Impact of juvenile social isolation on corticothalamic interactions controlling adult social behavior

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Project Summary/Abstract Social functioning deficits are associated with a variety of different disorders and represent a substantial public health burden. Adult social functioning is strongly influenced by social experience during development and social deficits are highly pronounced in neurodevelopmental disorders such as autism and schizophrenia, which may reflect disrupted consolidation of social experience. Attempts to treat and prevent social deficits have been largely unsuccessful. This is due, in part, to a lack of understanding of the brain network mechanisms underlying social functioning and poor characterization of the experience-dependent developmental processes responsible for maturation of social functioning. This proposal aims to fill the gaps in our understanding of the neurobiological mechanisms governing social behavior and social experience-dependent maturation. We employ a mouse juvenile social isolation (JSI) paradigm to model disrupted social experience-dependent maturation and interrogate the neurobiological bases of social deficits. JSI is known to reduce sociability and cause physiological abnormalities in the medial prefrontal cortex (mPFC) in adulthood. Our recent findings suggest that neurons projecting from the mPFC to the posterior paraventricular thalamus (mPFCpPVT neurons) play a key role in sociability and are selectively impacted by JSI. We show that optogenetic stimulation of mPFCpPVT neurons rescues sociability in JSI mice, raising the possibility that this circuit can be targeted for therapeutic purposes. However, it is unclear how mPFCpPVT neurons influence broader brain network activity and ultimately affect social functioning. Recent studies suggest that neural oscillations play a central role in coordinating the flow of information across distributed brain networks during complex behaviors. mPFCpPVT neurons are well-positioned to generate and synchronize corticothalamic oscillations. However, corticothalamic oscillations have not been explicitly linked to social behavior. Therefore, the overarching hypothesis of this proposal is that mPFCpPVT neurons facilitate corticothalamic oscillations that support social functioning, and that juvenile isolation will lead to a loss of mPFCpPVT recruitment and corticothalamic synchrony during social behavior. To test this hypothesis, we will conduct state-of-the-art electrophysiological recording of mPFC and pPVT activity with optogenetic tagging of mPFCpPVT neurons during tests of social behavior. Further, we will explore the mechanisms underlying rescue of JSI-induced sociability deficits mediated by optogenetic stimulation of mPFCpPVT neurons, asking whether recovery of sociability is associated with restoration of normal mPFCpPVT recruitment and corticothalamic synchrony during social behavior. Overall, this project will provide novel insight into the neurobiological basis of social functioning and has the potential to inspire improved treatment and prevention of social deficits and disorders where social experience-dependent maturation is compromised.