Somatostatin (SST) neurons in the suprachiasmatic nucleus (SCN) regulate circadian rhythms, yet their role in chronic sleep deprivation (cSD)-induced mood dysregulation is unclear. Our study shows SCNneurons are essential for cSD-induced anxiety- and depression-like behaviors. Through in vivo calcium imaging recordings, we demonstrate that following cSD, the dynamic range of SCNneuronal activity in response to anxiogenic stimuli is significantly attenuated compared to baseline conditions. Under physiological homeostasis, chemogenetic suppression of SCNneurons elicits a pronounced augmentation of anxiety- and depression-like behaviors. Conversely, both chemogenetic and optogenetic activation of SCNneurons effectively ameliorate cSD-induced alterations in emotional behaviors. Furthermore, by employing optogenetic interrogation of specific neural circuits, we identify differential roles of SCNefferent pathways in regulating cSD-induced mood disturbances. Optogenetic activation of the SCN-paraventricular nucleus of the hypothalamus (PVN) or SCN-medial preoptic area (MPOA) projections significantly mitigates anxiety- and depression-like behaviors in cSD-exposed mice. In contrast, activation of the SCN-paraventricular thalamic nucleus (PVT) circuit fails to produce significant effects on these behavioral endpoints. Collectively, these findings delineate the pivotal role of SCNneurons and their specific efferent circuits in mediating cSD-induced alterations in emotional processing. The identification of these neural substrates provides a mechanistic framework for understanding the comorbidity of anxiety and depression following sleep disruption, and offers potential targets for the development of precision therapeutics aimed at ameliorating these debilitating disorders. SST SST SST SST SST SST SST SST SST
