Adolescence is a neurobiologically distinct developmental period characterized by high rates of experimental drug use and vulnerability to the development of substance abuse disorders. Adolescent substance abuse increases the likelihood of developing lifelong addiction, and cocaine addiction emerges with particular virulence-for example, 15-16% of adolescent cocaine users will develop dependence within 10 years of first exposure. Thus, identifying mechanisms of cocaine vulnerability is a critical research imperative. It is now widely accepted that psychostimulant exposure reorganizes dendritic spines within the prefrontal cortex, but whether the long-term consequences of cocaine exposure on neural structure are causally related to addiction vulnerability at any age represents a lively debate in the field. This is in part because few labs are equipped with the tools to model addiction in animal systems, to capture and enumerate dendritic spines, and to manipulate the molecular regulators of dendritic spine structure in discrete neurocircuits in order to isolate causal relationships. We will apply precisely these tools to identify the organizational and behavioral impact of adolescent cocaine self-administration, with the ultimate goal of reversing the adverse consequences of early- life cocaine exposure. As a model system, we use mice, which like humans, readily self-administer cocaine. We will focus on orbitofrontal cortical Brain-derived Neurotrophic Factor (BDNF) and its high-affinity receptor trkB. Postnatal BDNF expression is a critical determinant of adolescent cortical spine development and refinement. However, early-life stimulant exposure decreases Bdnf in the orbitofrontal cortex, a structure widely implicated in addiction pathology. Thus, BDNF systems may present a promising target in reversing the organizational and functional consequences of adolescent cocaine self-administration. We propose 3 discrete experiments using experimental protocols already established in my lab: 1) We will isolate and reconstruct in 3D deep-layer orbitofrontal cortical neurons from mice that had self- administered cocaine in adolescence and then showed either behavioral vulnerability or resilience to cocaine seeking and stimulus-response habit formation in adulthood. We hypothesize that cocaine vulnerability will be associated with neural simplification in deep-layer orbitofrontal cortex. 2) We will block the long-term behavioral effects of adolescent cocaine self-administration (context-induced cocaine seeking and stimulus-response habit formation) with neurotrophin-based intervention strategies. Specifically, we expect that treating cocaine-exposed adolescent mice with the novel trkB agonist 7,8-DHF will occlude the long-term negative impact of early-life cocaine self-administration. 3) Finally, we will test a neuroanatomical model in which orbitofrontal cortical Bdnf deficiency results in stimulus-response habits due to perturbations in an orbitofrontal-amygdala neurocircuit. Substantial preliminary findings support each aim and will ensure the completion of this project.

Public Health Relevance

Abundant epidemiological evidence indicates that adolescence is a period of increased vulnerability to the development of addiction, and that cocaine exposure during adolescence has both immediate and long-term negative consequences for complex decision-making and drug vulnerability. These outcomes may relate to the effects of psychostimulants on prefrontal cortical neuronal refinement during adolescence. We will identify developmentally-regulated molecular signaling cascades of action in order to pharmacologically target specific mechanisms towards therapeutic-like outcomes.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Lynch, Minda
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Emory University
Schools of Medicine
United States
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Swanson, Andrew M; DePoy, Lauren M; Gourley, Shannon L (2017) Inhibiting Rho kinase promotes goal-directed decision making and blocks habitual responding for cocaine. Nat Commun 8:1861
Zimmermann, Kelsey S; Yamin, John A; Rainnie, Donald G et al. (2017) Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor. Biol Psychiatry 81:366-377
DePoy, L M; Allen, A G; Gourley, S L (2016) Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences. Transl Psychiatry 6:e875
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Pitts, Elizabeth G; Taylor, Jane R; Gourley, Shannon L (2016) Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors. Neurobiol Dis 91:326-35
DePoy, Lauren M; Gourley, Shannon L (2015) Synaptic Cytoskeletal Plasticity in the Prefrontal Cortex Following Psychostimulant Exposure. Traffic 16:919-40
DePoy, Lauren M; Perszyk, Riley E; Zimmermann, Kelsey S et al. (2014) Adolescent cocaine exposure simplifies orbitofrontal cortical dendritic arbors. Front Pharmacol 5:228