Fig. 5

Stroke exacerbates behavioral deficits in aged hAPP-SL mice on tests of motor, cognition, and anxiety. a Study design: 18 month-old (mo) hAPP-SL mice were assessed on the ladder rung, Y-maze spontaneous alternation behavior (SAB), novel object recognition, and light dark transition tests prior to a distal hypoxic (DH) stroke or sham surgery at the indicated timepoints. Mice were also weighed at each indicated timepoint. Mice were euthanized and brains were harvested for histology and immunostaining at 12 weeks post-surgery, along with spleen for organ weight. b Motor ability on the ladder rung test was assessed at 1-week pre-surgery, and at 1 week, 6 weeks, and 11 weeks post-surgery. At 1 week prior to a stroke, there was no difference in motor performance in the naïve hAPP-SL mice, as mice displayed a similar number of acceptable (<12% error) baseline foot placements on the rungs. These naïve mice would later be assigned into the sham or stroke experimental groups. At 1 week post-surgery, stroked hAPP-SL mice exhibited an enhanced motor deficit, as they displayed a significantly fewer number of correct foot placements relative to sham-operated hAPP-SL mice. Significant motor deficits continued to manifest in stroked hAPP-SL mice at 6 and 11 weeks post-surgery compared to sham-operated hAPP-SL mice at those timepoints. c Cognitive function using the Y-maze SAB test was assessed at 1 week pre-stroke, and at 1 week, 6 weeks, and 11 weeks post-surgery. At 1 week prior to surgery, there was no difference in cognitive function in naïve hAPP-SL mice, as mice displayed similar levels of spontaneous alternations. At 1 and 6 weeks post-surgery, there was no difference in the cognitive status of sham- and stroke-operated hAPP-SL mice. However, at 11 weeks post-surgery, stroked hAPP-SL mice exhibited aggrevated short-term spatial memory impairment, as they displayed significantly less spontaneous alternations compared to sham-operated hAPP-SL mice. d Cognitive function using the novel object recognition test was assessed at 1 week pre-stroke, and at 1 week, 6 weeks, and 11 weeks post-surgery. At 1 week prior to surgery, there was no difference in cognitive function in naïve hAPP-SL mice, as mice displayed similar recognition indexes, which corresponds to similar exploration time for an unfamiliar (novel) and a familiar object. At 1 and 6 weeks post-surgery, there was no difference in the cognitive status of the sham- and stroke-operated hAPP-SL mice. However, at 11 weeks post-surgery, the stroked hAPP-SL mice exhibited worsened intermediate recognition memory impairment, as they displayed significantly lower recognition indexes calculated from less time spent distinguishing and exploring an unfamiliar/novel object compared to the sham-operated hAPP-SL mice. e Using the light dark transition test, we assessed mice on the anxiety-impulsivity spectrum of behavior at 1 week pre-surgery, and at 1 week, 6 weeks, and 11 weeks post-surgery. At 1 week prior to surgery, there was no difference in the amount of time spent in the light, open (intimidating space) versus the dark, enclosed (safe space) arenas of the chamber in the naïve hAPP-SL mice. At 1 week prior to surgery, the amount of time spent in each arena remained similar between sham- and stroke-operated hAPP-SL mice, and this pattern was seen at 6 weeks post-surgery. However, at 11 weeks post-surgery, stroked hAPP-SL mice spent significantly more time in the light arena than sham-operated hAPP-SL mice, suggesting that stroke initiated behavioral impulsivity or a lack of inhibition in the hAPP-SL mice by reducing their anxiety of open spaces. f No significant weight changes were seen in the sham- and stroke-operated experimental hAPP-SL mouse groups at pre- and post-surgery timepoints. g There was no spleen weight difference between experimental groups at 12 weeks post-surgery. h There was no significant difference in any of the selected frailty outcomes depicted, with the exception of kyphosis, in the 18 mo sham- versus stroke-operated hAPP-SL mice at pre- and post-surgery timepoints. Data represent mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001