In humans, onset of depressive illness frequently occurs in the late adolescent period, often in conjunction with significant life stress. In additio, adolescent stress or trauma are frequently linked to later development of PTSD. Both disorders affect nearly twice as many women as men, suggesting a sexually dimorphic course of disease development. Notably, the adolescent period coincides with the terminal development of prefrontal cortex connectivity, which comprises the key cognitive-emotional circuit affected in both depressive illness and PTSD. The prefrontal cortex and its targets undergo aberrant structural rearrangement as a consequence of stress or stress hormone exposure in adults. Prior studies indicate that glucocorticoid stress hormone responses are exaggerated in adolescence, predicting that these groups may be selectively vulnerable to negative effects of stress on brain structure. Thus, adversity during adolescence may compromise the final development of this key emotional regulatory pathway, resulting in inappropriate mood regulation. This proposal uses a rat model to test the hypothesis that adolescent chronic stress produces short- and long-term reorganization of prefrontal cortical emotional control circuits, resulting in pronounced impairments in cortical regulation of mood, impulsivity, and stress reactivity.
Aim 1 uses a battery of behavioral and physiological tests to establish the impact of adolescent chronic stress and sex on depression-like behavior, extinction of fear conditioning, delayed response learning, and glucocorticoid homeostasis, functions controlled by the prefrontal cortex and known to be disrupted in depression and PTSD.
Aim 2 uses anatomical methods to test the integrity of prefrontal projection pathways, focusing on changes in synaptology of the prefrontal cortex and downstream targets and, using a novel viral tracing approach, the development of prefrontal efferent connectivity over time, again focusing on both males and females.
Aim 3 tests the role of glucocorticoid receptor signaling in immediate and lasting behavioral and endocrine effects of adolescent stress in males and females, using time-constrained knockdown of receptor synthesis during stress exposure. Together, these studies are expected to clearly identify a role for adolescent stress in prefrontal cortical pathologies in both males and females, and provide insight into possible interventions for minimizing development of stress-related diseases in both sexes.

Public Health Relevance

Depression and PTSD are debilitating mental illnesses that affect a substantial proportion of the population, and affects twice as many women as men. Onset of depression occurs most commonly during adolescence, and frequently coincides with significant life stressors. In addition, adolescent trauma or abuse is often connected with subsequent susceptibility to PTSD. Importantly, adolescence represents the time of terminal development of prefrontal cortical cognitive emotional circuits, and is also a period of marked stress sensitivity, suggesting a possible link between life adversity and brain pathology. This proposal uses rodent models to examine the link between adolescent stress and stress hormone signaling and subsequent development of prefrontal cortical pathology (both functional and anatomical) in males and females. Data obtained will provide novel information on brain mechanisms mediating stress effects on emotion, which will be of considerable value in the design of sex-specific interventions and therapies designed to attenuate the development of emotional pathologies during adolescence.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Zehr, Julia L
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University of Cincinnati
Schools of Medicine
United States
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