Effects of early life sleep disruption on prefrontal cortex electrophysiological state and affiliation/attachment

摘要 自闭症谱系障碍（ASD）是一种人类神经发育状况，其特征在于 依恋行为和早期睡眠。草原田鼠（Microtus ochrogaster）是一种野生啮齿动物 物种是一个理想的动物模型，在其中研究附属/附件（RDoC域），因为不像 与传统的实验室大鼠和小鼠不同，它们表现出与异性伴侣的强烈联系。内侧变异 前额叶皮层（mPFC）结构预测的隶属/依恋行为的差异， 在田鼠物种中。此外，mPFC-NAcc（核受体）网络是必要的， 足以让草原田鼠形成社会联系此外，mPFC和mPFC-NAcc还涉及 ASD 1、2和神经型人类依恋。然而，mPFC-NAcc网络失调 在大脑发育过程中发生，在细胞水平上以什么形式发生，仍然是未知的。 由于mPFC成熟较晚，出生后的依恋/依恋可能特别容易受到影响。 我们报道了草原田鼠幼鼠的早期睡眠中断（ELSD）， 出生后第3周导致生活后期的联系/依恋减少和mPFC增加 树突棘这反映了早期睡眠中断、mPFC网络变化和 ASD患者的附属/依恋行为减少。然而，尽管我们最近的发现，两个 主要的知识差距仍然存在：1）ELSD如何影响关系/依恋的纵向发展，以及 早期变化如何预测成人表型，以及2）mPFC网络功能状态如何改变， 与E/I平衡的影响有关的具体知识差距。我们假设mPFC的变化， ELSD将导致依恋/依恋的发展轨迹和mPFC的改变 电生理活性和ELSD诱导的社会缺陷将通过光遗传学刺激来拯救。 θ频率下的mPFC-NAcc投影。我们将通过追求3个目标来测试这些假设：目标1： 确定生命早期睡眠中断（ELSD）对关系/依恋纵向发展的影响 使用连续、高分辨率、高通量的行为表型分析。目标2：确定 ELSD对依恋/依恋行为过程中mPFC电生理状态的影响目标3：操纵mPFC， NAcc投射活动，以拯救ELSD诱导的联系/依恋行为缺陷。我们假设 theta频率刺激mPFC-NAcc将拯救ELSD田鼠中的联系/依恋缺陷。这些 实验将大大扩展我们对ELSD社会赤字模型的认识。他们还直接测试了 使用mPFC光遗传学刺激拯救行为缺陷以产生新的干预。今后工作 可以在此基础上，通过在发展过程中进行干预， 使用睡眠，分子和网络水平的方法。

ABSTRACT Autism spectrum disorder (ASD) is a human neurodevelopmental condition that features deficits in affiliation/attachment behavior and early life sleep. Prairie voles (Microtus ochrogaster) are a wild rodent species that are an ideal animal model in which to study affiliation/attachment (an RDoC domain), since unlike traditional lab rats and mice, they display strong affiliation with opposite-sex mates. Variation in medial prefrontal cortex (mPFC) structure predicts differences in affiliation/attachment behavior, both across and within vole species. Additionally, the mPFC-NAcc (nucleus accumbens) network is both necessary and sufficient for social bond formation in prairie voles. Moreover, mPFC and mPFC-NAcc have been implicated in both ASD1,2 and neurotypical human attachment. However, exactly how mPFC-NAcc network dysregulation occurs during the course of brain development, and what form this takes at the cellular level, is still unknown. Due to the late maturation of the mPFC, affiliation/attachment may be particularly vulnerable to postnatal events such as sleep disruption and we reported that early life sleep disruption (ELSD) in prairie vole pups in the 3rd postnatal week led to a combination of reduced affiliation/attachment later in life and increases in mPFC dendritic spines. This mirrors the combination of early-life sleep disruption, mPFC network changes, and reductions in affiliation/attachment behavior in humans with ASD. However, despite our recent findings, two major knowledge gaps remain: 1) How ELSD affects the longitudinal development of affiliation/attachment, and how early changes may predict adult phenotypes, and 2) How the mPFC network functional state is altered, with a specific knowledge gap related to effects on E/I balance. We hypothesize that the mPFC changes in ELSD will result in alterations in both the developmental trajectory of affiliation/attachment and mPFC electrophysiological activity, and ELSD-induced social deficits will be rescued by optogenetic stimulation of mPFC-NAcc projections at theta frequencies. We will test these hypotheses by pursuing 3 aims: Aim 1: Determine effects of early life sleep disruption (ELSD) on the longitudinal development of affiliation/attachment using continuous, high-resolution, high-throughput behavioral phenotyping. Aim 2: Determine the effects of ELSD on mPFC electrophysiological state during affiliation/ attachment behaviors. Aim 3: Manipulate mPFC to NAcc projection activity to rescue ELSD-induced deficits in affiliation/ attachment behaviors. We hypothesize that theta-frequency stimulation of mPFC-NAcc will rescue affiliation/attachment deficits in ELSD voles. These experiments will greatly expand our knowledge of the ELSD model of social deficits. They also directly test the rescue of behavioral deficits using mPFC optogenetic stimulation to generate a new intervention. Future work can build on this foundation by intervening during developmental to alter life-long trajectories in social affiliation-attachment using sleep, molecular, and network-level approaches.