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， 母婴互动的质量（即产妇护理）。例如，经历产后逆境的母亲 可能对婴儿失去兴趣，难以照顾婴儿的需要。然而，神经 不利的母性环境导致异常母性行为的机制仍然不清楚 明白一个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），并主要参与奖励相关的过程，包括母性行为，以及 抑郁症的病理生理学。重要的是，在患有PPD的女性中观察到DA失调， 在与抑郁症研究相关的啮齿动物模型中的研究表明，DA系统与抑郁症之间存在因果关系。 失调（即降低的VTADA神经元活性）和负面的情感相关行为（即快感缺乏， 被动应对）。因此，产后逆境引起的腹侧被盖区DA神经元活性受损可能会干扰 与奖励相关的过程是母亲的动机和反应所必需的。然而，人们对 产后啮齿动物DA系统功能在基线和逆境条件下的调节。的 该提案的总体目标是确定不利的产后环境的影响，如以下模型所示： 从产后第2-9天开始为母鼠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制作用 （目标1）。这项工作将为今后的实验奠定必要的基础， 类型特异性在体内光学记录的遗传鉴定腹侧被盖区DA神经元的表达过程中的母体 随着时间的推移，适应（控制）和适应不良状态（LBN）的行为，同时还能够评估时间- 锁定行为/DA反应（目的2），并因果操纵潜在的神经回路驱动LBN诱导 VTA DA功能的改变（目的3）。重要的是，这些目标是基于我的初步数据显示， 破坏母婴相互作用和减弱腹侧被盖区DA活性的LBN母鼠。在颁奖期间，我将 使用一个综合的系统导向的方法，包括行为测定，激素测量，体内 电生理学和纤维光度学，以及化学发生学方法，使因果操纵 参与VTA DA活性调节的特定细胞和回路。这一建议涉及一个重要的 知识的差距，是符合NIMH的使命，以增加对女性的研究，以提高妇女的 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 （通过我的顾问团队/共同导师的帮助），这将帮助我开始一个独立的研究生涯。