Fig. 1.

Chronic fluoxetine (FLX), but not exercise, reverses behavioral phenotype in mice with poststroke depression (PSD). Timeline: mice were individually housed 14 days prior to surgery (Housing), microinjected with vehicle (sham ctrl) or endothelin 1 (ET-1; PSD) in the left medial prefrontal cortex (mPFC; surg, day 0); at 4 days poststroke, lesions were verified by magnetic resonance imaging (MRI), and at 7 days anxiety phenotype verified using elevated plus maze (EPM; 1 week); from 7 days onwards treatment was with FLX (PSD/FLX) or free running wheel (PSD/RW), with fixed wheel and vehicle as control (for PSD and sham ctrl) and compared with Sham-ctrl. Behavioral assays [EPM 4 weeks; open field (OF); forced swim test (FST); tail suspension (TS) test; novelty suppressed feeding test (NSF)] were done from days 28 to 40 followed by the Morris water maze (MWM; see Fig. 2) and perfusion (perfuse). (A) ET-1 lesion site visualized in vivo by MRI. Shown is a representative 7-Tesla MRI image done in an anaesthetized, living mouse at 4 days poststroke showing a 300-μm MRI section in which the lesion site is visualized and limited to the left mPFC [left (L); right (R)]. Infarct volumes obtained from in vivo MRI scanning were quantified at 2 different distances from Bregma, and showed low variability (n = 4 per experimental group). (B) EPM 1 week: prior to treatment at 7 days poststroke the 3 randomized stroke groups (PSD) compared with sham control showed anxiety phenotype with significantly reduced open-arm duration in EPM. (C) EPM 4 weeks: PSD reduced open-arm time compared with sham, indicative of an anxiety phenotype; this was reversed by chronic 3-week treatment with FLX (PSD/FLX) but not exercise (PSD/RW). As control for locomotion, total distance travelled did not differ between groups. (D) OF: PSD reduced large center duration and FLX or exercise reversed this anxiety phenotype, with no change in distance travelled. (E) NSF: PSD increased latency to feed in open field, and FLX but not exercise reversed this phenotype. As control for hunger, the latency to feed in home cage did not differ between groups. (F) FST: immobility time in PSD vs sham group was increased indicating behavioral despair, and this was reversed by FLX but not exercise. (G) TS: immobility increase in PSD was reversed by FLX but not exercise. Data represent mean ± SEM, n = 8 per group, *p <0.05, **p <0.01