<p>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 SCN^SST neurons 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 SCN^SST neuronal activity in response to anxiogenic stimuli is significantly attenuated compared to baseline conditions. Under physiological homeostasis, chemogenetic suppression of SCN^SST neurons elicits a pronounced augmentation of anxiety- and depression-like behaviors. Conversely, both chemogenetic and optogenetic activation of SCN^SST neurons effectively ameliorate cSD-induced alterations in emotional behaviors. Furthermore, by employing optogenetic interrogation of specific neural circuits, we identify differential roles of SCN^SST efferent pathways in regulating cSD-induced mood disturbances. Optogenetic activation of the SCN^SST-paraventricular nucleus of the hypothalamus (PVN) or SCN^SST-medial preoptic area (MPOA) projections significantly mitigates anxiety- and depression-like behaviors in cSD-exposed mice. In contrast, activation of the SCN^SST-paraventricular thalamic nucleus (PVT) circuit fails to produce significant effects on these behavioral endpoints. Collectively, these findings delineate the pivotal role of SCN^SST neurons 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.</p>