Dopamine Neuron Activity and Stress Signaling as Links Between Social Hierarchy and Psychopathology Vulnerability.

BACKGROUND: Social status in humans, generally reflected by socioeconomic status, has been associated, when constrained, with heightened vulnerability to pathologies including psychiatric diseases. Social hierarchy in mice translates into individual and interdependent behavioral strategies of animals within a group. The rules leading to the emergence of a social organization are elusive, and detangling the contribution of social status from other factors, whether environmental or genetic, to normal and pathological behaviors remains challenging. METHODS: We investigated the mechanisms shaping the emergence of a social hierarchy in isogenic C57BL/6 mice raised in groups of 4 using conditional mutant mouse models and chemogenetic manipulation of dopamine midbrain neuronal activity. We further studied the evolution of behavioral traits and the vulnerability to psychopathological-like phenotypes according to the social status of the animals. RESULTS: Higher sociability predetermined higher social hierarchy in the colony. Upon hierarchy establishment, higher-ranked mice showed increased anxiety and better cognitive abilities in a working memory task. Strikingly, the higher-ranked mice displayed a reduced activity of dopaminergic neurons within the ventral tegmental area, paired with a decreased behavioral response to cocaine and a decreased vulnerability to depressive-like behaviors following repeated social defeats. The pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signaling in dopamine-sensing brain areas that resulted in decreased dopaminergic activity promoted accession to higher social ranks. CONCLUSIONS: Dopamine activity and its modulation by the stress response shapes social organization in mice, potentially linking interindividual and social status differences in vulnerability to psychopathologies.

Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety.

Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on ß2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.