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

Abstract

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.

Figure 1

Experimental timeline illustrating the sequence of events in the current experiment. The dotted line represents pretraining prior to stroke surgery. The solid line refers to postsurgery events, with reference to the number of days after stroke.

Figure 2

Schematic representation of the mean infarct area in aged (dark blue) and young (light blue) mice following a 22-minute bilateral PFC stroke. Stroke damage extends from 1.54 to 0.14 AP (a). Infarct volume was measured for both the left (blue bar) and right (red bar) hemispheres and for the whole brain (pink dots; b) in young stroke, aged stroke, and aged+TrkB-Fc stroke animals. Data are expressed as mean ± S.E.M. for n = 10-14 per group.

Figure 3

Survival curve of the number of sessions each animal is required to make to reach the criterion (≥80% accuracy across two consecutive days) in the reversal (a) or rereversal (b) tasks. Aged animals (sham—dotted blue line; stroke—solid blue line) take longer to learn both tasks compared to young animals (sham—dotted red line; stroke—solid red line). Aged stroke animals performed better than aged sham controls.

Figure 4

The effect of age (young (red) versus aged (blue)) and PFC stroke (filled boxes) on the number of consecutive days (a), total trials (b), total correction trials (c), and total ITI touches (d) required to master the reversal task compared to sham (open boxes) controls. $$ = p < 0.01, $$$ = p < 0.001, and $$$$ = p < 0.0001 compared to young sham. ^∗ = p < 0.05 compared to aged-matched sham controls.

Figure 5

The effect of age (young (red) versus aged (blue)) and PFC stroke (filled boxes) on the number of consecutive days (a), total trials (b), total correction trials (c), and total ITI touches (D) required to master the rereversal task compared to sham (open boxes) controls.

Figure 6

Survival curve of the number of sessions each animal is required to make to reach the criterion (≥80% accuracy across two consecutive days) in the reversal (a) or rereversal (b) tasks. Aged stroke animals (solid blue line) take longer to learn both tasks compared to aged sham controls (dotted blue line). Aged stroke animals performed better than aged sham controls. This effect was blocked following the administration of the BDNF decoy, TrkB-Fc (solid black line).

Figure 7

The effect of PFC stroke and TrkB-Fc treatment on the number of consecutive days (a), total trials (b), total correction trials (c), and total ITI touches (d) required to master the reversal task. Aged sham: nonfilled blue box; aged stroke+IgG-Fc (hydrogel control): filled blue box; aged stroke+TrkB-Fc: filled grey box. $ = p < 0.05 and $$ = p < 0.01 compared to aged sham. ^∗ = p < 0.05 and ^∗∗ = p < 0.01 compared to TrkB-Fc-treated aged stroke animals.

Figure 8

The effect of PFC stroke and TrkB-Fc treatment on the number of consecutive days (a), total trials (b), total correction trials (c), and total ITI touches (d) required to master the rereversal task. Aged sham: nonfilled blue box; aged stroke: filled blue box; aged stroke+TrkB-Fc: filled grey box. $ = p < 0.05, $$ = p < 0.01, and $$$ = p < 0.001 compared to aged sham. ^∗ = p < 0.05 compared to TrkB-Fc-treated aged stroke animals.