Environmental modulation of maternal behavior and mesolimbic DA function

母亲行为和中脑边缘 DA 功能的环境调节

基本信息

批准号：
10613927
负责人：
Millie Rincon Cortes
金额：
$ 16.78万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613927
关键词：
Address Advisory Committees Affective Amygdaloid structure Anhedonia Attenuated Automobile Driving Award Beds Behavior Behavioral Behavioral Assay Caring Cells Childbirth Chronic Chronic stress Corticosterone Data Development Dopamine Down-Regulation Electrophysiology (science)Environment Event Exhibits Exposure to Female Fiber Functional disorder Future Genetic Globus Pallidus Goals Hormonal Hormones Human Hyperactivity Impairment Infant Knowledge Link Maternal Behavior Measurement Mediating Mediator Mental Depression Mental Health Mentors Metyrapone Mission Modeling Mood Disorders Moods Mothers Motivation National Institute of Mental Health Neural Pathways Optics Ovarian Pathway interactions Pharmacology Photometry Population Postpartum Depression Postpartum Period Process Pyramidal Cells Rat Transgene Rattus Regulation Research Resources Retrieval Rewards Risk Risk Factors Rodent Rodent Model Role Stress Structure Symptoms System Testing Time Transgenic Animals Ventral Tegmental Area Withdrawal Woman Work attenuation awake career cell type coping designer receptors exclusively activated by designer drugs dopamine system dopaminergic neuron experience experimental study genetic approach improved in vivo insight interest male maltreatment mesolimbic system motherhood negative affect neglect neural circuit neuromechanism pharmacologic pup response skills social

项目摘要

PROJECT SUMMARY In humans, postpartum stress exposure is associated with increased risk for mood disorders and compromised quality of mother-infant interactions (i.e. maternal care). For example, mothers that undergo postpartum adversity may lose interest in their babies and have difficult caring for their infant’s needs. However, the neural mechanisms by which adverse maternal environments contribute to aberrant maternal behavior remain poorly understood. One potential pathway is the mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA) and is critically involved in reward-related processes, including maternal behavior, and the pathophysiology of depression. Importantly, DA dysregulation has been observed in women with PPD and studies in rodent models relevant for the study of depression have shown a causal link between DA system dysregulation (i.e. decreased VTA DA neuron activity) and negative affect-related behaviors (i.e. anhedonia, passive coping). Thus, compromised activity of VTA DA neurons induced by postpartum adversity may interfere with reward-related processes necessary for maternal motivation and responsiveness. Yet, little is known about the regulation of DA system function in postpartum rodents at baseline and under conditions of adversity. The overall goal of this proposal is to determine the impact of an adverse postpartum environment, as modeled by providing the dam with limited bedding and nesting (LBN) materials from postpartum days 2-9, on maternal behaviors and mesolimbic DA function while testing a mechanistic role for the stress hormone corticosterone (CORT) (Aim 1). This work will lay the necessary groundwork for future experiments aimed at conducting cell- type specific in vivo optical recordings of genetically identified VTA DA neurons during the expression of maternal behavior in adaptive (control) and maladaptive states (LBN) over time, while also enabling assessment of time- locked behavior/DA responses (Aim 2), and causally manipulating potential neural circuits driving LBN-induced alterations in VTA DA function (Aim 3). Importantly, these aims are based on my preliminary data showing disrupted mother-infant interactions and attenuated VTA DA activity in LBN dams. During the award period, I will use an integrated systems-oriented approach including behavioral assays, hormonal measurements, in vivo electrophysiology and fiber photometry, and chemogenetic approaches that enable causal manipulations of specific cells and circuits involved in the regulation of VTA DA activity. This proposal addresses an important gap in knowledge, is consistent with the NIMH’s mission to increase research in females to improve women’s mental health, while enabling me to acquire new conceptual, technical, experimental and analytical skills (through the help of my Advisory Team/Co-Mentors) that will help me launch an independent research career.

项目概要在人类中，产后压力暴露与情绪障碍和受损的风险增加有关母婴互动的质量（即母亲护理）例如，经历产后逆境的母亲。可能会对婴儿失去兴趣，并且难以满足婴儿的需求。不良产妇环境导致异常产妇行为的机制仍然很薄弱一种潜在的途径是中脑边缘多巴胺（DA）系统，它起源于腹侧。被盖区（VTA），并且关键参与奖励相关过程，包括母亲行为和重要的是，在患有 PPD 的女性中观察到 DA 失调。与抑郁症研究相关的啮齿动物模型研究表明，DA 系统之间存在因果关系失调（即 VTA DA 神经元活性降低）和负面情绪相关行为（即快感缺乏、因此，产后逆境引起的 VTA DA 神经元活性受损可能会产生干扰。然而，人们对母亲动机和反应所必需的奖励相关过程知之甚少。产后啮齿类动物在基线和逆境条件下 DA 系统功能的调节。该提案的总体目标是确定不利的产后环境的影响，建模为从产后 2 至 9 天，为母亲提供有限的垫料和筑巢 (LBN) 材料行为和中脑边缘 DA 功能，同时测试应激激素皮质酮的机械作用（CORT）（目标 1）。这项工作将为未来进行细胞实验奠定必要的基础。母体表达期间遗传鉴定的 VTA DA 神经元的类型特异性体内光学记录随着时间的推移，适应（控制）和适应不良状态（LBN）的行为，同时还可以评估时间- 锁定行为/DA 反应（目标 2），并因果操纵驱动 LBN 诱导的潜在神经回路 VTA DA 功能的改变（目标 3）。重要的是，这些目标是基于我的初步数据显示的。中断母婴互动并减弱 LBN 母鼠的 VTA DA 活动在奖励期间，我会。使用集成系统导向的方法，包括行为测定、激素测量、体内电生理学和纤维光度测定法以及化学遗传学方法可以进行因果操作参与 VTA DA 活动调节的特定细胞和电路该提案解决了一个重要问题。知识差距，这与 NIMH 的使命是一致的，即增加对女性的研究，以改善女性的健康状况心理健康，同时使我能够获得新的概念、技术、实验和分析技能（通过我的顾问团队/共同导师的帮助）这将帮助我开展独立的研究生涯。