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. Recently, we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighbouring dopaminergic neurons (Nagaeva et al., 2020). Here, we report that mouse Sst+ neurons especially from the anterolateral part of the VTA also project far outside the VTA and innervate forebrain regions that are mainly involved in the regulation of emotional behaviour, including the ventral pallidum (VP), lateral hypothalamus (LH), the medial part of the central amygdala (CeM), anterolateral division of the bed nucleus of stria terminalis (alBNST), and paraventricular thalamic nucleus (PVT). Deletion of these VTA neurons in mice affected several behaviours, 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 neurons have selective projection targets distinct from the main targets of VTA dopamine neurons. VTA neurons are involved in the regulation of behaviours primarily associated with the stress response, making them a relevant addition to the efferent VTA pathways and stress-related neuronal network.The ventral tegmental area (VTA) is involved in many reward- and aversion-related processes contributing to brain disorders, but the cellular composition and brain-wide connections of this subcortical brain region are still poorly known. We recently described a heterogeneous somatostatin-expressing (Sst) neuron population in the mouse VTA, and, here, we revealed that, in addition to being local interneurons, VTA Sst neurons send long-distance projections to specific forebrain regions. Deletion of these neurons altered behavioural reactions to acute stressors and to repeated morphine administration. The results add the VTA Sst neurons to the stress-related network of the brain and establish a possibility to find out the exact roles of these neurons acting as behaviourally relevant interneurons and/or projection neurons.