Tuesday, April 23, 2024
4/23/2024
Adolescence is an age of increased vulnerability to psychopathology, including drug abuse. My work concerns the molecular events underlying the maturation of the medial prefrontal cortex (mPFC) in adolescence and the effect of stimulant drugs on these processes. My ultimate goal is to unravel the molecular factors mediating risk and resilience in adolescence to the deleterious effects of drugs of abuse in males and females. Our work has focused on the impact of amphetamine (AMPH) on the development of the dopamine (DA) innervation to the mPFC. We discovered that DA axons are still growing toward the mPFC across adolescence, remaining particularly susceptible to disruption. This delayed DA axon growth is controlled by the guidance cue receptor DCC, which determines whether, when, and where DA axons stop or continue to grow. Notably, AMPH in early adolescence dysregulates DCC expression and also induces profound changes in mPFC DA synaptic connectivity/function and causes deficits in cognitive control in adulthood. Until very recently all our studies have been focused on male mice only. In addition, we have been investigating only AMPH effects of doses that reach plasma levels equivalent to those seen in recreational drug users. Our recent preliminary data suggest, however, that the vulnerability to the effects of AMPH on mPFC DA development is sex-specific. Also, recently published results show that therapeutic-like doses during this time induce opposite, even beneficial enduring effects. The experiments now proposed are designed to test the following working hypotheses: (a) that the vulnerability to AMPH-induced disruption of mPFC development at particular adolescent time windows is sexually biased, (b) that this dimorphism also impacts detrimental drug effects on adult cognitive processing, (c) that sex-specific control over DCC receptor expression in DA neurons mediates differential drug vulnerability/resilience (d) that these effects are dependent upon recreational- versus therapeutic-like exposure. Methods: To address these questions, we will conduct molecular, anatomical, neurochemical, and behavioral experiments in male and female mice. Our studies will combine dual viral transduction strategies and quantitative neuroanatomical analyses to track DA axon targeting and growth in adolescence. To measure DA function, we will use novel and temporal-sensitive measurements of in vivo DA signaling (dLIght1) in freely moving mice. To identify mechanisms underlying the dimorphic vulnerability to AMPH, we will perform gain- and loss-of-function experiments using neuron optimized CRISPR and Cre-Lox recombination strategies.
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