28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18371391

64 

Bednarczyk MR, Aumont A, Decary S, Bergeron R, Fernandes KJ. Prolonged voluntary wheel-running stimulates neural precursors in the hippocampus and forebrain of adult CD1 mice. Hippocampus [Internet]. 2009;19(10):913-27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19405143

65 

Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M, et al. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell [Internet]. 2010;6(5):445-56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20452319

66 

Farioli-Vecchioli S, Mattera A, Micheli L, Ceccarelli M, Leonardi L, Saraulli D, et al. Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells. Stem Cells [Internet]. 2014 Jul [cited 2015 Jul 2];32(7):1968-82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24604711

67 

Fischer TJ, Walker TL, Overall RW, Brandt MD, Kempermann G. Acute effects of wheel running on adult hippocampal precursor cells in mice are not caused by changes in cell cycle length or S phase length. Front Neurosci [Internet]. 2014;8:314. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25339861

68 

Bednarczyk MR, Hacker LC, Fortin-Nunez S, Aumont A, Bergeron R, Fernandes KJ. Distinct stages of adult hippocampal neurogenesis are regulated by running and the running environment. Hippocampus [Internet]. 2011;21(12):1334-47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20623741

69 

Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature [Internet]. 1997;386(6624):493-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9087407

70 

Mustroph ML, Chen S, Desai SC, Cay EB, DeYoung EK, Rhodes JS2012Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J miceNeuroscience2196271

71 

Fabel K, Wolf SA, Ehninger D, Babu H, Leal-Galicia P, Kempermann G2009Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in miceFront Neurosci350

72 

Christie BR, Eadie BD, Kannangara TS, Robillard JM, Shin J, Titterness AK2008Exercising our brains: How physical activity impacts synaptic plasticity in the dentate gyrusNeuroMolecular Medicine4758

73 

Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR2004Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo Neuroscience12417179

74 

Kim S-E, Ko I-G, Kim B-K, Shin M-S, Cho S, KimC-J 2010Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampusExp Gerontol455357365

75 

O’Callaghan RM, Ohle R, Kelly AM2007The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial- and non-spatial learningBehav Brain Res1762362366

76 

Zagaar M, Dao A, Levine A, Alhaider I, Alkadhi K2013Regular exercise prevents sleep deprivation associated impairment of long-term memory and synaptic plasticity in the CA1 area of the hippocampusSlee365751761

77 

Kumar A, Rani A, Tchigranova O, Lee W-H, Foster TC2012Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiologyNeurobiol Aging334828.e1828.e17

78 

Dao AT, Zagaar MA, Levine AT, Salim S, Eriksen JL, Alkadhi KA2013Treadmill exercise prevents learning and memory impairment in Alzheimer’s disease-like pathologyCurr Alzheimer Res105507515

79 

Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH2002Functional neurogenesis in the adult hippocampusNature41510301034

80 

Burgess N, Barry C, Keefe JO, Al BET, O’Keefe J2007An oscillatory interference model of grid cell firingHippocampus00013

81 

Eadie BD, Redila VA, Christie BR2005Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine densityJ Comp Neurol48613947

82 

Neeper SA, Gómez-Pinilla F, Choi J, Cotman CW1996Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brainBrain Res7261-24956

83 

Korte M, Kang H, Bonhoeffer T, Schuman E1998A role for BDNF in the late-phase of hippocampal long-term potentiationNeuropharmacology374-5553559

84 

Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T1995Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factorProc Natl Acad Sci921988568860

85 

Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW2004The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exerciseNeurosci Lett36314348

86 

Clark PJ, Brzezinska WJ, Thomas MW, Ryzhenko NA, Toshkov SA, Rhodes JS2008Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J miceNeuroscience155410481058

87 

P C, NR R, KE B. Cued and Contextual Fear Conditioning for Rodents [Internet]. CRC Press, Boca Raton (FL); 2009 [cited 2015 May 1]. Available from: http://europepmc.org/abstract/med/21204331

88 

Baruch DE, Swain RA, Helmstetter FJ2004Effects of Exercise on Pavlovian Fear ConditioningBehav Neurosci118511231127

89 

Burghardt PR, Pasumarthi RK, Wilson MA, Fadel J2006Alterations in fear conditioning and amygdalar activation following chronic wheel running in ratsPharmacol Biochem Behav842306312

90 

Greenwood BN, Strong PV, Foley TE, Fleshner M2009A behavioral analysis of the impact of voluntary physical activity on hippocampus-dependent contextual conditioningHippocampus19109881001

91 

Anderson BJ, Rapp DN, Baek DH, McCloskey DP, Coburn-Litvak PS, Robinson JK2000Exercise influences spatial learning in the radial arm mazePhysiol Behav705425429

92 

Schweitzer NB, Alessio HM, Berry SD, Roeske K, Hagerman AE2006Exercise-induced changes in cardiac gene expression and its relation to spatial maze performanceNeurochem Int481916

93 

Van der Borght K, Havekes R, Bos T, Eggen BJL, Van der Zee EA2007Exercise improves memory acquisition and retrieval in the Y-maze task: Relationship with hippocampal neurogenesisBehav Neurosci1212324334

94 

Antunes M, Biala G2012The novel object recognition memory: Neurobiology, test procedure, and its modificationsCognitive Processing93110

95 

Aggleton JP, Albasser MM, Aggleton DJ, Poirier GL, Pearce JM2010Lesions of the rat perirhinal cortex spare the acquisition of a complex configural visual discrimination yet impair object recognitionBehav Neurosci12415568

96 

Clark RE, Zola SM, Squire LR2000Impaired recognition memory in rats after damage to the hippocampusJ Neurosci202388538860

97 

Lafenêtre P, Leske O, Ma-Högemeie Z, Haghikia A, Bichler Z, Wahle P2010Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesisFront Behav Neurosci334

98 

Hopkins ME, Bucci DJ2010BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memoryNeurobiol Learn Mem942278284

99 

Hopkins ME, Nitecki R, Bucci DJ2011Physical exercise during adolescence versus adulthood: Differential effects on object recognition memory and brain-derived neurotrophic factor levelsNeuroscience1948494

100 

Yau S, Li A, So K2015Involvement of Adult Hippocampal Neurogenesis in Learning and ForgettingNeural Plast501

101 

Feng R, Rampon C, Tang Y-P, Shrom D, Jin J, Kyin M, et al. Deficient Neurogenesis in Forebrain-Specific Presenilin-1 Knockout Mice Is Associated with Reduced Clearance of Hippocampal Memory Traces. Neuron [Internet]. 2001 Dec [cited 2015 May 15];32(5):911-26. Available from: http://www.sciencedirect.com/science/article/pii/S0896627301005232

102 

Saxe MD, Malleret G, Vronskaya S, Mendez I, Garcia AD, Sofroniew M V, et al. Paradoxical influence of hippocampal neurogenesis on working memory. Proc Natl Acad Sci U S A [Internet]. 2007 Mar 13 [cited 2015 May 5];104(11):4642-6. Available from: http://www.pnas.org/content/104/11/4642.full

103 

Kitamura T, Saitoh Y, Takashima N, Murayama A, Niibori Y, Ageta H, et al. Adult Neurogenesis Modulates the Hippocampus-Dependent Period of Associative Fear Memory. Cell [Internet]. 2009 Nov [cited 2015 Mar 13];139(4):814-27. Available from:http://www.sciencedirect.com/science/article/pii/S0092867409013099

104 

Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang H-LL, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science [Internet]. 2014 May 9 [cited 2015 May 25];344(6184):598-602. Available from: http://www.sciencemag.org/content/344/6184/598.abstract

105 

Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet [Internet]. 1973/11/03 ed. 1973;302(7836):999-1001. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4127281

106 

Sokol RJ, Delaney-Black V, Nordstrom B. Fetal alcohol spectrum disorder. JAMA [Internet]. 2003;290(22):2996-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14665662

107 

Gil-Mohapel J, Boehme F, Kainer L, Christie BR. Hippocampal cell loss and neurogenesis after fetal alcohol exposure: Insights from different rodent models. Brain Res Rev [Internet]. 2010/05/18 ed. 2010;64(2):283-303. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20471420

108 

Patten AR, Fontaine CJ, Christie BR. A comparison of the different animal models of fetal alcohol spectrum disorders and their use in studying complex behaviors. Front Pediatr [Internet]. 2014 Jan [cited 2015 Feb 10];2:93. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4153370&tool=pmcentrez&rendertype=abstract

109 

Redila VA, Olson AK, Swann SE, Mohades G, Webber AJ, Weinberg J, et al. Hippocampal cell proliferation is reduced following prenatal ethanol exposure but can be rescued with voluntary exercise. Hippocampus [Internet]. 2006;16(3):305-11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16425237

110 

Hamilton GF, Jablonski SA, Schiffino FL, St Cry SA, Stanton ME, Klintsova AY2014Exercise and environment as an intervention for neonatal alcohol effects on hippocampal adult neurogenesis and learningNeuroscience265274290

111 

Helfer JL, Goodlett CR, Greenough WT, Klintsova AY2009The effects of exercise on adolescent hippocampal neurogenesis in a rat model of binge alcohol exposure during the brain growth spurtBrain Res1294111

112 

Hamilton GF, Murawski NJ, St.cyr SA, Jablonski SA, Schiffino FL, Stanton ME2011Neonatal alcohol exposure disrupts hippocampal neurogenesis and contextual fear conditioning in adult ratsBrain Res141288101

113 

Hamilton GF, Boschen KE, Goodlett CR, Greenough WT, Klintsova AY2012Housing in Environmental Complexity Following Wheel Running Augments Survival of Newly Generated Hippocampal Neurons in a Rat Model of Binge Alcohol Exposure During the Third Trimester EquivalentAlcohol Clin Exp Res3611961204

114 

Boehme F, Gil-Mohapel J, Cox A, Patten A, Giles E, Brocardo PS2011Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disordersEur J Neurosci3317991811

115 

Redila VA, Christie BR2006Exercise-induced changes in dendritic structure and complexity in the adult hippocampal dentate gyrusNeuroscience13712991307

116 

Sutherland RJ, McDonald RJ, Savage DD. Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus [Internet]. 1997;7(2):232-8. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9136052

117 

Titterness AK, Christie BR. Prenatal ethanol exposure enhances NMDAR-dependent long-term potentiation in the adolescent female dentate gyrus. Hippocampus [Internet]. 2010/11/17 ed. 2012;22(1):69-81. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21080406

118 

Christie BR, Swann SE, Fox CJ, Froc D, Lieblich SE, Redila V2005Voluntary exercise rescues deficits in spatial memory and long-term potentiation in prenatal ethanol-exposed male ratsEur J Neurosci2117191726

119 

Varaschin RK, Akers KG, Rosenberg MJ, Hamilton DA, Savage DD. Effects of the cognition-enhancing agent ABT-239 on fetal ethanol-induced deficits in dentate gyrus synaptic plasticity. J Pharmacol Exp Ther [Internet]. 2010/03/24 ed. 2010;334(1):191-8. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20308329

120 

Brady ML, Diaz MR, Iuso A, Everett JC, Valenzuela CF, Caldwell KK2013Moderate prenatal alcohol exposure reduces plasticity and alters NMDA receptor subunit composition in the dentate gyrusJ Neurosci3310621067

121 

Sickmann HM, Patten AR, Morch K, Sawchuk S, Zhang C, Parton R, et al. Prenatal ethanol exposure has sex-specific effects on hippocampal long-term potentiation. Hippocampus [Internet]. 2013/09/03 ed. 2013; Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=23996604

122 

Patten AR, Sickmann HM, Dyer RA, Innis SM, Christie BR2013Omega-3 fatty acids can reverse the long-term deficits in hippocampal synaptic plasticity caused by prenatal ethanol exposureNeurosci Lett551711

123 

Patten AR, Brocardo PS, Sakiyama C, Wortman RC, Noonan A, Gil-Mohapel J, et al. Impairments in hippocampal synaptic plasticity following prenatal ethanol exposure are dependent on glutathione levels. Hippocampus [Internet]. 2013/09/03 ed. 2013; Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=23996467

124 

Streissguth AP, Sampson PD, Barr HM. Neurobehavioral dose-response effects of prenatal alcohol exposure in humans from infancy to adulthood. Ann N Y Acad Sci [Internet]. 1989/01/01 ed. 1989;562:145-58. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2742272

125 

Uecker A, Nadel L. Spatial locations gone awry: Object and spatial memory deficits in children with fetal alcohol syndrome. Neuropsychologia [Internet]. 1996/03/01 ed. 1996;34(3):209-23. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8868278

126 

Mattson SN, Riley EP. Implicit and explicit memory functioning in children with heavy prenatal alcohol exposure. J Int Neuropsychol Soc [Internet]. 1999;5:462-71. Available from: <Go to ISI>://WOS:000081714500008

127 

Hamilton DA, Kodituwakku P, Sutherland RJ, Savage DD2003Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water taskBehav Brain Res1438594

128 

Malisza KL, Allman AA, Shiloff D, Jakobson L, Longstaffe S, Chudley AE. Evaluation of spatial working memory function in children and adults with fetal alcohol spectrum disorders: A functional magnetic resonance imaging study. Pediatr Res [Internet]. 2005;58:1150-7. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16306185

129 

Spadoni AD, Bazinet AD, Fryer SL, Tapert SF, Mattson SN, Riley EP2009BOLD response during spatial working memory in youth with heavy prenatal alcohol exposureAlcohol Clin Exp Res3320672076

130 

Sowell ER, Lu LH, O’Hare ED, McCourt ST, Mattson SN, O’Connor MJ2007Functional magnetic resonance imaging of verbal learning in children with heavy prenatal alcohol exposureNeuroreport18635639

131 

O’Hare ED, Lu LH, Houston SM, Bookheimer SY, Mattson SN, O’Connor MJ2009Altered frontal-parietal functioning during verbal working memory in children and adolescents with heavy prenatal alcohol exposureHum Brain Ma3032003208

132 

Astley SJ, Aylward EH, Olson HC, Kerns K, Brooks A, Coggins TE2009Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disordersAlcohol Clin Exp Res3316711689

133 

Blanchard BA, Riley EP, Hannigan JH. Deficits on a spatial navigation task following prenatal exposure to ethanol. Neurotoxicol Teratol [Internet]. 1987;9:253-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3627089

134 

Gianoulakis C1990Rats exposed prenatally to alcohol exhibit impairment in spatial navigation testBehav Brain Res36217228

135 

Westergren S, Rydenhag B, Bassen M, Archer T, Conradi NG1996Effects of Prenatal Alcohol Exposure on Activity and Learning in Sprague Dawley RatsPharmacolBiochemBehav55515520

136 

Kim CK, Kalynchuk LE, Kornecook TJ, Mumby DG, Dadgar NA, Pinel JP1997Object-recognition and spatial learning and memory in rats prenatally exposed to ethanolBehav Neurosci111985995

137 

Matthews DB, Simson PE1998Prenatal exposure to ethanol disrupts spatial memory: Effect of the training-testing delay periodPhysiol Behav646367

138 

Gabriel KI, Johnston S, Weinberg J2002Prenatal ethanol exposure and spatial navigation: Effects of postnatal handling and agingDev Psychobiol40345357

139 

Richardson DP, Byrnes ML, Brien JF, Reynolds JN, Dringenberg HC2002Impaired acquisition in the water maze and hippocampal long-term potentiation after chronic prenatal ethanol exposure in the guinea-pigEur J Neurosci1615931598

140 

Iqbal U, Dringenberg HC, Brien JF, Reynolds JN2004Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and impairs spatial learning in the guinea pigBehav Brain Res150117125

141 

Incerti M, Vink J, Roberson R, Wood L, Abebe D, Spong CY2010Reversal of alcohol-induced learning deficits in the young adult in a model of fetal alcohol syndromeObstet Gynecol115350356

142 

Goodlett CR, Peterson SD1995Sex differences in vulnerability to developmental spatial learning deficits induced by limited binge alcohol exposure in neonatal ratsNeurobiol Learn Mem64265275

143 

Pauli J, Wilce P, Bedi KS1995Spatial learning ability of rats following acute exposure to alcohol during early postnatal lifePhysiol Behav5810131020

144 

Tomlinson D, Wilce P, Bedi KS1998Spatial learning ability of rats following differing levels of exposure to alcohol during early postnatal lifePhysiol Behav63205211

145 

Johnson TB, Goodlett CR2002Selective and enduring deficits in spatial learning after limited neonatal binge alcohol exposure in male ratsAlcohol Clin Exp Res268393

146 

Wozniak DF, Hartman RE, Boyle MP, Vogt SK, Brooks AR, Tenkova T2004Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adultsNeurobiol Dis173403414

147 

Thomas JD, Sather TM, Whinery LA. Voluntary exercise influences behavioral development in rats exposed to alcohol during the neonatal brain growth spurt. Behav Neurosci [Internet]. 2008/12/03 ed. 2008;122(6):1264-73. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19045946

148 

Thomas JD, Idrus NM, Monk BR, Dominguez HD2010Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in ratsBirth Defects Res A Clin Mol Teratol88827837

149 

Schreiber WB, St.Cyr SA, Jablonski SA, Hunt PS, Klintsova AY, Stanton ME2013Effects of exercise and environmental complexity on deficits in trace and contextual fear conditioning produced by neonatal alcohol exposure in ratsDev Psychobiol55483495

150 

Murawski NJ, Jablonski SA, Brown KL, Stanton ME2013Effects of neonatal alcohol dose and exposure window on long delay and trace eyeblink conditioning in juvenile ratsBehav Brain Res236307318

151 

Murawski NJ, Stanton ME2010Variants of contextual fear conditioning are differentially impaired in the juvenile rat by binge ethanol exposure on postnatal days 4-9Behav Brain Res212133142

152 

Caldwell KK, Sheema S, Paz RD, Samudio-Ruiz SL, Laughlin MH, Spence NE2008Fetal alcohol spectrum disorder-associated depression: Evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse modelPharmacol Biochem Behav90614624

153 

Famy C, Streissguth AP, Unis AS1998Mental illness in adults with fetal alcohol syndrome or fetal alcohol effectsAm J Psychiatry155552554

154 

O’Connor MJ, Kasari C2000Prenatal alcohol exposure and depressive features in childrenAlcohol Clin Exp Res2410841092

155 

Roebuck TM, Mattson SN, Riley EP1999Behavioral and psychosocial profiles of alcohol-exposed childrenAlcohol Clin Exp Res2310701076

156 

Brocardo PS, Boehme F, Patten A, Cox A, Gil-Mohapel J, Christie BR2012Anxiety- and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: Protective effects of voluntary physical exerciseNeuropharmacology6216071618

157 

Faul M, Xu L, Wald M, Coronado V2010Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002-2006Atlanta, GA

158 

Beauchamp MH, Ditchfield M, Maller JJ, Catroppa C, Godfrey C, Rosenfeld J V2011Hippocampus, amygdala and global brain changes 10 years after childhood traumatic brain injuryInt J Dev Neurosci292137143

159 

Monti JM, Voss MW, Pence A, McAuley E, Kramer AF, Cohen NJ2013History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in lifeFront Aging Neurosci5August19

160 

Tate DF, Bigler ED2000Fornix and hippocampal atrophy in traumatic brain injuryLearn Mem7442446

161 

Hicks RR, Smith DH, Lowenstein DH, Saint Marie R, McIntosh TK1993Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampusJ Neurotrauma104405414

162 

Vakil E2005The effect of moderate to severe traumatic brain injury (TBI) on different aspects of memory: A selective reviewJournal of Clinical and Experimental Neuropsychology

163 

Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci [Internet]. 2013;14(2):128-42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3951995&tool=pmcentrez&rendertype=abstract

164 

Majerske CW, Mihalik JP, Ren D, Collins MW, Reddy CC, Lovell MR2008Concussion in sports: Postconcussive activity levels, symptoms, and neurocognitive performanceJ Athl Train433265274

165 

Piao CS, Stoica BA, Wu J, Sabirzhanov B, Zhao Z, Cabatbat R2013Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injuryNeurobiol Dis54252263

166 

Chytrova G, Ying Z, Gomez-Pinilla F2007Exercise normalizes levels of MAG and Nogo-A growth inhibitors after brain traumaEur J Neurosci27October 2007111

167 

Griesbach GS, Hovda DA, Gomez-Pinilla F2009Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activationBrain Res12886105115

168 

Griesbach GS, Hovda D a, Molteni R, Wu a, Gomez-Pinilla F2004Voluntary exercise following traumatic brain injury: Brain-derived neurotrophic factor upregulation and recovery of functionNeuroscience1251129139

169 

Griesbach GS, Gómez-Pinilla F, Hovda D a2007Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependentJ Neurotrauma24711611171

170 

Griesbach GS, Hovda D a, Gomez-Pinilla F, Sutton RL2008Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in ratsNeuroscience. IBRO1542530540

171 

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics–2014 update: A report from the American Heart Association. [Internet]. Circulation. 2014. e28-e292 p. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24352519

172 

Lim C, Alexander MP2009Stroke and episodic memory disordersNeuropsychologia4730453058

173 

Marin R, Williams A, Hale S, Burge B, Mense M, Bauman R2003The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the ratPhysiol Behav802-3167175

174 

Ke Z, Yip SP, Li L, Zheng XX, Tong KY2011The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: A rat brain ischemia modelPLoS One62111

175 

Ploughman M, Granter-Button S, Chernenko G, Tucker BA, Mearow KM, Corbett D2005Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemiaNeuroscience13649911001

176 

Chun XL, Jiang J, Qi GZ, Xin JZ, Wang W, Zhi JZ2007Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from strokeJ Neurosci Res85816371646

177 

Geibig CS, Keiner S, Redecker C2012Functional recruitment of newborn hippocampal neurons after experimental strokeNeurobiol Dis462431439

178 

Patten DA, Germain M, Kelly MA, Slack RS2010Reactive oxygen species: Stuck in the middle of neurodegenerationJ Alzheimers Dis20Suppl 2S357S367

179 

Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M1998Genetic dissection of Alzheimer’s disease and related dementias: Amyloid and its relationship to tauNat Neurosci15355358

180 

Shulman JM, De Jager PL, Feany MB2011Parkinson’s disease: Genetics and pathogenesisAnnu Rev Pathol6193222

181 

Vonsattel JP, DiFiglia M1998Huntington diseaseJ Neuropathol Exp Neurol575369384

182 

Perl DPNeuropathology of Alzheimer’s diseaseMt Sinai J Med7713242

183 

Hardy J, Selkoe DJ2002The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeuticsScience2975580353356

184 

Selkoe DJ2001Alzheimer’s Disease: Genes, Proteins, and TherapyPhysiol Rev812741766

185 

Hardy JA, Higgins GA1992Alzheimer’s disease: The amyloid cascade hypothesisScience2565054184185

186 

Shen J, Kelleher RJ. The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A [Internet]. 2007 Jan 9 [cited 2015 Jun 1];104(2):403-9. Available from: http://www.pnas.org/content/104/2/403.short

187 

Braak H, Braak E1997Staging of Alzheimer-related cortical destructionInt Psychogeriatr9Suppl 1257261discussion 269-72

188 

Dodart J-C, May P2005Overview on rodent models of Alzheimer’s diseaseCurr Protoc NeurosciNov; Chapter 9:Unit 9.22

189 

Mu Y, Gage FH2011Adult hippocampal neurogenesis and its role in Alzheimer’s diseaseMol Neurodegener685

190 

Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ2006Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s diseaseJ Comp Neurol49517083

191 

Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP2002Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s diseaseJ Neurochem83615091524

192 

Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG2004Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stressNeuroscience1273601609

193 

Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C2007Alzheimer’s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesisJ Neurosci272567716780

194 

Zhang C, McNeil E, Dressler L, Siman R2007Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer’s diseaseExp Neurol20417787

195 

Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG2004The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult miceExp Neurol1882224237

196 

Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH2005Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutationAm J Pathol1671151159

197 

Rodríguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM2008Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s diseasePLoS One38e2935

198 

Kolecki R, Lafauci G, Rubenstein R, Mazur-Kolecka B, Kaczmarski W, Frackowiak J2008The effect of amyloidosis-beta and ageing on proliferation of neuronal progenitor cells in APP-transgenic mouse hippocampus and in cultureActa Neuropathol1164419424

199 

Jin K, Galvan V, Xie L, Mao XO, Gorostiza OF, Bredesen DE2004Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw,Ind) miceProc Natl Acad Sci U S A101361336313367

200 

López-Toledano MA, Shelanski ML2007Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind)J Alzheimers Dis123229240

201 

Tapia-Rojas C, Aranguiz F, Varela-Nallar L, Inestrosa NC2015Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer’s diseaseBrain Pathol

202 

Yuede CM, Zimmerman SD, Dong H, Kling MJ, Bero AW, Holtzman DM2009Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tgmouse model of Alzheimer’s diseaseNeurobiol Dis Elsevier Inc353426432

203 

Mirochnic S, Wolf S, Staufenbiel M, Kempermann G2009Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer diseaseHippocampus191010081018

204 

García-Mesa Y, López-Ramos JC, Gimènez-Llort L, Revilla S, Guerra R, Gruart A2011Physical exercise protects against Alzheimer’s disease in 3xTg-AD miceJ Alzheimer’s Dis24421454

205 

Ashe KHLearning and memory in transgenic mice modeling Alzheimer’s diseaseLearn Mem86301308

206 

Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH2001Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group membersProc Natl Acad Sci U S A98634403445

207 

Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y2009Physical Activity, Diet, and Risk of Alzheimer DiseaseJAMA3026627

208 

Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA2002Participation in cognitively stimulating activities and risk of incident Alzheimer diseaseJAMA2876742748

209 

Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW2009Exercise improves cognition and hippocampal plasticity in APOE epsilon4 miceAlzheimers Dement54287294

210 

Adlard P a, Perreau VM, Pop V, Cotman CW2005Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s diseaseJ Neurosci251742174221

211 

Schindowski K, Bretteville A, Leroy K, Bègard S, Brion J-P, Hamdane M2006Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficitsAm J Pathol1692599616

212 

Van der Jeugd A, Ahmed T, Burnouf S, Belarbi K, Hamdame M, Grosjean M-E2011Hippocampal tauopathy in tau transgenic mice coincides with impaired hippocampus-dependent learning and memory, and attenuated late-phase long-term depression of synaptic transmissionNeurobiol Learn Mem953296304

213 

Belarbi K, Burnouf S, Fernandez-Gomez F-J, Laurent C, Lestavel S, Figeac M2011Beneficial effects of exercise in a transgenic mouse model of Alzheimer’s disease-like Tau pathologyNeurobiol Dis43248694Elsevier Inc

214 

Ambrèe O, Touma C, Görtz N, Keyvani K, Paulus W, Palme R2006Activity changes and marked stereotypic behavior precede A β pathology in TgCRND8 Alzheimer miceNeurobiol Aging277955964

215 

Richter H, Ambrèe O, Lewejohann L, Herring A, Keyvani K, Paulus W2008Wheel-running in a transgenic mouse model of Alzheimer’s disease: Protection or symptom?Behav Brain Res1907484

216 

Wolf S a, Kronenberg G, Lehmann K, Blankenship A, Overall R, Staufenbiel M2006Cognitive and Physical Activity Differently Modulate Disease Progression in the Amyloid Precursor Protein (APP)-23 Model of Alzheimer’s DiseaseBiol Psychiatry60Mdc13141323

217 

Herring A, Ambrèe O, Tomm M, Habermann H, Sachser N, Paulus W2009Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathologyExp Neurol2161184192Elsevier Inc

218 

Costa D a, Cracchiolo JR, Bachstetter AD, Hughes TF, Bales KR, Paul SM2007Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanismsNeurobiol Aging28831844

219 

Liu HL, Zhao G, Cai K, Zhao HH, Shi L De2011Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiationBehav Brain Res2182308314Elsevier B.V

220 

Liu HL, Zhao G, Zhang H, Shi L De2013Long-term treadmill exercise inhibits the progression of Alzheimer’s disease-like neuropathology in the hippocampus of APP/PS1 transgenic miceBehav Brain Res256261272Elsevier B.V

221 

Um H-S, Kang E-B, Koo J-H, Kim H-T, Jin-Lee , Kim E-J2011Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer’s diseaseNeurosci Res692161173Elsevier Ireland Ltd and Japan Neuroscience Society

222 

Kim B-K, Shin M-S, Kim C-J, Baek S-B, Ko Y-C, Kim Y-P2014Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid beta-induced Alzheimer disease ratsJ Exerc Rehabil10128

223 

Ke HC, Huang HJ, Liang KC, Hsieh-Li HM2011Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exerciseBrain Res1403111Elsevier B.V

224 

Hoveida R, Alaei H, Oryan S, Parivar K, Reisi P2011Treadmill running improves spatial memory in an animal model of Alzheimer’s diseaseBehav Brain Res2161270274Elsevier B.V

225 

Kang EB, Cho JY2014Effects of treadmill exercise on brain insulin signaling and β -amyloid in intracerebroventricular streptozotocin induced-memory impairment in rats1818996

226 

Choi DH, Kwon IS, Koo JH, Jang YC, Kang EB, Byun JE2014The effect of treadmill exercise on inflammatory responses in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type182225233

227 

Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA. Parkinson's disease is associated with hippocampal atrophy. Mov Disord [Internet]. 2003;18(7):784-90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12815657

228 

Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson's disease. Neuron [Internet]. 2010;66(5):646-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20547124

229 

Steidl J V, Gomez-Isla T, Mariash A, Ashe KH, Boland LM. Altered short-term hippocampal synaptic plasticity in mutant alpha-synuclein transgenic mice. Neuroreport [Internet]. 2003;14(2):219-23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12598733

230 

Gureviciene I, Gurevicius K, Tanila H. Aging and alpha-synuclein affect synaptic plasticity in the dentate gyrus. J Neural Transm [Internet]. 2009;116(1):13-22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19002552

231 

Bonito-Oliva A, Pignatelli M, Spigolon G, Yoshitake T, Seiler S, Longo F, et al. Cognitive impairment and dentate gyrus synaptic dysfunction in experimental parkinsonism. Biol Psychiatry [Internet]. 2014;75(9):701-10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23541633

232 

Pendolino V, Bagetta V, Ghiglieri V, Sgobio C, Morelli E, Poggini S, et al. l-DOPA reverses the impairment of Dentate Gyrus LTD in experimental parkinsonism via beta-adrenergic receptors. Exp Neurol [Internet]. 2014;261:377-85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25058044

233 

Zhu G, Li J, He L, Wang X, Hong X. MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway. Br J Pharmacol [Internet]. 2015; Available from: http://www.ncbi.nlm.nih.gov/pubmed/25560396

234 

Regensburger M, Prots I, Winner B. Adult hippocampal neurogenesis in Parkinson's disease: Impact on neuronal survival and plasticity. Neural Plast [Internet]. 2014 Jan [cited 2015 Mar 2];2014:454696. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4106176&tool=pmcentrez&rendertype=abstract

235 

Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci [Internet]. 2004;7(7):726-35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15195095

236 

Lesemann A, Reinel C, Huhnchen P, Pilhatsch M, Hellweg R, Klaissle P, et al. MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice. Brain Res [Internet]. 2012;1457:51-69. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22520437

237 

Crews L, Mizuno H, Desplats P, Rockenstein E, Adame A, Patrick C, et al. Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci [Internet]. 2008;28(16):4250-60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18417705

238 

Nuber S, Petrasch-Parwez E, Winner B, Winkler J, von Horsten S, Schmidt T, et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease. J Neurosci [Internet]. 2008;28(10):2471-84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18322092

239 

Tajiri N, Yasuhara T, Shingo T, Kondo A, Yuan W, Kadota T, et al. Exercise exerts neuroprotective effects on Parkinson's disease model of rats. Brain Res [Internet]. 2010;1310:200-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19900418

240 

Döbrössy MD, Nikkhah G2012Role of experience, training, and plasticity in the functional efficacy of striatal transplantsProg Brain Res200303328

241 

Costa C, Sgobio C, Siliquini S, Tozzi A, Tantucci M, Ghiglieri V, et al. Mechanisms underlying the impairment of hippocampal long-term potentiation and memory in experimental Parkinson's disease. Brain [Internet]. 2012;135(Pt 6):1884-99. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22561640

242 

Fisher BE, Wu AD, Salem GJ, Song J, Lin CH, Yip J, et al. The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson's disease. Arch Phys Med Rehabil [Internet]. 2008;89(7):1221-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18534554

243 

Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease. Lancet Neurol [Internet]. 2013;12(7):716-26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23769598

244 

Tillerson JL, Caudle WM, Reveron ME, Miller GW. Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease. Neuroscience [Internet]. 2003;119(3):899-911. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12809709

245 

Fisher BE, Petzinger GM, Nixon K, Hogg E, Bremmer S, Meshul CK, et al. Exercise-induced behavioral recovery and neuroplasticity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse basal ganglia. J Neurosci Res [Internet]. 2004;77(3):378-90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15248294

246 

Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosci [Internet]. 2007;27(20):5291-300. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17507552

247 

Pothakos K, Kurz MJ, Lau YS. Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration. BMC Neurosci [Internet]. 2009;10:6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19154608

248 

Smith BA, Goldberg NR, Meshul CK. Effects of treadmill exercise on behavioral recovery and neural changes in the substantia nigra and striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse. Brain Res [Internet]. 2011;1386:70-80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21315689

249 

Calabresi P, Picconi B, Tozzi A, Di Filippo M. Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends Neurosci [Internet]. 2007;30(5):211-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17367873

250 

Yin HH, Mulcare SP, Hilario MR, Clouse E, Holloway T, Davis MI, et al. Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nat Neurosci [Internet]. 2009;12(3):333-41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19198605

251 

1993The Huntington’s Disease Collaborative Research GrouA novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomesThe Huntington’s Disease Collaborative Research Grou.Cell726971983

252 

DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP1997Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brainScience277533419901993

253 

Li S-H, Li X-J2004Huntingtin and its role in neuronal degenerationNeuroscientist105467475

254 

Myers RH, Vonsattel JP, Stevens TJ, Cupples LA, Richardson EP, Martin JB1988Clinical and neuropathologic assessment of severity in Huntington’s diseaseNeurology383341347

255 

Gil JM, Rego AC2008Mechanisms of neurodegeneration in Huntington’s diseaseEur J Neurosci271128032820

256 

Lazic SE, Grote H, Armstrong RJE, Blakemore C, Hannan AJ, van Dellen A2004Decreased hippocampal cell proliferation in R6/1 Huntington’s miceNeuroreport155811813

257 

Grote HE, Bull ND, Howard ML, van Dellen A, Blakemore C, Bartlett PF2005Cognitive disorders and neurogenesis deficits in Huntington’s disease mice are rescued by fluoxetineEur J Neurosci22820812088

258 

Lazic SE, Grote HE, Blakemore C, Hannan AJ, van Dellen A, Phillips W2006Neurogenesis in the R6/1 transgenic mouse model of Huntington’s disease: Effects of environmental enrichmentEur J Neurosci23718291838

259 

Walker TL, Turnbull GW, Mackay EW, Hannan AJ, Bartlett PF2011The Latent Stem Cell Population Is Retained in the Hippocampus of Transgenic Huntington’s Disease Mice but Not Wild-Type MicePLoS OneZheng J63e18153

260 

Gil J, Mohapel P, Araújo IM, Popovic N, Li J-Y, Brundin P2005Reduced hippocampal neurogenesis in R6/2 transgenic Huntington’s disease miceNeurobiol Dis203744751

261 

Peng Q, Masuda N, Jiang M, Li Q, Zhao M, Ross CA2008The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington’s disease mouse modelExp Neurol2101154163

262 

Phillips W, Morton AJ, Barker RA2005Abnormalities of Neurogenesis in the R6/2 Mouse Model of Huntington’s Disease Are Attributable to the In Vivo MicroenvironmentJ Neurosci25501156411576

263 

Gil JMAC, Leist M, Popovic N, Brundin P, Petersèn A2004Asialoerythropoietin is not effective in the R6/2 line of Huntington’s disease miceBMC Neurosci517

264 

Kandasamy M, Couillard-Despres S, Raber KA, Stephan M, Lehner B, Winner B2010Stem Cell Quiescence in the Hippocampal Neurogenic Niche Is Associated With Elevated Transforming Growth Factor-β Signaling in an Animal Model of Huntington DiseaseJ Neuropathol Exp Neurol697717728

265 

Renoir T, Pang TY, Zajac MS, Chan G, Du X, Leang L2012Treatment of depressive-like behaviour in Huntington’s disease mice by chronic sertraline and exerciseBr J Pharmacol165513751389

266 

Ransome MI, Hannan AJ2013Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD miceMol Cell Neurosci5493107

267 

Pang TYC, Stam NC, Nithianantharajah J, Howard ML, Hannan a J2006Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington’s disease transgenic miceNeuroscience141569584

268 

Kohl Z, Kandasamy M, Winner B, Aigner R, Gross C, Couillard-Despres S1155Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse model of Huntington’s diseaseBrain Res2433

269 

Potter MC, Yuan C, Ottenritter C, Mughal M, van Praag H2010Exercise is not beneficial and may accelerate symptom onset in a mouse model of Huntington’s diseasePLoS Curr117

270 

Van Dellen A, Cordery PM, Spires TL, Blakemore C, Hannan AJ2008Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington’s diseaseBMC Neurosci934

271 

Harrison DJ, Busse M, Openshaw R, Rosser AE, Dunnett SB, Brooks SP2013Exercise attenuates neuropathology and has greater benefit on cognitive than motor deficits in the R6/1 Huntington’s disease mouse modelExp Neurol248457469Elsevier Inc

272 

Neeper SA, Gómez-Pinilla F, Choi J, Cotman C. Exercise and brain neurotrophins. Nature [Internet]. 1995 Jan 12 [cited 2011 Dec 4];373(6510):109. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7816089

273 

Van Der Borght K, Kóbor-Nyakas DÉ, Klauke K, Eggen BJL, Nyakas C, Van Der Zee EA2009Physical exercise leads to rapid adaptations in hippocampal vasculature: Temporal dynamics and relationship to cell proliferation and neurogenesisHippocampus1910928936

274 

Molteni R, Ying Z, Gómez-Pinilla F2002Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarrayEur J Neurosci16611071116

275 

Lipsky RH, Marini AM2007Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticityAnnals of the New York Academy of Sciences130143

276 

Cowansage KK, LeDoux JE, Monfils M-H2010Brain-derived neurotrophic factor: A dynamic gatekeeper of neural plasticityCurr Mol Pharmacol311229

277 

Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci [Internet]. 2013 Oct [cited 2014 Jul 15];17(10):525-44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24029446

278 

Hötting K, Röder B. Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci Biobehav Rev [Internet]. 2013 Nov [cited 2014 Aug 21];37(9 Pt B):2243-57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23623982

279 

Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR2002Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticityJ Neurophysiol88521872195

280 

Chaddock L, Erickson KI, Prakash RS, Kim JS, Voss MW, Vanpatter M, et al. A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children. Brain Res [Internet]. 2010 Oct 28 [cited 2011 Aug 25];1358:172-83. Available from: http://dx.doi.org/10.1016/j.brainres.2010.08.049

281 

Monti JM, Hillman CH, Cohen NJ2012Aerobic fitness enhances relational memory in preadolescent children: The FITKids randomized control trialHippocampus22918761882

282 

Herting MM, Nagel BJ2012Aerobic fitness relates to learning on a virtual Morris Water Task and hippocampal volume in adolescentsBehav Brain Res2332517525

283 

Stroth S, Hille K, Spitzer M, Reinhardt R2009Aerobic endurance exercise benefits memory and affect in young adultsNeuropsychol Rehabil192223243

284 

Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A [Internet]. 2011 Feb 15 [cited 2014 Jul 11];108(7):3017-22. Available from: http://www.pnas.org/content/108/7/3017.abstract

285 

Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: Interactions between exercise, depression, and BDNF. Neuroscientist [Internet]. 2012 Feb 1 [cited 2015 Mar 2];18(1):82-97. Available from: http://nro.sagepub.com/content/18/1/82.short

286 

Erickson KI, Leckie RL, Weinstein AM. Physical activity, fitness, and gray matter volume. Neurobiol Aging [Internet]. 2014 Sep [cited 2015 Mar 7];35 Suppl 2:S20-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24952993

287 

Erickson KI, Weinstein AM, Lopez OL. Physical activity, brain plasticity, and Alzheimer's disease. Arch Med Res [Internet]. 2012 Nov [cited 2015 Jun 9];43(8):615-21. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3567914&tool=pmcentrez&rendertype=abstract

288 

Intlekofer KA, Cotman CW. Exercise counteracts declining hippocampal function in aging and Alzheimer's disease. Neurobiol Dis [Internet]. 2013 Sep [cited 2015 Mar 4];57:47-55. Available from: http://www.sciencedirect.com/science/article/pii/S0969996112002264

Figures and Tables

Fig.1

A simplified hippocampal circuitry illustrating trisynaptic and monosynaptic circuits. The basic circuitry of the hippocampus is commonly termed the trisynaptic circuit. Layer II of the entorhinal cortex provides input to the granule cells of the dentate gyrus via the medial (light blue) and lateral (purple) perforant paths. The dentate granule cells project to pyramidal cells of the CA3 via the mossy fibre pathway (green). CA3 pyramidal neurons project to the CA1 via schaffer collaterals (pink). The CA1 pyramidal cells project to both the subiculum and to layers V and VI of the entorhinal cortex. Abbreviations: Cornu Ammonis (CA); Dentate Gyrus (DG); Entorhinal Cortex (EC); Lateral Perforant Path (LPP); Medial Perforant Path (LPP); Mossy Fibres (MF); Schaffer Collaterals (SC); Subiculum (S).

A simplified hippocampal circuitry illustrating trisynaptic and monosynaptic circuits. The basic circuitry of the hippocampus is commonly termed the trisynaptic circuit. Layer II of the entorhinal cortex provides input to the granule cells of the dentate gyrus via the medial (light blue) and lateral (purple) perforant paths. The dentate granule cells project to pyramidal cells of the CA3 via the mossy fibre pathway (green). CA3 pyramidal neurons project to the CA1 via schaffer collaterals (pink). The CA1 pyramidal cells project to both the subiculum and to layers V and VI of the entorhinal cortex. Abbreviations: Cornu Ammonis (CA); Dentate Gyrus (DG); Entorhinal Cortex (EC); Lateral Perforant Path (LPP); Medial Perforant Path (LPP); Mossy Fibres (MF); Schaffer Collaterals (SC); Subiculum (S).
Table 1

Effect of voluntary running on hippocampal plasticity in healthy rodents

Hippocampal neurogenesis
Animal ageSpeciesRunning periodMarkers examinedEffect of runningReference
3 months oldMouse12 daysBrdUIncreased cellvan Praag et al.,
(Proliferation andproliferation,1999
Survival)cell survival and
NeuNnet neurogenesis
(neurogenesis)
3 months oldMouse30 daysBrdU (survival)Increased cellvan Praag et al.,
BrdU/NeuNsurvival and1999
(neuronalneuronal
differentiation)differentiation
3 months oldMouse45 daysBrdU (survival)Increased cellvan Praag et al., 2005
or 19 months oldsurvival and
neuronal differentiation
BrdU/NeuN/S100β
triple labeling
6–8 weeks oldMouse selectively40 daysBrdU (survival)Increased cellRhodes et al., 2003
bred for highproliferation,
levels of runningsurvival and
BrdU/Neuro/neuronal
S100β tripledifferentiation
labeling
6 weeks oldMouse12 days or 19 daysBrdU (survival)Increased cellSynder et al., 2009
PCNA (cellproliferation
proliferation)after 14 days
running,
Increased cell
survival in after
both 14 days
and 19 days of
running
3 months oldMouse12 daysBrdU(ProliferationIncreased cellBrown et al., 2003
and survival)proliferation and
survival
8-9 weeks oldMouse14 daysBrdU, Ki67 (cellIncreased cellYau et al., 2014
proliferation)proliferation,
DCXneuronal
(neurogenesis)differentiation
BrdU/DCXand net
(neuronalneurogenesis
differentiation)
8 weeks oldMouse24 hours, 3BrdU, IdU, CldUIncreased cellBrandt et al., 2010
days, 7 days orproliferation at
35 days24 hours, 3 days
and 7 days
(peak at 3
days). Return to
baseline at 35
days
12 weeks oldTransgenic4 weeksBrdU and nestin-SpecificKronenberg et al., 2003
mouseGFP positive cellsincrease in type
expressing2b transient
GFP driven byamplifying
nestin geneprogenitor cells
promotor
74 days at endMouse3, 10 or 32 daysBrdU, Ki67,Increased cellKronenberg et al., 2006
of experimentDCX, calretininproliferation at 3
days and 10
days (peak at 3
days). Returned
to baseline at 35
days. DCX and
Calretinin
increased at 10
days and 32 days.
2 months oldMouse12 daysBrdU and PCNAIncreased cellKannangara et al., 2009
(cell proliferation)proliferation
6–8 weeks oldRat7 days or 28 daysBrdu (cellIncreased cellYau et al., 2012
proliferation)proliferation and
BrdU/DCXdifferentiation
(neuronalfollowing 28
differentiation)days of running
6–8 weeks oldRat14 daysBrdU (cellIncreased cellYau et al., 2011
proliferation)proliferation and
BrdU/DCX co-neuronal
labeling (Neuronaldifferentiation
differentiation)
2 months oldRat3, 7, 14, 28, 56 daysKi 67 (cellIncreased cellPatten et al., 2013
proliferation)proliferation
NeuroD (neuronalafter 3,7 or 28
differentiation)days of running
Increased
neuronal
differentiation
after 14 or 28
days of running
Hippocampal synaptic plasticity
Animal ageSpeciesRunning periodArea(s) analyzedEffect of runningReference
3 months oldMouse30 daysDG and CA1Enhanced LTPVan Praag et al., 1999
In vitroin the DG, but
not CA1
2 months oldRat3, 7, 14, 28, 56 daysDGEnhanced LTPPatten et al., 2013
In vivofollowing 56
days of running
Adult (exactRat7+ daysDGEnhanced STPFarmer et al., 2004
age notIn vivoand LTP,
specified)reduced
threshold for
LTP
3–5 weeks oldMouse7–10 daysDGEnhanced LTP,Vasuta et al., 2007
In vitrono effect on
LTD, both
abolished by
NR2A blockade
Hippocampal dependent behavior
Animal ageSpeciesRunning periodBehavioral testEffect of runningReference
3 months oldMouse30 daysMWMRapidVan Praag et al., 1999
acquisition
(day 3), better
memory in
probe test
2 months oldRat3 weeksMWMRapidAdlard et al., 2004
acquisition
(day 2)
6–8 weeks oldMouse34 daysMWMRapidRhodes et al., 2003
acquisition in
control runners
but not
selectively-bred
runners
3 months oldRat1 weekMWMCAMKIIVaynman et al., 2007
blockade
improves
acquisition in
runners but
impairs memory
on probe test
∼7–9 weeks oldRat30 daysContextual fearIncreasedBaruch et al., 2004
conditioningfreezing 24hr
later
∼4–6 weeks oldRat8 weeksContextual fearIncreasedBurghardt et al., 2006
conditioningfreezing 24hr
later, most
freezing in rats
that ran the
most
Adult (exactRat6 weeksContextual fearIncreasedGreenwood et al., 2009
age notconditioningfreezing when
specified)running
occurred before
conditioning but
no effect when
running
occurred
between
conditioning and
testing
2 months oldMouse3 weeksContextual fearReduced fearAkers et al., 2014
conditioningmemory in
runners
6–8 weeks oldMouse5 weeksContextual fearNo effect onKitamura et al., 2009
conditioningmemory
expression,
speed up decay
rate of
hippocampal
dependency of
memory
5 months oldRat7 weeksRadial arm mazeFewer trials toAnderson et al., 2000
criterion
10 weeks oldMouse14 daysY-MazeRapidVan der Borght et al.,
acquisition by2006
trial 2, after
learning in non-
runners, 14
days of running
improved
memory
retention

Abbreviations: BrdU, bromodeoxyuridine; CA, Cornu Ammonis; DG, dentate gyrus; DCX, doublecortin; MWM, Morris Water Maze; PCNA, proliferating cell nuclear antigen.

Table 2

Effects of voluntary running on adult hippocampal neurogenesis in animal models of neurological disorders

Disease modelAnimal age/ ModelRunning periodMarkers examinedEffect of runningReference
FASD7 weeks old/7 daysBrdURescued deficitRedila et al., 2006
Rat(proliferationin proliferation
and survival)and survival
4 weeks old/12 daysBrdUIncreasedHelfer et al., 2009
Rat(proliferationproliferation, no
and survival)effect on
survival
7 weeks old/12 daysKi67, BrdU,IncreasedBoehme et al., 2011
RatNeuroDproliferation
and neuronal
differentiation
4 weeks old/12 days (followed byBrdU (survival)Rescued deficitHamilton et al., 2014
Rat30 days enrichment)in cell survival
TBINot reported
StrokeAdult/ Mouse/42 days (beginning dayBrdU (Proliferaion)IncreasedGeibig et al., 2012
of infarct)proliferation
photothromboticrelative to
cortical infarctsedentary
stroke group
Adult/ Mouse/42 days (beginning 7BrdU (Proliferation)No change inChun et al., 2007
days after MCAO)proliferation
MCAO
Adult/ Mouse/42 days (beginning 7BrdU (Survival)IncreasedChun et al., 2007
days after MCAO)
MCAOsurvival relative
to sedentary
stroke
AD5 months old/10 weeksNissl staining;PreventedTapia-Rojas et al., 2015
Mouse/BrdU (proliferationneuronal loss;
APPswe/PS1and survival)Increased
ΔE 9proliferation
and neuronal
differentiation
5 months old/16 weeksNissl stainingGreaterYuede et al., 2009
Mouse/hippocampal
Tg2576volume
6 and 18 months10 daysBrdU, DCX, NeuNIncreasedMirochnic et al., 2009
old / Mouse/proliferation
APP23and neuronal
differentiation
in 18 month-old
mice only
PDNot reported
HD8–12 weeks old/4 weeksBrdUNo effectRenoir et al., 2012
Mouse/(proliferation
R6/1and survival)
3 months old/8 daysKi67, BrdU,No effectRansome and Hannan, 2013
Mouse/NeuN
R6/1

Abbreviations: AD, Alzheimer’s Disease; BrdU, bromodeoxyuridine; DCX, doublecortin; FASD, fetal alcohol spectrum disorder; HD, Huntington’s Disease; MCAO, intraluminal middle cerebral artery occlusion; PD, Parkinson’s Disease; TBI, traumatic brain injury.

Table 3

Effects of voluntary running on hippocampal synaptic plasticity in animal models of neurological disorders

Animal modelAnimal ageRunning periodArea analyzedEffect of runningReference
FASD8 weeks old/ Rat10 daysDGRescued deficit in LTPChristie et al., 2005
TBINot reported
StrokeNot reported
AD7 months old/ Mouse/
3xTg-AD6 monthsCA1Rescued deficit in LTPGarcía-Mesa et al., 2011
PDNot reported
HDNot reported

Abbreviations: AD, Alzheimer’s disease; CA, Cornu Ammonis; DG, dentate gyrus; FASD, fetal alcohol spectrum disorders; HD, Huntington’s disease; LTP, long-term potentiation; PD, Parkinson’s disease; TBI, traumatic brain injury.

Table 4

Effects of voluntary running on hippocampal dependent behaviours in animal models of neurological disorders

Animal modelAnimal age/ ModelRunning periodBehaviour examinedEffect of runningReference
FASD8 weeks old/10 daysMWMDeficits inChristie et al., 2005
Ratreference and
working
memory were
reversed
3 weeks old/30 daysMWMRescuedThomas et al., 2008
Ratdeficits in
reference
memory
4 weeks old/12 daysContextual fearNo effectSchreiber et al., 2012
Rat(followed byconditioning
30 days
enrichment)
4 weeks old/12 daysContext pre-RescuedHamilton et al., 2014
Rat(followed byexposuredeficits
30 daysfacilitation
enrichment)
TBIAdult/ Rat/7 daysMWMReducedGrace et al., 2009
Lateral FPI(starting 14deficits in
days postacquisition of
injury)spatial memory
Adult/ Mouse/4 weeksMWMReducedPiao et al., 2013
Left parietal(starting 1 orimpairment in
CCI5 weeks postacquisition of
injury)spatial memory,
reference
memory,
reversal
memory
acquisition, and
reversal
reference
memory after 5
week delay in
exercise onset
No change after
1-week delay in
exercise onset
Adult/ Rat/7 daysMWMIncreasedGriesbach et al., 2004
Lateral FPI(starting dayimpairment in
of injury)acquisition of
spatial memory
Adult/ Rat/7 daysMWMDecreasedGriesbach et al., 2004
Lateral FPI(starting 14impairment in
days post injury)acquisition of
spatial memory
after delayed
exercise
initiation
StrokeAdult/ Mouse/42 daysMWMIncreased rateGeibig et al., 2012
photothrombotic(beginningof spatial
cortical infarctday of infarct)memory
acquisition. No
change in
reference
memory
Adult/ Mouse/ MCAO42 daysMWMRescuedChun et al., 2007
(beginning 7impairment in
days afteracquisition of
MCAO)spatial memory
AD5 months old/16 weeksNovel object recognitionReducedYuede et al., 2009
Mouse/ Tg2576decline in
recognition
memory
10–12 months6 weeksRadial-arm water mazeImprovedNichol et al., 2009
old/ Mouse/performance
APOE ɛ4(less errors)
1 month old/5 monthsMWMEnhancedAdlard et al., 2005
Mouse/learning rate
TgCRND8
3 months old/10 weeksOne-trial objectNo effectRichter et al., 2008
recognition paradigm,
Barnes maze
Mouse/
TgCRND8
3 months old/9 monthsTwo-trial Y-mazePreventedBelbarbi et al., 2011
Mouse/development of
THY-Tau22memory
alterations
4 and 7 months1 month andMWM; Startle Response;RescuedGarcía-Mesa et al., 2011
Dark and Light
box test
old/ Mouse/6 monthsretention
3xTg-ADdeficiency;
reduced BPSD-
like behaviours
5 months old/10 weeksMWMPreventedTapia-Rojas et al., 2015
Mouse/impairment in
APPswe-spatial acuity
PS1ΔE9and memory
acquisition
PDNot reported
HD10 weeks old/10 weeksT-maze; Y-mazeRear-pawPang et al., 2006
Mouse/ R6/1clasping onset
delayed;
rescued deficit
in spatial
working
memory
8–12 weeks old/4 weeksForced-swim testAnti-depressiveRenoir et al., 2012
Mouse/ R6/1effects
(reduced
immobility)

Abbreviations: AD, Alzheimer’s disease; CCI, controlled cortical impact; FASD, fetal alcohol spectrum disorder; FPI, fluid percussion injury; HD, Huntington’s disease; MCAO, middle cerebral artery occlusion; MWM, Morris Water Maze; PD, Parkinson’s disease; TBI, traumatic brain injury.