Thursday, April 25, 2024
4/25/2024
Project Summary This proposal centers on the role of the paraventricular nucleus of the thalamus (PVT) in mediating the impact of early life adversity (ELA) on reward-seeking behaviors later in life. I will identify and characterize PVT neuronal populations that are engaged by ELA, test the hypothesis that these neurons execute the enduring effects of ELA on reward-seeking behaviors, and investigate a potential mechanism behind this process. Early life adversity (ELA) consisting of factors such as poverty, trauma, or chaotic environment impacts the lives of over 30% of children in the United States. ELA is associated with poor cognitive and emotional health and increased risk for affective disorders, including depression, PTSD, and addiction, which involve aberrant reward- circuit function. Studies in animals have demonstrated causal relations between ELA and impaired reward- seeking behaviors and enable the establishment of underlying neurobiological mechanisms. It is crucial to understand these associations, because ELA and its consequences, unlike genetic contributors to vulnerability to psychopathologies, may be amenable to prevention or mitigation. The paraventricular nucleus of the thalamus (PVT) is an important component of the reward circuit that encodes remote emotionally-salient experiences to influence future reward-related behaviors. However, it remains unknown if the PVT encodes experiences as remote as ELA and whether PVT neurons activated during ELA contribute to deficits in reward-seeking behaviors later in life. Building on my robust preliminary data and a potent validated naturalistic model of ELA in mice, which provokes deficits in reward-seeking behaviors later in life, my central hypothesis states that PVT neuronal populations are activated during ELA and contribute to ELA- provoked deficits in reward-seeking behaviors later in life. To test this hypothesis I will (a) capitalize on a transgenic mouse for activity-dependent genetic labeling [Targeted Recombination in Active Populations (TRAP2) mice] to determine the the location of neuronal populations within the PVT that are activated by ELA and establish their molecular identity; (b) use chemogenetics to probe the role of PVT neurons activated during ELA in governing reward behaviors later in life; (c) establish the differential PVT activation during reward-seeking behaviors in adult ELA and control mice, with a potential role in the observed behavioral impairments. Together, the proposed experiments will provide critical information about the developmental functions of the PVT and its contributions to the impact of ELA on reward-seeking behaviors, significantly advancing our understanding of the neurobiological mechanisms underlying reward-related psychopathologies.
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