Epidemiological evidence indicates that adolescence represents a period of increased vulnerability to the development of depression, specifically depression that is treatment-resistant. Moreover, treatment options for depressed adolescents are more limited than for adults, and depression onset in adolescence increases the risk of smoking, obesity, substance abuse, unemployment, and depression recurrence across the lifespan. These outcomes may relate to the effects of adversity-such as social isolation or stress hormone exposure- on the prefrontal cortex, which reaches full structural maturity only at the end of adolescence. We and others have hypothesized that the long-term effects of adversity on cellular structure within the prefrontal cortex may be exaggerated when it coincides with the marked neural plasticity of adolescence, and may thereby have additive, persistent, and perhaps even permanent consequences. Empirical evidence is limited, however, because little is known about the behavioral impact of biological events that coordinate structural maturation during adolescence under typical, much less pathological, circumstances. To fill this gap in current knowledge, we will first isolate the neurobiological consequences of early-life adversity on the structure of deep-layer prefrontal cortical neurons. We will utilize in vitro and in vivo imaging, as well as two mouse models of depression that have been developed for male and female adolescents, respectively. This is crucial because adolescent-emergent depression is more common among women, yet female populations remain grossly understudied. Next, to test the potential for therapeutic interventions that target the molecular mechanisms of prefrontal cortical cellular refinement, we will screen two pharmacological compounds that act on regulators of the actin cytoskeleton, measuring their antidepressant-like efficacy.
We aim to block the long-term behavioral consequences of early-life adversity. Finally, because depression attenuates reward sensitivity, disrupts decision-making processes essential to accomplishing goals, and diminishes motivation to perform even everyday tasks, we will, as a last aim, use viral-mediated gene silencing and modified surgical disconnection techniques to simultaneously isolate the molecular and neuroanatomical mechanisms of goal-directed action selection. We will focus on molecular interactions critical to postnatal structural refinement: Brain-derived Neurotrophic Factor binding to the high- affinity trkB receptor and formation of the p120RasGAP-p190RhoGAP signaling complex. This proposal is uniquely suited to the NIMH BRAINS program: Using diverse experimental approaches, and drawing on an advisory committee comprised of luminaries in the field, we will chart the trajectory of cellular and behavioral outcomes after early-life adversity;we will refine novel treatment approaches to depression psychopathology in understudied populations;and we will isolate developmental and molecular mechanisms of core components of psychiatric disease.
Abundant epidemiological evidence indicates that adolescence is a period of increased vulnerability to the development of depression that is persistent and treatment-resistant. These outcomes may relate to the effects of adversity-such as social isolation-on prefrontal cortical neuronal refinement during adolescence. We will identify common molecular regulators of structural refinement in adolescence and of adolescent-emergent depressive-like behavior in order to develop strategies to pharmacologically arrest cellular and behavioral decline.
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