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

项目摘要/摘要 社会功能缺陷与各种不同的障碍有关，并代表着相当大的公众 健康负担。成人的社会功能在发育和发展过程中受到社会经验的强烈影响 社会缺陷在自闭症和精神分裂症等神经发育障碍中非常明显， 这可能反映了社会经验被打乱的巩固。治疗和预防社会赤字的尝试 在很大程度上都不成功。这在一定程度上是由于缺乏对大脑网络的了解 社会功能的潜在机制和对经验依赖型的不良描述 负责社会功能成熟的发育过程。 这项提议旨在填补我们对支配社会的神经生物学机制的理解上的空白。 依赖于行为和社会经验的成熟。我们雇佣了一只小鼠少年社交隔离(JSI) 模拟被破坏的社会经验依赖的成熟和询问神经生物学的范式 社会赤字的基础。众所周知，JSI降低了社交能力，并导致内侧的生理异常 成年期的前额叶皮质(MPFC)。我们最近的发现表明，从mPFC投射到 后脑室旁丘脑(mpfc、、ppvt神经元)在社交活动中起关键作用，并具有选择性。 受到JSI的影响。我们表明，光遗传刺激mPFCpPVT神经元可以挽救JSI的社交能力。 这增加了这种回路被靶向用于治疗目的的可能性。然而，目前还不清楚是如何 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起着核心作用。 复杂行为过程中的分布式大脑网络。MpfcpPVT神经元处于良好的位置，可以产生 并同步皮质丘脑的振荡。然而，皮质丘脑的振荡还没有明确地被发现。 与社会行为有关。因此，这一提议的首要假设是mpfcppvt神经元 促进支持社会功能的皮质丘脑振荡，青少年孤立将导致损失 社会行为中mpfc、、pPVT募集和皮质丘脑同步性的关系。为了检验这一假设，我们 将使用光遗传标记技术对mPFC和pPVT活动进行最先进的电生理记录 在社会行为测试中对mpfcppvt神经元的影响。进一步，我们将探索潜在的机制 通过光基因刺激mPFC-pPVT神经元，挽救JSI诱导的社交功能缺陷 社交能力的恢复是否与mpfcpPVT募集的恢复有关 社会行为过程中皮质丘脑的同步性。总体而言，该项目将提供对 社会功能的神经生物学基础，并有可能激励改进治疗和预防 社会缺陷和障碍，其中依赖社会经验的成熟受到损害。

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.