Dissecting neural circuits underlying early life stress-induced PFC dysfunction

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Project Summary Autism Spectrum Disorders (ASDs) comprise a group of severe neurodevelopmental disorders that are typified by communication deficits and social impairment. Given that the onset of symptoms occurs by the age of 3, it is largely agreed that neuronal dysfunction arises during early brain development. A developing brain shows a remarkable capacity for plastic changes in response to experiences; thus, its development is most vulnerable to the environmental factors that can derail normal brain function. Exposure to early life stress in the form of abuse/neglect during a critical period of brain development has demonstrated behavioral and psychological deficits that closely resemble autistic symptoms in both animal models and human studies. Thus, it is essential to identify the neural mechanisms underlying early life stress-induced social dysfunction for the development of treatment strategies for complex behavioral deficits in children with ASD. Recent studies have shown that early life stress in rodents induces long-lasting brain alterations similar to the deficits seen in patients with ASDs, including dysfunctions in the prefrontal cortex (PFC) and the stress/reward-related circuitry originating in the ventral tegmental area (VTA). Formation of excitatory synapses in the PFC is known to be essential for the initial establishment of functional neural circuits. Conversely, disrupted synapse development impairs PFC function and is thought to underlie the pathology of multiple neurodevelopmental disorders. The PFC is densely innervated by dopaminergic axon terminals and associated with higher cognitive processes that may be disrupted in illnesses such as ASDs. In this R21 proposal, we utilize a novel combination of methods including early social deprivation stress paradigm and two-photon imaging and uncaging to test our hypothesis that early life stress-induced dysregulation of PFC-projecting dopamine neurons constitutes a neural mechanism by which adverse events early in life alter PFC function and may cause behavioral dysfunction in adulthood. Guided by strong preliminary data, we will examine this hypothesis in two specific aims: 1) Define functional changes in PFC-projecting VTA dopamine neurons following early life stress. 2) Determine mechanisms of dopamine- induced synapse development in the PFC following early life stress. Results from these studies will further our understanding of the unique and detailed mechanisms by which dopamine regulates brain development, with critical relevance to cellular underpinnings of neurodevelopmental disorders. Approximately 1 per 100 children in the U.S. is a victim of abuse and neglect. We expect that our results will highlight new avenues into the investigation of the pathophysiology underlying neurodevelopmental disorders resulting from early perturbation of dopamine signaling.