Motivational and Cognitive Circuit Mechanisms of Environmental Toxin-Induced Risk for Psychiatric Disorders. - Millions of Americans suffer from deficits in reward processing and working memory, in the context of psychiatric disorders, such as major depressive disorder, schizophrenia, and attention deficit hyperactivity disorder. Socioeconomically disadvantaged individuals experience disproportionate levels of early life stress (ELS) and exposure to environmental pollution, which increase the risk of developing these disorders. We hypothesize that exposure to these environmental insults disrupt the specific brain circuits needed for reward processing and working memory. Critically, only invasive animal studies can directly causally test the causal relationship between environmental exposure, brain circuit pathology, and deficits in reward processing and working memory. Such studies rely on the evolutionarily conserved circuitry that underlies domain-general cognitive processes. For example, the ability to learn about predictable rewards relies on ventral tegmental area (VTA) dopamine (DA) neuron computations of reward prediction error (RPE), while working memory to depends on neural activity in the hippocampus (HC). Our preliminary experimental studies in mice reveal that early exposure to pollution and stress alter DA circuitry and the behavioral response to unexpected outcomes. We also find that ELS disrupts the ability to maintain sequences while navigating by altering HC circuitry. These data raise the possibility that exposure to ELS and pollution cause reward processing and working memory deficits by disrupting VTA DA and HC circuits. Crucially, the HC and DA system (particularly projections from the ventral tegmental area [VTA]) work in tandem for both reward processing and working memory. We therefore propose to systematically test how ELS and diesel fuel interact to disrupt HC and VTA structure and function to cause enduring deficits in RPE and WM. Aim 1 will test how ELS and diesel fuel exposure (alone and in tandem) impact VTA circuitry and reward learning and WM. Aim 2 will test how these environmental insults impact HC circuitry and reward learning and WM. Finally Aim 3 will test how ELS and diesel fuel pollution impacts VTA-HC interactions during reward learning and WM. To do so, we will use state- of-the-art circuit dissection, optogenetics manipulation, and in vivo neural recording approaches. Experiments from this proposal will yield a comprehensive understanding of how neurotoxic pollutants and ELS impact the evolutionarily conserved circuits and cognitive functions that underlie the reward processing and concentration deficits that cut across multiple psychiatric disorders. This knowledge will prove critical for informing policy to mitigate environmental injury as well as for designing circuit-based interventions for symptoms caused by early life pollution and stress exposure.
