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

• 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
• 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

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.

项目摘要 在人类中，产后压力暴露与情绪障碍的风险增加有关 母亲相互作用的质量（即物心护理）。例如，经历产后广告的母亲 可能会对婴儿失去兴趣，并且很难照顾婴儿的需求。但是，中立 不利的母系环境导致异常母子行为的机制仍然很差 理解。一种潜在的途径是中脑脱脂胺（DA）系统，该系统起源于腹侧 对段区域（VTA），并与奖励相关的过程非常重要，包括母校行为和 抑郁的病理生理学。重要的是，在患有PPD的女性和 与抑郁症研究相关的啮齿动物模型的研究显示了DA系统之间的因果关系 失调（即VTA DA神经元活性降低）和与影响相关的行为（即Anhedonia， 被动应对）。那是产后广告引起的VTA DA神经元的妥协活动可能会干扰 具有孕妇动机和响应能力所需的奖励相关过程。但是，对 在基线和广告条件下，在产后啮齿动物中DA系统功能的调节。 该建议的总体目标是确定不良产后环境的影响， 在产后第2-9天，在母体上为大坝提供有限的床上用品和筑巢（LBN）材料 在测试压力马可皮质酮的机械作用时，行为和中脑da功能 （Cort）（AIM 1）。这项工作将为未来的实验奠定必要的基础，以进行细胞 - 在母体表达期间，特定于特定于体内的VTA DA神经元的体内光学记录 随着时间的推移，适应性（对照）和不良适应状态（LBN）的行为，同时还可以评估时间 锁定的行为/DA响应（AIM 2），并为操纵潜在的神经回路驱动LBN引起 VTA DA功能的变化（AIM 3）。重要的是，这些目标是基于我的初步数据 lbn大坝中的母亲相互作用破坏并减弱了VTA DA活性。在奖励期间，我将 使用集成的面向系统的方法，包括行为测定，荷尔蒙测量，体内 电生理学和纤维光度法以及化学发生方法，使因果关系能够因果关系 参与VTA DA活性调节的特定细胞和电路。该提案解决了一个重要的 知识的差距与NIMH增加女性的研究以改善妇女的使命是一致的 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 （在我的咨询团队/联合主管的帮助下），这将帮助我启动独立的研究职业。