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

项目摘要 对子女的需求敏感的母性行为对于健康的发育和 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机制 协调并没有得到很好的理解。我们先前在大鼠身上的工作表明，内侧视前区(MPOA)， 这是调节母性行为的回路中的一个关键节点，在这一关键的母性能力中起着至关重要的作用 (这里指的是母性敏感)，允许母亲迅速、灵活地调整照顾行为 以满足其后代不断变化的需求。产后抑郁症是一个严重的健康问题。 影响世界各地的妇女及其婴儿，往往对新母亲的能力产生悲剧性的影响 细心地照顾她的孩子。我们的总体目标是提供亟需的机械洞察 产后抑郁影响母体敏感性的神经生物学机制。至 为了实现这一目标，我们将使用跨部门的病毒战略，并利用威斯塔尔-京都的许多优势 (WKY)抑郁症动物模型，用于分子、电路水平和行为分析。我们之前的工作 证明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。 这一建议建立在我们之前的发现的基础上，研究了mPOA神经元是如何投射到下缘的 大脑皮层(mPOAàIL，AIM 1)和腹侧被盖区(mPOAàVTA，AIM 2)对母体 敏感度。这两种结构都接受mPOA的直接输入，长期以来一直被认为与认知和 目标导向行为的激励方面，包括育儿和抑郁。第一批 实验将使用依赖CRE的抑制性(HM4Di)或兴奋性(HM3Dq)设计器的组合注射 由特制药物(DREADD)专一激活的受体进入mPOA，并通过逆行转导 CAV2-Cre病毒进入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GCaMP6结合CAV2-CRE来选择性地监测 MPOA？IL和mPOA？VTA神经元，而WKY和对照母亲与具有不同需求的后代相互作用。 考虑到母亲敏感度受损对母亲和儿童健康的影响，它具有重大意义 了解神经生物学对这一关键母体能力的贡献具有临床意义。这项提议将 生成关键的新知识，了解大脑如何计算需要的动态修改信号以生成 母性行为的敏感模式。

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.