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

本项目旨在阐明早期生活应激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引起的精神疾病表现在 在经过一个明显的潜伏期后进入青春期，对传统疗法没有反应。我们的实验室和 其他人进一步表明，这些可归因于ELS的效应在男性中遵循不同的时间过程， 女性因此，有必要了解异常的发展机制，可能需要 对接触ELS的个人进行有针对性的干预和治疗。我们最近的研究表明，ELS 导致前额叶皮层（PFC）中NMDA受体亚单位NR2A的过度表达 男性青少年。重要的是，NR2A的靶向操作保护了暴露于ELS的雄性， 行为缺陷，如焦虑样行为增加。我们的初步数据进一步表明， 暴露于ELS的女性在发育过程中出现NMDAR变化和焦虑增加， 与暴露于ELS的男性相比。了解ELS暴露与 并且改变PFC感受性对于有效地干预预防性治疗是必要的。PFC 感受性在很大程度上是由来自边缘系统输入的PFC中的谷氨酸活性驱动的，因此 皮质边缘连接的ELS需要描述。拟议项目旨在针对 暴露于ELS的男性和女性PFC功能障碍的发育起源。核心假设是 ELS以性别特异性方式改变PFC神经支配和谷氨酸受体的发育。 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）， 神经支配（目标2）在整个发展。ELS对PFC连接的影响将提供 翻译数据可以与ELS暴露男孩和女孩的近期临床发现并列， 将阐明ELS如何导致生命后期受体改变的可能机制。目标3将 探讨ELS后突触后NMDA受体亚单位变化的发育轨迹。我们 还将确定停用PFC NR2A功能可以防止ELS诱导的关键时期 行为缺陷由于最近的证据表明，女性表现出更早的ELS归因于 我们将确定女性是否需要比男性更早的干预， 防止ELS引起的行为功能障碍。总之，这些研究将填补知识的关键空白， 关于ELS对PFC电路影响的发育和性别特异性，预计 对制定暴露于ELS的特定预防目标具有重大影响。 人口。

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.