SPECIFIC AIMS
Mechanisms and reversal of habitual decision-making after early-life cocaine PI: Shannon L. Gourley,
Assistant Professor, Dept. Pediatrics, Yerkes National Primate Research Center, Emory School of Medicine
Background & Significance
Abundant epidemiological evidence indicates that adolescence represents a period of increased
vulnerability to the development of addiction; that adolescent drug addiction markedly increases risk of relapse
in adulthood; and that cocaine exposure in particular during adolescence has both immediate and long-term
negative consequences for decision-making and higher-order cognition. All of these outcomes may relate to
the effects of psychostimulants 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 psychostimulant exposure on
neuronal structure within the prefrontal cortex may be exaggerated when psychostimulant abuse coincides with
the marked neural plasticity of adolescence and thereby have additive, persistent, and perhaps permanent
consequences. Empirical evidence is limited, however, because little is known about the biochemical events
that coordinate wide-scale structural refinement during adolescence under typical, much less pathological,
circumstances. This is despite the potential for therapeutic interventions that target the molecular signaling
cascades that orchestrate prefrontal cortical refinement.
β1-integrin is a receptor for extracellular matrix proteins that serve to anchor neurons and allow for growth
and neuroplasticity. β1-integrin expression was recently implicated in addiction in two independent human
populations and is also regulated by cocaine in experimental animals. This is relevant to adolescents because
during adolescence, β1-integrin binding activates p190RhoGAP, one of the few known signaling factors that
orchestrates neuronal maturation during this late developmental period. We have shown that p190RhoGAP
and its partner Arg mitigate sensitivity to cocaine and methylphenidate, providing empirical support for the
perspective that dendritic spine refinement confers resilience to the long-term consequences of cocaine.
Here we will show evidence that cocaine exposure during adolescence but not preadolescence or
adulthood biases decision-making strategies from those governed by goal-directed action-outcome associative
contingencies to those driven by stimulus-response habits. Concurrently, dendritic spine refinement across
adolescence is derailed, and dendritic spines are eliminated in the orbitofrontal prefrontal cortex. We propose
to test the hypothesis that genetic manipulation of p190RhoGAP and the downstream Brain-derived
Neurotrophic Factor (BDNF) within the orbitofrontal cortex will recapitulate the long-term consequences of
adolescent cocaine exposure. We will identify whether orbitofrontal cortical p190RhoGAP and BDNF confer
resilience to the development of stimulus-response habits by supporting the development of a major regulatory
circuit that connects the prefrontal cortex with the dorsomedial striatum. We will also test the therapeutic-like
properties of pharmacological agents that act on p190RhoGAP, BDNF, and NMDA receptors. Finally, we will
ascertain whether adolescent-emergent decision-making traits are: 1) heritable, and 2) predictive of cocaine
self-administration and reinstatement in adulthood. Throughout, morphological characteristics of deep-layer
orbitofrontal cortical dendritic spines will be catalogued using GFP-expressing mice and high-resolution 3-D
cellular reconstruction to ascertain the relationship between cellular ontogeny and behavioral outcomes.
There are no current pharmacological treatments for cocaine addiction at any age; this proposal aims to
better characterize the neurobiological consequences of adolescent cocaine exposure with the ultimate goal of
developing specialized pharmacotherapies to treat substance abuse disorders.
Specific Aim I: To identify molecular and neuroanatomical mechanisms of stimulus-response
decision-making. We will test whether site-selective genetic manipulations p190RhoGAP and BDNF confer
vulnerability to the development of stimulus-response habits, and whether these vulnerabilities emerge through
disruption of orbitofrontal – striatal interactions during postnatal critical periods.
Specific Aim II: To develop therapeutic approaches to reversing cocaine-induced habits. We will
identify the efficacy of pharmacological compounds that amplify p190RhoGAP / BDNF signaling in reversing
cocaine-induced stimulus-response habits. Dendritic spines in the orbitofrontal cortex will be cataloged with the
expectation that dendritic spine morphology and density will mirror behavioral outcomes. Targeted infusions of
latrunculin A will be used to confirm that behavioral outcomes depend on structural reorganization.
Specific Aim III: To identify adolescent-emergent predictors of long-term behavioral outcomes. In
this final aim, we will ascertain whether self-administered, rather than experimenter-administered, cocaine
during adolescence biases decision-making strategies in adulthood. Conversely, we will use selective breeding
to exaggerate decision-making traits and identify how adolescent-emergent behavioral characteristics predict
cocaine sensitivities in adulthood. Finally, we will evaluate the consequences of adolescent corticosteroid
exposure and environmental enrichment on stimulus-response decision-making. Throughout, we will compare
prefrontal cortical dendritic spine profiles between typically developing, high-risk, and resilient populations.