Affiliations: [a] Laboratory of Diabetes and Obesity Research, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petah Tikva, Israel
| [b] Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petah Tikva, Israel
| [c] Laboratory of Transplantation, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Petah Tikva, Israel
| [d] Research Unit, Geha Mental Health Center, Petah Tikva, Israel
Correspondence:
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Correspondence to: Konstantin Bloch, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Beilinson Campus, Petah Tikva 49100, Israel. Tel.: +972 30 9376280; Mobile; +972 547972660; E-mail: [email protected].
Abstract: Background:Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ). Objective:We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities. Methods:Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues. Results:The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases. Conclusions:Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.
Keywords: Animal models, body weight changes, cognitive decline, intracerebroventricular administration of streptozotocin, neuroinflammation, peripheral metabolic dysfunctions
