Environmental modulation of maternal behavior and mesolimbic DA function

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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.