Chronic stress facilitates behavioral engagement and alters lateral habenula activity during flexible decision making in a sex-dependent manner

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Abstract
The ability to integrate feedback and flexibly adjust behavior under shifting environmental demands is required to optimize decision-making strategies. Clinical and preclinical data indicate that individuals with stress-related disorders and rodents exposed to chronic stress exhibit impaired behavioral flexibility. The lateral habenula (LHb) has emerged as a key brain region contributing to the effects of stress on cognitive performance. However, the extent to which the LHb is recruited to fine-tune decision-making strategies, as well as the impacts of chronic stress on LHb recruitment during task performance, remain largely unknown. To this end, we used a three-week model of chronic unpredictable stress (CUS) and performed in vivo fiber photometry to investigate Ca 2+ transients in LHb neurons during an attentional set-shifting task in adult male and female Sprague Dawley rats (n=7-12/sex/group). We found that CUS exposure did not significantly impair behavioral flexibility. Rather, CUS-exposed rats made fewer omissions and exhibited shorter response latencies compared to controls, suggesting enhanced task engagement. We also observed sex differences in LHb Ca 2+ activity. In control animals, we found that male rats showed stronger LHb signal prior to decision making, and greater activation following trial outcome than females. These differences were normalized by CUS, resulting in similar signaling patterns across sexes. Altogether, these findings reveal that chronic stress alters LHb activity in a sex-dependent manner without overtly impairing behavioral flexibility, thereby underscoring the importance of the LHb in decision making under stressful conditions. Highlights: Chronic stress decreased response latency without impairing behavioral flexibility Male rats displayed greater inhibition of LHb activity prior to decision making Chronic stress abolished sex differences in LHb activity during decision making
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