Developmental exposure to lead and noradrenergic regulation of the acute stress response

PROJECT SUMMARY Anxiety and depression are stress-related disorders afflicting at least a quarter of the world’s population and imposing an enormous economic burden on societies. These disorders are highly comorbid owing to the fact that both stem from disruptions in the stress circuitry. An appropriate stress response relies on the proper development and functionality of noradrenergic (NA) signaling. Disruptions in this system can lead to behavioral alterations, which can onset or aggravate stress-related psychiatric disorders, including pathological anxiety and depression. Genetic susceptibility does not fully explain individual vulnerability, and thus, the environment is likely a significant factor contributing to their development. Developmental exposure to lead (Pb) affects a third of children worldwide and is associated with stress-related behavioral disorders. Despite the increasing incidence of these disorders, a significant gap exists in our understanding of the mechanisms underlying Pb-induced alterations in stress responses. The central aim of this study is to examine the role of NA signaling and its chief regulator, the locus coeruleus (LC) NA neurons, in mediating Pb-induced stress behavior phenotypes. Our preliminary investigations demonstrate aberrant stress responses for only trace Pb exposures, and pharmacological modulation of NA signaling can recapitulate Pb-induced behavioral phenotypes. Therefore, we hypothesize that early developmental exposure to Pb induces stress pathologies by disrupting NA signaling through its chief regulator, the LC/NA neurons. We will test this hypothesis through two specific aims: 1) To delineate the role of Pb- induced aberrant NA signaling in the propagation of altered stress responses and 2) To uncover the structural and functional changes by which early developmental Pb exposure alters the sensitivity of LC/NA neurons to subsequent stressors and Pb accumulation within this group of neurons. This R21 exploratory grant promises crucial insights into the overlooked role of Pb-induced insults to neuronal populations regulating the acute stress response, paving the way to more targeted therapeutic and mitigation strategies. It will also generate models readily adaptable for broader applications, encompassing other neuronal populations, environmental contaminants, or stressors. This project leverages the genetic tractability, transparency, and extrauterine development of the zebrafish model, along with cutting-edge technologies, to observe neural changes in the brain and their behavioral correlates non-invasively.