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Developmental and Sex-Dependent Targets for Prevention after Early Life Stress

早期生活压力后预防的发育和性别依赖性目标

基本信息

批准号：
9900590
负责人：
Heather C Brenhouse
金额：
$ 37.76万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-10 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900590
关键词：
Adolescence Adolescent Adult Age Amygdaloid structure Animal Model Animals Anxiety Behavior Behavior assessment Behavioral Clinical Communication Data Development Diffusion Magnetic Resonance Imaging Early Intervention Equilibrium Exposure to Female Fiber Functional disorder Glutamate Receptor Glutamates Goals Hippocampus (Brain)Image Individual Individual Differences Interneurons Intervention Knowledge Life Longevity Male Adolescents Measures Membrane Mental Depression Mental disorders Morphology N-Methyl-D-Aspartate Receptors N-Methylaspartate Nature Peptides Population Prefrontal Cortex Prevention Preventive Intervention Preventive treatment Rattus Reporting Research Rest Risk Factors Structure Synapses Testing Time TimeLine Work adverse childhood events anxiety-like behavior boys brain circuitry critical period discrete time early adolescence early life stress emerging adult experimental study girls glutamatergic signaling male nerve supply neural circuit overexpression prevent receptor response sex sexual dimorphism traditional therapy treatment strategy

项目摘要

This project aims to elucidate developmental neurocircuitry effects of early life stress (ELS) in an animal model. Growing clinical evidence suggests that many ELS-attributable mental illnesses manifest in adolescence after an apparent latent period, and are unresponsive to traditional therapies. Our lab and others have further shown that these ELS-attributable effects follow a different time-course in males and females. Therefore, there is a need to understand aberrant developmental mechanisms that likely require targeted intervention and treatments in ELS-exposed individuals. Our recent studies revealed that ELS causes overexpression of the glutamatergic NMDA receptor subunit NR2A in the prefrontal cortex (PFC) of male adolescents. Importantly, targeted manipulation of NR2A protected ELS-exposed males from behavioral deficits such as increased anxiety-like behavior. Our preliminary data further suggests that NMDAR changes and increased anxiety appear earlier in development in ELS-exposed females, compared to ELS-exposed males. Understanding the developmental trajectory between ELS exposure and altered PFC receptivity is necessary to effectively intervene with preventative treatments. PFC receptivity is largely driven by glutamate activity in the PFC from limbic inputs, therefore the impact of ELS on corticolimbic connectivity requires delineation. The proposed project aims to target developmental origins of PFC dysfunction in ELS-exposed males and females. The central hypothesis is that ELS alters development of PFC innervation and glutamate receptivity in a sex-specific manner. These studies will first reveal sex-specific ELS effects on corticolimbic connectivity (Aim 1) and innervation (Aim 2) throughout development. Effects of ELS on PFC connectivity will provide translational data that can be juxtaposed with recent clinical findings in ELS-exposed boys and girls and will elucidate a likely mechanism behind how ELS leads to receptor alterations later in life. Aim 3 will investigate the developmental trajectory of post-synaptic NMDA receptor subunit changes after ELS. We will also determine critical periods when deactivating PFC NR2A function can prevent ELS-induced behavioral deficits later in life. Since recent evidence suggests that females show earlier ELS-attributable changes than males, we will determine whether females require an earlier intervention than males to prevent ELS-induced behavioral dysfunction. Together, these studies will fill critical gaps in knowledge about the developmental and sex-specific nature of ELS effects on PFC circuitry and are expected to have significant impact on the development of specific targets for prevention in ELS-exposed populations.

该项目旨在阐明早期生活压力 (ELS) 对动物发育神经回路的影响模型。越来越多的临床证据表明，许多 ELS 所致的精神疾病表现为青春期后经历了明显的潜伏期，并且对传统疗法没有反应。我们的实验室和其他人进一步表明，这些 ELS 归因效应在男性和女性中遵循不同的时间进程。女性。因此，有必要了解可能需要的异常发育机制对 ELS 暴露个体进行有针对性的干预和治疗。我们最近的研究表明，ELS 导致前额皮质 (PFC) 谷氨酸能 NMDA 受体亚基 NR2A 过度表达的男性青少年。重要的是，对 NR2A 进行有针对性的操作可以保护暴露于 ELS 的雄性免受行为缺陷，例如焦虑样行为增加。我们的初步数据进一步表明在暴露于 ELS 的女性中，NMDAR 变化和焦虑增加出现在发育早期，与暴露于 ELS 的男性相比。了解 ELS 暴露之间的发展轨迹改变 PFC 的接受性对于有效干预预防性治疗是必要的。全氟碳化物接受性很大程度上是由边缘输入的 PFC 中的谷氨酸活动驱动的，因此皮质边缘连接的 ELS 需要描绘。拟议项目的目标是 ELS 暴露的男性和女性 PFC 功能障碍的发育起源。中心假设是 ELS 以性别特异性方式改变 PFC 神经支配和谷氨酸感受性的发育。这些研究将首先揭示性别特异性 ELS 对皮质边缘连接的影响（目标 1）和整个发展过程中的神经支配（目标 2）。 ELS 对 PFC 连接的影响将提供转化数据可与最近暴露于 ELS 的男孩和女孩的临床发现并列将阐明 ELS 如何导致晚年受体改变背后的可能机制。目标3将研究 ELS 后突触后 NMDA 受体亚基变化的发育轨迹。我们还将确定停用 PFC NR2A 功能可以防止 ELS 诱发的关键时期晚年的行为缺陷。由于最近的证据表明女性表现出较早的 ELS 归因比男性发生变化，我们将确定女性是否需要比男性更早的干预预防 ELS 引起的行为功能障碍。这些研究将共同填补知识领域的关键空白关于 ELS 对 PFC 电路的影响的发育和性别特异性，预计对制定 ELS 暴露预防的具体目标具有重大影响人口。