Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice.

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.

Prefrontal cortex stroke induces delayed impairment in spatial memory.

Stroke is the leading cause of long-term disability. Little is known about the effects of stroke on cognitive deficits. The subtle nature of cognition and its respective domains in areas such as working memory and attention can make this difficult to diagnose and treat. We aimed to establish a model of focal ischemia that targets the prefrontal cortex (PFC) and induce memory impairments. Stroke and sham mice were assessed at one and four-weeks post-stroke on various tests: open-field task to assess activity; grid-walk and cylinder task to assess motor impairments; elevated plus maze to assess anxiety; novel-object and object-location recognition tasks to assess memory impairment. Stroke mice in the open-field showed a small increase in activity with no effects on gross motor tasks or anxiety levels (P ≥ 0.05) at one and four-weeks post-stroke. Assessment of stroke mice on the novel object task showed no differences at either one or four-weeks compared to sham mice (P ≥ 0.05). However, assessment of stroke mice on the object-location recognition task revealed a significant (P ≥ 0.05) impairment in spatial memory by four-weeks compared to controls. Further, we show that stroke results in a small decrease in volume of the medial dorsal nucleus of the thalamus (P ≥ 0.05). This is the first evidence that demonstrates stroke to the PFC results in delayed onset impairment in spatial memory, similar to findings in human epidemiological data. We suggest that this model may be a useful tool in assessing potential rehabilitative/cognitive therapies after stroke.