Adverse early life experiences such as prolonged child neglect and abuse increase the risk of developing mental health disorders including substance abuse and psychiatric disorders in childhood, adolescence and adulthood. Understanding the consequences of child abuse and neglect on early brain development and neural processes that shape memories and guide behaviors based on past experiences are important goals of research aiming to improve prospects for successful treatment of abused children. Pathological reward-dependent learning within the ventral tegmental area (VTA) and the subsequent dysregulation of dopamine (DA) signaling from the VTA seems to be central to the onset of addiction and stress-related disorders, suggesting the potential therapeutic benefits of selective intervention in this brain area in treatment of such disorders. A single 24h episode o early maternal deprivation (MD) in rodents is widely used as an animal model of severe early life stress. Studies using this model have provided a strong link between the dysregulation of DA signaling and a later propensity to develop stress-related disorders. However it is still unknown how early MD affects the reward learning processes in the VTA. In this proposal, we will test our hypothesis that MD triggers epigenetic mechanisms that selectively reduce expression of critical memory-associated genes that support GABAergic plasticity in the VTA, and these epigenetic changes in part contribute to the development of later psychopathology. Our preliminary data also indicate that MD selectively disrupts GABAergic plasticity in the VTA through epigenetic modifications of critical signaling molecules underlying this plasticity. We will use a combination of molecular, cellular, immunohistochemical, biochemical, epigenetic, and behavioral techniques in nave, maternally-deprived (MD), and non-maternally-deprived (non-MD) juvenile rats to drive a mechanistic understanding of experimental MD that may be highly applicable to recovery of child abuse and neglect. Understanding the effects of MD on neurons in the VTA will expand our knowledge of an important but neglected part of the cellular basis of child abuse and neglect. Consequently, we will identify novel mechanisms in the regulation of synaptic plasticity, memory formation and DA signaling within the VTA that can be selectively targeted in a cell-type and circuit-specific manner in the period immediately following an episode of MD or other severe stress during early development.
Child neglect and abuse is a pervasive and costly public health concern with serious negative long-term effects on child health and development including the increased risk of developing mental health disorders and substance abuse in later life. Therefore, understanding the consequences of child abuse and neglect on neural processes induced by negative experiences that shape memories and guide behaviors are important goals of research aiming to provide early psychological and pharmacological interventions to improve children's outcomes. The proposal seeks to provide a mechanistic understanding of early life stress-induced neuroplasticity in the ventral tegmental area (VTA: an important part of the brain reward circuitry involved in reward perception and reward memories) that can be targeted in early stages after trauma to limit or reverse the neuroadaptations induced by such traumas. Our findings should help to prevent the harmful neurobiological and psychopathological consequences of severe early life stresses to which too many children are exposed.
