Somatostatin-Expressing Neurons in the Ventral Tegmental Area Innervate Specific Forebrain Regions and Are Involved in Stress Response

Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Previously we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighboring dopaminergic neurons (Nagaeva et al., 2020). Here, we report that Sst+ neurons especially from the anterolateral part of the mouse VTA also project far outside the VTA and innervate forebrain regions that are mainly involved in the regulation of emotional behavior, including the ventral pallidum, lateral hypothalamus, the medial part of the central amygdala, anterolateral division of the bed nucleus of stria terminalis, and paraventricular thalamic nucleus. Deletion of these VTA(Sst) neurons in mice affected several behaviors, such as home cage activity, sensitization of locomotor activity to morphine, fear conditioning responses, and reactions to the inescapable stress of forced swimming, often in a sex-dependent manner. Together, these data demonstrate that VTA(Sst) neurons have selective projection targets distinct from the main targets of VTA dopamine neurons. VTA(Sst) neurons are involved in the regulation of behaviors primarily associated with the stress response, making them a relevant addition to the efferent VTA pathways and stress-related neuronal network.