SEX-SPECIFIC DISSOCIATION BETWEEN MOTIVATED BEHAVIOR AND HEDONIC RESPONSE AFTER ADULT HIPPOCAMPAL NEUROGENESIS ABLATION AND PROLONGED SOCIAL ISOLATION IN C57BL/6J MICE

Adult hippocampal neurogenesis (AHN) has been implicated in mood regulation and stress resilience, yet its specific contribution to motivational and hedonic behavioral domains, as well as potential sex differences under basal conditions, remains poorly defined. Here, we investigated whether pharmacological ablation of AHN using temozolomide (TMZ) induces depressive-like behaviors in male and female C57BL/6J mice, and whether such effects persist following a drug-free recovery period associated with prolonged individual housing. Eight-week-old male and female mice (n=8 per group) were assigned to Control, Vehicle, or TMZ (5 or 25 mg/kg) groups treated for four weeks and evaluated immediately post-treatment, as well as to recovery groups (Vehicle or TMZ 25 mg/kg) assessed after an additional 10-day washout. Motivated behavior was assessed using the Nest Building Test (NBT), and hedonic processing was evaluated using the Sucrose Preference Test (SPT). In males, TMZ treatment did not alter goal-directed behavior, with NBT scores remaining high and comparable across groups (χ²=6.40, p=0.269). Recovery groups displayed a significant increase in sucrose preference (p < 0.05), indicating preserved or enhanced reward sensitivity. In contrast, females exhibited a dissociated behavioral profile, with preserved NBT performance immediately after treatment, whereas both Vehicle and TMZ recovery groups showed reduced nest quality (χ² = 18.1, p = 0.003) alongside sucrose preference exceeding 90%, independently of treatment. These findings indicate that AHN ablation via TMZ does not induce depressive-like behavior per se but reveal a female-specific vulnerability to prolonged individual housing, characterized by a dissociation between motivated behavior and hedonic response.