Dopamine control of social novelty preference is constrained by an interpeduncular-tegmentum circuit

Animals are inherently motivated to explore social novelty cues over familiar ones, resulting in a novelty preference (NP), although the behavioral and circuit bases underlying NP are unclear. Combining calcium and neuro-transmitter sensors with fiber photometry and optogenetics in mice, we find that mesolimbic dopamine (DA) neurotransmission is strongly and pre-dominantly activated by social novelty controlling bout length of interaction during NP, a response significantly reduced by familiarity. In contrast, inter-peduncular nucleus (IPN) GABAergic neurons that project to the lateral dorsal tegmentum (LDTg) were inhibited by social novelty but activated during ter-minations with familiar social stimuli. Inhibition of this pathway during NP increased interaction and bout length with familiar social stimuli, while acti-vation reduced interaction and bout length with novel social stimuli via decreasing DA neurotransmission. These data indicate interest towards novel social stimuli is encoded by mesolimbic DA which is dynamically regulated by an IPN→LDTg circuit to control NP.