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.

该项目旨在阐明动物早期生命压力（EL）的发育神经记录作用模型。越来越多的临床证据表明，许多ELS诱导的精神疾病在明显的潜在时期之后的青春期，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-Atibutut效应遵循男性的不同时间，并且女性。因此，有必要了解可能需要的异常发展机制在暴露的个体中有针对性的干预和治疗。我们最近的研究表明ELS 引起谷氨酸能NMDA受体亚基NR2A的过表达（PFC）男性青少年。重要的是，针对NR2A受保护的ELS暴露的雄性的有针对性操纵行为缺陷，例如增加焦虑症行为。我们的初步数据进一步表明 NMDAR的变化和焦虑增加出现在ELS暴露的女性的发育中，与暴露于ELS的男性相比。了解ELS暴露之间的发展轨迹 PFC接受性的改变对于有效干预预防治疗是必要的。 PFC 接受性在很大程度上是由PFC中边缘输入中的谷氨酸活性驱动的，因此 Corticolimbic连接性上的EL需要划定。拟议的项目旨在针对 PFC功能障碍在ELS暴露的男性和女性中的发育起源。中心假设是 Els以性别特异性的方式改变了PFC神经和谷氨酸接受的发展。这些研究将首先揭示性别特异性EL对皮质胶质连通性的影响（AIM 1）和神经（目标2）在整个发展中。 ELS对PFC连接的影响将提供可以与ELS暴露的男孩和女孩的近期临床发现并置的翻译数据将阐明ELS以后生活的受体改变背后的可能机制。目标3意志 ELS后，研究突触后NMDA受体亚基的变化的发育轨迹。我们还将确定停用PFC NR2A功能可以防止ELS诱导的关键时期以后生活中的行为赤字。由于最近的证据表明，女性表现出早期的Els-Atibutut 比男性的变化，我们将确定女性是否需要比男性更早的干预措施防止EL诱导的行为功能障碍。这些研究一起将填补知识的关键空白关于ELS对PFC电路影响的发展和性别特定性质，预计将对ELS暴露的预防特定目标的发展产生重大影响人群。