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

产后抑郁症和育儿：mPOA 回路在母亲敏感性中的作用

• 批准号: 10726256
• 负责人: Mariana Pereira Arboleya
• 金额: $ 41.82万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726256
• 关键词: Affect; Animal Model; Behavior; Behavioral; Brain; Calcium; Canine Adenoviruses; Child; Child Abuse and Neglect; Child Care; Child Health; Child Rearing; Clinical; Cognitive; Coupled; Data; Development; Drug Combinations; Enterobacteria phage P1 Cre recombinase; Exhibits; Exposure to; Fiber; Genetic; Goals; Health; Health Benefit; Human; Impairment; Incidence; Infant; Injections; Intervention; Investigation; Knowledge; Maternal Behavior; Medial; Mental Depression; Methods; Modeling; Modification; Molecular; Monitor; Mothers; Motivation; Neurobiology; Neurons; Pathway interactions; Pattern; Personal Satisfaction; Photometry; Play; Postpartum Depression; Prefrontal Cortex; Preoptic Areas; Public Health; Rattus; Research; Role; Signal Transduction; Structure; Syndrome; Technology; Testing; Ventral Tegmental Area; Viral; Well in self; Woman; Work; adverse outcome; caregiving; child neglect; clinically significant; depression model; depressive symptoms; designer receptors exclusively activated by designer drugs; effective intervention; experimental group; experimental study; flexibility; health of the mother; in vivo monitoring; insight; neural circuit; neurobiological mechanism; neuromechanism; offspring; pre-clinical; response; severe mental illness; success; virus Cre recombinase

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.

项目概要 对后代需求敏感的母亲行为对于健康发展和发育至关重要。 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 我们之前对大鼠的研究表明，内侧视前区（mPOA）， 调节母性行为的电路中的关键节点，在这种关键的母性能力中发挥着重要作用 （这里指母体敏感性），让妈妈们能够及时做出行为，灵活调整照顾方式 解决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及其婴儿，往往对新妈妈的能力产生悲剧性影响 我们的总体目标是提供急需的机制洞察力来照顾她的孩子。 产后抑郁症损害母亲敏感性的神经生物学机制。 为了实现这一目标，我们将采用交叉病毒式传播策略并利用 Wistar-Kyoto 的众多优势 （WKY）用于分子、回路水平和行为分析的抑郁症动物模型。 与对照品系相比，WKY 母鼠表现出行为缺陷综合症 模拟产后抑郁症的主要临床特征，包括母亲敏感性的紊乱。 该提议建立在我们之前的研究结果之上，通过检查 mPOA 神经元如何投射到下边缘 皮质（mPOAàIL，AIM 1）和腹侧被盖区（mPOAàVTA，AIM 2），有助于产妇 这两种结构都接收来自 mPOA 的直接输入，并且长期以来都与认知和敏感性有关。 目标导向行为的动机方面，包括养育子女和抑郁症。 实验将使用 Cre 依赖性抑制 (hM4Di) 或兴奋 (hM3Dq) 设计器的组合注射 受体专门由设计药物 (DREADD) 激活进入 mPOA，并具有逆行转导 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 我们还将使用 GCaMP6 与 CAV2-Cre 结合来选择性监测母体敏感性。 mPOAàIL 和 mPOAàVTA 神经元，而 WKY 和对照母亲则与具有不同需求的后代相互作用。 考虑到孕产妇敏感性受损对母婴健康的影响，这一点具有重大意义。 该提案对于了解有助于这种关键母性能力的神经生物学具有临床意义。 生成关于大脑如何计算需要信号的动态修改以生成的关键新知识 母亲行为的敏感模式。