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

项目概要/摘要 社会功能缺陷与各种不同的疾病有关， 健康负担。成年人的社会功能在发展过程中受到社会经验的强烈影响， 社交缺陷在神经发育障碍如自闭症和精神分裂症中非常明显， 这可能反映了社会经验的中断巩固。治疗和预防社会赤字的尝试 基本上都不成功。这在一定程度上是由于对大脑网络缺乏了解 社会功能的潜在机制和经验依赖型的不良特征 负责社会功能成熟的发展过程。 这项提议旨在填补我们对控制社交活动的神经生物学机制的理解空白。 行为和社会经验依赖的成熟。我们采用了一种小鼠青少年社会隔离（JSI） 范式模型中断的社会经验依赖的成熟，并询问神经生物学 社会赤字的基础。众所周知，JSI会降低社交能力，并导致中膜细胞的生理异常。 前额叶皮层（mPFC）。我们最近的研究结果表明，从mPFC投射到 后室旁丘脑（mPFC和pPVT神经元）在社会性中起关键作用， 受JSI影响。我们发现，光遗传学刺激mPFC和pPVT神经元拯救了JSI中的社交能力。 小鼠，提高了这种回路可以用于治疗目的的可能性。然而，目前还不清楚如何 mPFC pPVT神经元影响更广泛的大脑网络活动，并最终影响社会功能。 最近的研究表明，神经振荡在协调信息流方面发挥着核心作用。 在复杂的行为中分散的大脑网络。mPFC和pPVT神经元能够很好地产生 并使皮质丘脑振荡同步。然而，皮质丘脑振荡还没有明确的， 与社会行为有关。因此，该提议的首要假设是mPFC抑制pPVT神经元 促进支持社会功能的皮质丘脑振荡，青少年隔离将导致丧失 mPFC和pPVT的募集和皮质丘脑的同步性。为了验证这个假设，我们 将利用光遗传标记对mPFC和pPVT活动进行最先进的电生理记录 在社交行为测试中mPFC神经元的数量。此外，我们还将探讨 通过光遗传学刺激mPFC pPVT神经元介导的JSI诱导的社交缺陷的拯救， 社交能力的恢复是否与正常mPFC/pPVT募集的恢复相关， 皮质丘脑的同步性。总的来说，这个项目将提供新的见解， 社会功能的神经生物学基础，并有可能激发改善治疗和预防 社会经验依赖性成熟受到损害的社会缺陷和障碍。

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.