Environmental modulation of maternal behavior and mesolimbic DA function

项目总结 在人类中，产后压力暴露与情绪障碍的风险增加有关，并与 母婴互动的质量(即产妇护理)。例如，经历产后逆境的母亲 可能会对婴儿失去兴趣，难以照顾婴儿的需求。然而，神经 不良孕产环境导致异常孕产行为的机制仍然很差 明白了。一种可能的途径是中脑边缘多巴胺(DA)系统，它起源于腹侧 被盖区(VTA)，主要参与奖赏相关的过程，包括母性行为，以及 抑郁症的病理生理学。重要的是，在PPD和PPD的女性中观察到DA调节失调 与抑郁症研究相关的啮齿动物模型的研究表明，DA系统之间存在因果联系 调节失调(即VTA DA神经元活性降低)和负面情感相关行为(即快感缺乏， 被动应对)。因此，产后逆境引起的VTA DA神经元活动受损可能会受到干扰。 与奖励相关的过程对于母亲的动力和反应是必要的。然而，人们对此知之甚少。 产后啮齿动物在基线和逆境条件下DA系统功能的调节。这个 这项提案的总体目标是确定不利的产后环境的影响，如 从产后第2天到第9天，为产妇提供有限的床上用品和筑巢材料(LBN) 测试应激激素皮质酮的机制作用时的行为和中脑边缘DA功能 (CORT)(目标1)。这项工作将为未来旨在进行细胞- 遗传鉴定的VTA DA神经元在母体表达过程中的特定类型体内光学记录 适应(控制)和不适应状态(LBN)随时间的行为，同时还支持对时间的评估- 锁定行为/DA反应(目标2)，以及因果操纵驱动LBN诱导的潜在神经回路 VTA DA功能改变(目标3)。重要的是，这些目标是基于我的初步数据显示的 LBN大坝中母婴相互作用中断，VTA DA活性减弱。在颁奖期间，我将 使用集成的面向系统的方法，包括行为分析、体内荷尔蒙测量 电生理学和纤维光度学，以及使因果处理成为可能的化学发生方法 参与调节VTA DA活性的特定细胞和电路。这项提案涉及一项重要的 知识差距，与NIMH增加女性研究以改善女性健康的使命一致 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)，这将帮助我开始独立的研究生涯。

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.