Role of hypothalamic CRH neurons in regulating the impact of stress on memory and sleep

Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRH PVN ), similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task in male mice. Conversely, inhibiting CRH PVN neurons during stress reduces stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRH PVN neurons activate neurons in the lateral hypothalamus (LH), and that CRH PVN projections to the LH regulate stress-induced memory deficits and sleep disruptions. Our results suggest that CRH PVN neuronal pathways regulate the adverse effects of stress on memory and sleep - an important step toward improving sleep and ameliorating cognitive deficits associated with stress-related disorders. Significance statement Stress significantly affects both sleep and memory, with spatial memory being particularly vulnerable. In this study, we combine acute restraint stress with optogenetic manipulations and a spatial object recognition task to investigate how corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRH PVN ), and their projections to the lateral hypothalamus (LH), influence memory performance and sleep-wake states following stress. Our findings reveal that activating CRH PVN neurons impairs memory performance and increases wakefulness, whereas inhibiting CRH PVN neurons during stress improves memory and sleep. Inhibiting CRH PVN neuronal projections to the LH similarly improves memory performance and sleep. This work highlights the role of CRH PVN neurons and their projections to the LH in modulating stress-induced alterations in memory and sleep-wake states.