When and Where Stress Leaves a Mark: Circuit Insights Into Developmental Vulnerability
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The experience of stress during childhood, both acute and chronic, is a significant risk factor in the development of psychiatric disorders in later life. Avoidance of social interaction and social deficits are common shared characteristics of a number of these disorders, indicating that peri-adolescent stress may affect the developmental trajectory of nascent neuronal circuits underlying social behavior. Thus, this thesis investigates stressors capable of causing persistent changes in behavior – in the form of generalized fear and social avoidance – and seeks to identify aberrations in circuitry that mediate these effects. We first investigate a maladaptive fear response in adult mice that mirrors aspects of Post-Traumatic Stress Disorder. Then, we establish a mouse preadolescent stress paradigm and find that a variable foot shock stress delivered within a specific developmental window produces impairments in social interaction at a remote adult time point. Thereafter, we focus on the projection from the medial orbitofrontal cortex (mOFC) to the basolateral amygdala (BLA), in which suppression of circuit activity produces a reduction in social interaction. mOFC projections to the BLA begin to form during preadolescence, overlapping with a critical period of social development. We hypothesize that adversity suffered within this period disrupts the development of this circuit and drives asocial behavior in adulthood. Using tract-tracing techniques, we show that acute preadolescent stress alters the physical structure of the mOFC-BLA circuit. Additionally, we record mOFC-BLA circuit activity during sessions of social interaction in awake, freely moving mice using fiber photometry, and show that circuit activity is muted in preadolescent stressed animals. These findings suggest that the developing mOFC-BLA circuit may provide a period of vulnerability and a conduit through which stressors can detrimentally affect later adult behavior. Last, we discuss limitations of current behavioral analysis and present a 3D tracking-based methodology we developed to automate the capture of complex behaviors. We also demonstrate its ability to detect behaviors that normally go unrecognized, expanding the behavioral palette for future studies.