Postpartum Depression and Parenting: Role of mPOA circuits in maternal sensitivity

项目摘要 母亲的行为对后代的需要敏感，这对后代的健康发育至关重要， 人类的情绪健康;然而，允许这种动态的神经回路和神经生物学机制 协调还没有得到很好的理解。我们先前在大鼠中的工作表明，内侧视前区（mPOA）， 在调节母性行为的回路中的一个关键节点，在这种关键的母性能力中起着至关重要的作用。 （这里指母亲敏感性），让母亲及时灵活地调整生育行为 来满足后代不断变化的需求产后抑郁症是一个严重的健康问题 影响着全世界的妇女和她们的婴儿，往往对新妈妈的能力产生悲剧性的影响， 细心照顾她的孩子。我们的总体目标是提供急需的机械洞察力， 神经生物学机制，产妇的敏感性受到产后抑郁症的损害。到 为了实现这一目标，我们将使用交叉病毒战略，并利用Wistar-Kyoto的许多优势， (WKY)抑郁症动物模型的分子，电路水平和行为分析。我们以前的工作 表明WKY母鼠表现出相对于对照品系的行为缺陷综合征， 密切模拟产后抑郁症的主要临床特征，包括母体敏感性障碍。 这项建议建立在我们以前的研究结果，通过检查mPOA神经元，项目的边缘下 皮层（mPOAàIL，AIM 1）和腹侧被盖区（mPOAàVTA，AIM 2）参与了母体的 灵敏度这两种结构都接受来自mPOA的直接输入，长期以来一直与认知和 目标导向行为的动机方面，包括育儿和抑郁。第一组 实验将使用Cre依赖的抑制性（hM 4Di）或兴奋性（hM 3Dq）设计者的组合注射 受体专门激活的设计师药物（DREADD）进入mPOA，与逆行转导 将CAV 2-Cre病毒导入IL或VTA，以评估这些途径的功能必要性和充分性， 母性敏感我们还将使用GCaMP 6s与CAV 2-Cre的组合来选择性地监测GCaMP 6s的活性。 mPOAàIL和mPOAàVTA神经元，而WKY和对照组母亲与具有不同需求的后代互动。 考虑到母亲敏感性受损对母亲和儿童健康的影响， 临床意义，以了解神经生物学有助于这一关键的母亲的能力。这项建议会 产生关于大脑如何计算动态修改的关键新知识， 敏感的母性行为模式

Project Summary Maternal behavior that is sensitive to the needs of the offspring is essential for healthy development and emotional wellbeing in humans; yet the neural circuits and neurobiological mechanisms that allow such dynamic coordination are not well understood. Our prior work in rats demonstrates that the medial preoptic area (mPOA), a critical node in the circuitry regulating maternal behavior, plays an essential role in this critical maternal ability (referred to here as maternal sensitivity), allowing mothers to promptly and flexibly adjust caregiving behaviors to resolve the constantly changing needs of their offspring. Postpartum depression is a serious health problem affecting women and their babies worldwide, often with tragic implications for the new mother’s ability to sensitively care for her child. Our overall objective is to provide much-needed mechanistic insight into the neurobiological mechanisms by which maternal sensitivity is compromised by postpartum depression. To achieve this goal, we will use intersectional viral strategies and leverage the many strengths of the Wistar-Kyoto (WKY) animal model of depression for molecular, circuit-level and behavioral analysis. Our previous work demonstrated that WKY mother rats exhibit a syndrome of behavioral deficits relative to control strains that closely model major clinical features of postpartum depression, including disturbances in maternal sensitivity. This proposal builds on our previous findings by examining how mPOA neurons that project to the infralimbic cortex (mPOAàIL, AIM 1) and the ventral tegmental area (mPOAàVTA, AIM 2), contribute to maternal sensitivity. Both structures receive direct input from the mPOA and have long been implicated in cognitive and motivational aspects of goal-directed behaviors, including parenting and depression. The first group of experiments will use combined injections of a Cre-dependent inhibitory (hM4Di) or excitatory (hM3Dq) designer receptors exclusively activated by designer drugs (DREADD) into the mPOA, with a retrograde transducing CAV2-Cre virus into the IL or VTA to assess the functional necessity and sufficiency of these pathways for maternal sensitivity. We will also use GCaMP6s combined with CAV2-Cre to selectively monitor the activity of mPOAàIL and mPOAàVTA neurons while WKY and control mothers interact with offspring with varying needs. Considering the consequences of impaired maternal sensitivity on both mother and child health, it is of major clinical significance to understand the neurobiology contributing to this critical maternal ability. This proposal will generate critical new knowledge on how the brain computes dynamic modifications in need signals to generate sensitive patterns of maternal behavior.