Brain Plasticity - Volume 5, issue 2

Authors: Martin, Elodie | Aigrot, Marie-Stéphane | Grenningloh, Roland | Stankoff, Bruno | Lubetzki, Catherine | Boschert, Ursula | Zalc, Bernard

Article Type: Research Article

Abstract: Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte–macrophage colony-stimulating factor in vitro . However, the role of BTK in the CNS is unknown. Methods: Our aim was to investigate the effect of BTK inhibition on myelin repair in ex vivo and in vivo experimental models of demyelination and …remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated Xenopus MBP-GFP-NTR transgenic tadpoles. Results: Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination. Conclusion: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair. Show more

Keywords: Myelin, demyelination, remyelination, cerebellar slice culture, Xenopus, microglia

DOI: 10.3233/BPL-200100

Citation: Brain Plasticity, vol. 5, no. 2, pp. 123-133, 2020

Authors: Hoffman, Jay R. | Zuckerman, Amitai | Ram, Omri | Sadot, Oren | Cohen, Hagit

Article Type: Research Article

Abstract: Objective: The purpose of this study was to examine the effect of exposure of a low-intensity blast wave on androgen receptor (AR) density in the hippocampus and the potential influence on behavioral and cognitive responses. Methods: Sprague-Dawley rats were randomly assigned to either a blast exposed group (n  = 27) or an unexposed (control) group (n  = 10). Animals were treated identically, except that rats within the control group were not exposed to any of the characteristics of the blast wave. Behavior measures were conducted on day seven post-exposure. The rats were initially assessed in the elevated plus maze followed …by the acoustic startle response paradigm. Spatial memory performance using the Morris water-maze test was assessed at 8-days post-exposure, for seven consecutive days. Following all behavioral tests AR immunofluorescence staining was performed in different hippocampal subregions. Results: A significant elevation in anxiety index (p  < 0.001) and impaired learning (p  < 0.015) and spatial memory (p  < 0.0015) were noted in exposed rats. In addition, a significant attenuation of the AR was noted in the CA1 (p  = 0.006) and dentate gyrus (p  = 0.031) subregions of the hippocampus in blast exposed animals. Correlational analyses revealed significant associations between AR and both anxiety index (r  = –.36, p  = 0.031) and memory (r  = –0.38, p  = 0.019). Conclusions: The results of this study demonstrate that exposure to a low-pressure blast wave resulted in a decrease in AR density, which was associated with significant behavioral and cognitive changes. Show more

Keywords: Testosterone, mTBI, military, neurotrauma, stress

DOI: 10.3233/BPL-200107

Citation: Brain Plasticity, vol. 5, no. 2, pp. 135-145, 2020

Authors: Islam, Mohammad R. | Luo, Renhao | Valaris, Sophia | Haley, Erin B. | Takase, Hajime | Chen, Yinching Iris | Dickerson, Bradford C. | Schon, Karin | Arai, Ken | Nguyen, Christopher T. | Wrann, Christiane D.

Article Type: Research Article

Abstract: Background: Despite considerable research on exercise-induced neuroplasticity in the brain, a major ongoing challenge in translating findings from animal studies to humans is that clinical and preclinical settings employ very different techniques. Objective: Here we aim to bridge this divide by using diffusion tensor imaging MRI (DTI), an advanced imaging technique commonly applied in human studies, in a longitudinal exercise study with mice. Methods: Wild-type mice were exercised using voluntary free-wheel running, and MRI scans were at baseline and after four weeks and nine weeks of running. Results: Both hippocampal volume and fractional anisotropy, …a surrogate for microstructural directionality, significantly increased with exercise. In addition, exercise levels correlated with effect size. Histological analysis showed more PDGFRα + oligodendrocyte precursor cells in the corpus callosum of running mice. Conclusions: These results provide compelling in vivo support for the concept that similar adaptive changes occur in the brains of mice and humans in response to exercise. Show more

Keywords: DTI, MRI, exercise, hippocampus, neuroplasticity

DOI: 10.3233/BPL-190090

Citation: Brain Plasticity, vol. 5, no. 2, pp. 147-159, 2020

Authors: Massa, Nicholas | Alrohaibani, Alaaeddin | Mammino, Kevin | Bello, Medina | Taylor, Nicholas | Cuthbert, Bruce | Fargotstein, Molly | Coulter, Monica M. | Boatright, Jeffery H. | Nocera, Joe | Duncan, Erica

Article Type: Research Article

Abstract: Background: Schizophrenia (SCZ) is a severe, chronic illness characterized by psychotic symptoms and impairments in many cognitive domains. Dysregulation of brain derived neurotrophic factor (BDNF) is associated with the cognitive impairments seen in patients with SCZ. Given the growing literature supporting a positive effect of aerobic exercise on cognition in other populations, we hypothesized that a structured aerobic exercise program would improve cognitive and functional outcomes in subjects with SCZ, potentially mediated by increases in BDNF. Methods: The study was a small randomized parallel group clinical trial of subjects with SCZ comparing 12 weeks of aerobic exercise (AE) …against control (CON) stretching and balance training. At Baseline, Week 12, and Week 20 we collected serum samples for analysis of brain derived neurotrophic factor (BDNF), and assessed functional, physical, and cognitive outcomes. Linear regression models were used to compare change scores between timepoints. Results: We randomized 21 subjects to AE and 17 to CON; however, only 9 AE and 6 CON completed their programs. Subjects in both groups were slower at the 400 m walk in Week 12 compared to Baseline, but the AE group had significantly less slowing than the CON group (B = –28.32, p  = 0.011). Between Week 12 and Week 20, the AE group had a significantly greater change score on the Composite and Visual Learning Domain of the MATRICS Consensus Cognitive Battery (B = 5.11, p  = 0.03; B = 13.96, p  = 0.006). Conclusion: These results indicate that participation in a structured aerobic exercise paradigm may modestly blunt physical function decline and enhance cognitive function in individuals with SCZ. Show more

Keywords: Schizophrenia, aerobic exercise, cognition, brain derived neurotrophic factor

DOI: 10.3233/BPL-200105

Citation: Brain Plasticity, vol. 5, no. 2, pp. 161-174, 2020

Authors: Maxa, Kaitlin M. | Hoffman, Carson | Rivera-Rivera, Leonardo A. | Motovylyak, Alice | Turski, Patrick A. | Mitchell, Carol K. C. | Ma, Yue | Berman, Sara E. | Gallagher, Catherine L. | Bendlin, Barbara B. | Asthana, Sanjay | Sager, Mark A. | Hermann, Bruce P. | Johnson, Sterling C. | Cook, Dane B. | Wieben, Oliver | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: There is increasing evidence that vascular disease risk factors contribute to evolution of the dementia syndrome of Alzheimer’s disease (AD). One important measure of cerebrovascular health is pulsatility index (PI) which is thought to represent distal vascular resistance, and has previously been reported to be elevated in AD clinical syndrome. Physical inactivity has emerged as an independent risk factor for cardiovascular disease. Objective: This study aims to examine the relationship between a measure of habitual physical activity, cardiorespiratory fitness (CRF), and PI in the large cerebral vessels. Methods: Ninety-two cognitively-healthy adults (age = 65.34±5.95, 72% female) enrolled …in the Wisconsin Registry for Alzheimer’s Prevention participated in this study. Participants underwent 4D flow brain MRI to measure PI in the internal carotid artery (ICA), basilar artery, middle cerebral artery (MCA), and superior sagittal sinus. Participants also completed a self-report physical activity questionnaire. CRF was calculated using a previously-validated equation that incorporates sex, age, body-mass index, resting heart rate, and self-reported physical activity. A series of linear regression models adjusted for age, sex, APOE4 status, and 10-year atherosclerotic cardiovascular disease risk were used to analyze the relationship between CRF and PI. Results: Inverse associations were found between CRF and mean PI in the inferior ICA (p = .001), superior ICA (p = .035), and basilar artery (p = .040). No other cerebral vessels revealed significant associations between CRF and PI (p≥.228). Conclusions: Higher CRF was associated with lower PI in several large cerebral vessels. Since increased pulsatility has been associated with poor brain health and reported in persons with AD, this suggests that aerobic fitness might provide protection against cerebrovascular changes related to the progression of AD clinical syndrome. Show more

Keywords: Cardiorespiratory fitness, Alzheimer’s disease, pulsatility index, cerebrovasculature, hemodynamics

DOI: 10.3233/BPL-190096

Citation: Brain Plasticity, vol. 5, no. 2, pp. 175-184, 2020