Cognitive Rehabilitation Reduces Cognitive Impairment and Normalizes Hippocampal CA1 Architecture in a Rat Model of Vascular Dementia

Abstract

Dementia is a major cause of morbidity in the western society. Pharmacological therapies to delay the progression of cognitive impairments are modestly successful. Consequently, new therapies are urgently required to improve cognitive deficits associated with dementia. We evaluated the effects of physical and cognitive activity on learning and memory in a rat model of vascular dementia (VasD). Male Sprague-Dawley rats (6 months old) were exposed to either regular chow or a diet rich in saturated fats and sucrose and chronic bilateral common carotid artery occlusion or sham surgery. First, this model of VasD was validated using a 2  2 experimental design (surgery  diet) and standard cognitive outcomes. Next, using identical surgical procedures, we exposed animals to a paradigm of cognitive rehabilitation or a sedentary condition. At 16 weeks post surgery, VasD animals demonstrated significant learning and memory deficits in the Morris water maze, independent of diet. Rehabilitation significantly attenuated these cognitive deficits at this time point as well as at 24 weeks. Further, rehabilitation normalized hippocampal CA1 soma size (area and volume) to that of control animals, independent of cell number. Importantly, these findings demonstrate beneficial neuroplasticity in early middle-aged rats that promoted cognitive recovery, an area rarely explored in preclinical studies.

A Cognitive Rehabilitation Paradigm Effective in Male Rats Lacks Efficacy in Female Rats

“…Our results confirm previous reports from this laboratory 3 and others 4 that older animals exposed to permanent, bilateral carotid occlusion exhibit significant learning and memory impairments. Further, data from the current study extend these findings to include early middleaged female rats, a cohort of animals not commonly assessed in preclinical experimentation.…”

“…Further, data from the current study extend these findings to include early middleaged female rats, a cohort of animals not commonly assessed in preclinical experimentation. Interestingly, cognitive rehabilitation, efficacious in a male model of VasD, 3 failed to ameliorate learning and memory impairments in female rats exposed to 2VO in the current study. Additionally, the 2VO model of VasD with female rats did not significantly affect hippocampal CA1 cell number or size as previously reported in male animals.…”

“…Animals in the Sham, HSF, 2VO, and 2VO-HSF groups were housed in pairs and a single condition was represented within a cage. The PA/CA condition consisted of a paradigm previously used in our laboratory 3 and was implemented after 2VO surgery (Experiment 2). Animals in this condition were individually exposed to voluntary running wheels, 3 days/week and on alternate days were housed in pairs and exposed to cognitive activity, 3 days/week; the seventh day they were housed in pairs in the absence of PA or CA.…”

“…A three-dimensional optical dissector counting frame (x, y, and z dimensions of 35 Â 35 Â 13 mm, respectively) was applied to systematic random sample sites resulting in an average of 15 to 20 sampling sites superimposed on the circumscribed area of dorsal CA1. 3 The dorsal CA1 hippocampus was outlined using a 5 Â objective and this allowed for the generation of sampling sites using the Optical Fractionator method (300 mm in the x direction and 100 mm in the y direction). One hippocampus was measured in each brain because there were no anticipated asymmetric differences with this model of VasD.…”

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

“…35,36 Recent evidence, however, has shown that middle-aged animals benefit from combination rehabilitation in a model of vascular dementia with resultant neuroplastic architectural changes accompanied by substantial improvements in cognition. 37 Further research is required to determine if similar increases in FosB/DFosB expression would be observed in aged animals using the current model of stroke.…”