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

生命早期睡眠中断对前额皮质电生理状态和归属/依恋的影响

• 批准号: 10734842
• 负责人: Miranda M Lim
• 金额: $ 71.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734842
• 关键词: Address; Adult; Affect; Animal Model; Animals; Behavior; Behavioral; Biological Models; Brain; Climacteric; Cues; Custom; Dendritic Spines; Development; Elderly; Electrophysiology (science); Equilibrium; Event; Exposure to; Foundations; Frequencies; Future; Goals; Home; Human; Individual Differences; Infant; Intervention; Knowledge; Life; Machine Learning; Maps; Measures; Medial; Microtus; Modeling; Molecular; Monitor; Mus; Nucleus Accumbens; Partner in relationship; Phase; Phenotype; Prefrontal Cortex; Rattus; Reporting; Research Domain Criteria; Resolution; Rodent; Rodent Model; Same-sex; Shapes; Siblings; Sleep; Sleep disturbances; Social Behavior; Social Interaction; Structure; Testing; Time; Variant; Work; autism spectrum disorder; autistic children; behavioral phenotyping; comparison control; experimental study; individuals with autism spectrum disorder; novel; optogenetics; postnatal; prairie vole; preference; pup; response; sex; social; social attachment; social deficits; therapeutic target; tool

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.

抽象的 自闭症谱系障碍（ASD）是一种人类神经发育状况，具有缺陷 隶属/依恋行为和早期睡眠。草原田鼠（Microtus ochrogaster）是一种野生啮齿动物 是研究隶属/附着（RDOC域）的理想动物模型的物种，因为与 传统的实验室大鼠和小鼠，它们与异性伴侣表现出很强的隶属关系。内侧变化 前额叶皮层（MPFC）结构可以预测跨和依恋行为的差异 内部的物种。此外，MPFC-NACC（伏隔核）网络是必要的，并且 足以在草原田鼠中形成社会纽带。此外，MPFC和MPFC-NACC已与 ASD1,2和神经型人类的依恋。但是，确切的MPFC-NACC网络失调如何 发生在大脑发育过程中，以及在细胞水平上采取的何种形式仍然未知。 由于MPFC的成熟晚期，隶属/附件可能特别容易受到产后的影响 诸如睡眠中断之类的事件，我们报告说，早期的生命睡眠破坏（ELSD） 第三个后周导致生命后期的隶属关系/附件减少和MPFC的增加结合 树突状刺。这反映了早期睡眠中断，MPFC网络的变化和 ASD人类的隶属关系/依恋行为的减少。但是，尽管我们最近的发现，但两个 仍然存在主要知识差距：1）ELSD如何影响隶属/依恋的纵向发展，以及 早期变化如何预测成年表型，以及2）MPFC网络功能状态如何改变， 具有与对E/I平衡的影响有关的特定知识差距。我们假设MPFC改变了 ELSD将导致隶属/附件的发展轨迹和MPFC的变化 电生理活性和ELSD引起的社会缺陷将通过光遗传学刺激而挽救 MPFC-NACC在theta频率处投影。我们将通过追求3个目标来检验这些假设：目标1： 确定早期睡眠破坏（ELSD）对隶属/依恋纵向发展的影响 使用连续的高分辨率，高通量行为表型。目标2：确定 在隶属/附着行为期间，MPFC电生理状态的ELSD。目标3：操纵MPFC NACC投影活性以挽救ELSD引起的隶属/依恋行为缺陷。我们假设 MPFC-NACC的theta频率刺激将挽救ELSD田鼠的隶属关系/附着缺陷。这些 实验将大大扩展我们对ELSD社会缺陷模型的了解。他们还直接测试 使用MPFC光遗传学刺激来挽救行为缺陷以产生新的干预措施。未来的工作 可以通过在发展​​期间干预以改变社会中终身轨迹的基础上建立基础 使用睡眠，分子和网络级别方法的隶属关系。