Neural Circuits of Vulnerability and Social Stress Susceptibility in Adolescent Chlorpyrifos Exposure

/ABSTRACT Major depressive disorder (MDD) is a leading and rising cause of disability in adolescents, a group undergoing rapid brain development and therefore uniquely vulnerable to environmental stressors that increase psychiatric risk. Chlorpyrifos, a widely used organophosphate pesticide, has been linked to neuropsychiatric symptoms in adolescents, but whether it directly induces symptoms or instead produces latent neurobiological changes that increase vulnerability to future stressors remains unclear. Most animal studies have focused on prenatal or adult exposures, leaving a critical gap in understanding how chlorpyrifos affects the adolescent brain and shapes long-term psychiatric risk. Preliminary data demonstrate subtle but consistent anhedonia-relevant behaviors following adolescent chlorpyrifos exposure; while these changes do not constitute full pathology, they suggest chlorpyrifos alters brain function in ways consistent with a latent vulnerability state—sensitizing the brain in ways that predispose the brain to exhibit MDD-relevant outcomes following subsequent stressors. Social stressors such as bullying and isolation, which are well-established contributors to adolescent-onset MDD, are also on the rise. Real-world exposures often involve multiple, co-occuring risks, underscoring the need to investigate their combined impact on the developing brain. The objective of this research is to use a translational mouse exposure model to identify MDD-relevant behavioral, immunological, and brain circuit changes following adolescent chlorpyrifos alone and in combination with social stress. I hypothesize that chlorpyrifos induces a vulnerability state, producing brain circuit and immune changes with minimal MDD- relevant behaviors, and that co-exposure with social stress leads to susceptibility, marked by the active emergence of MDD-relevant behaviors and pathology. In Aim 1, I will test whether chlorpyrifos alone induces neurophysiological and immunological changes without many behavioral effects. In Aim 2, I will assess how combined chlorpyrifos and social stress exposures influence MDD-relevant behavioral, brain circuit, and immune outcomes. This project will uncover, for the first time, how adolescent chlorpyrifos exposure changes brain-wide mechanisms relevant to MDD, both independently and in interaction with social stress. More broadly, this fellowship will provide integrated training in psychiatry, neuroscience, and environmental toxicology through individualized mentorship and guided research. The highly collaborative and interdisciplinary environment at the University of Iowa through the Iowa Neuroscience Institute and Environmental Health Science Research Center offers an ideal setting for this work. This training plan will support my development as a physician-scientist focused on how environmental exposures during sensitive developmental windows shape long-term brain health. My long-term goal is to help advance environmental health approaches within psychiatry and neuroscience to better protect child and adolescent mental health. Project Number: 1F30ES038750-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Michelle Chen | Institution: UNIVERSITY OF IOWA, IOWA CITY, IA | Award Amount: $42,660 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F02A-D (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11385094