Adolescence is a critical period of vulnerability to develop drug abuse. This application is about the effects of stimulant drugs in adolescence on the development of the medial prefrontal cortex (mPFC), a brain region implicated in reward, motivation, and cognition. My long-term goal is to identify mechanisms whereby exposure to drugs of abuse in adolescence, as compared to adulthood, confers a higher risk for psychopathologies later in life. The proposed experiments are designed to assess the impact of amphetamine (AMPH) exposure in adolescence on the development of the dopamine (DA) innervation to the mPFC and to determine the role that DCC receptors play in this regard. DCC receptors respond to the guidance cue, netrin-1, to organize neuronal connectivity and are highly and conspicuously expressed by DA neurons in the ventral tegmental area (VTA) across the lifespan. My work in rodents is the first to identify dcc as a gene involved specifically in th adolescent development of mPFC DA inputs, and in turn, in the maturation of local circuitry. In addition, we have shown that AMPH regulates DCC receptor expression in the VTA during early adolescence. Remarkably, this same early adolescent exposure to AMPH increases the expanse of DA fibers in the adult mPFC, but denudes these fibers of synaptic sites. These enduring effects are not observed following adult exposure to AMPH. My working hypothesis is that AMPH in adolescence, by altering the expression of DCC receptors within DA neurons, produces changes in their normal developmental trajectory, leading to their ectopic innervation and faulty synaptogenesis in the mPFC. These changes in mPFC DA innervation, in turn, induce structural and functional reorganization of mPFC local circuitry, influencing cognitive processing in adulthood. Objectives: 1) to characterize the nature of the effects of AMPH exposure in adolescence on mPFC DA innervation and on local circuitry organization and function in adulthood, 2) to determine whether AMPH- induced regulation of VTA DCC receptor expression is required for drug-induced disruption of mPFC development and to identify the underlying mechanisms, 3) to examine the consequences that the DCC- mediated AMPH-induced disruption of mPFC development has on cognitive processing in adulthood. Methods: I will combine quantitative neuroanatomical analyses with genetic manipulations to unravel the fine architecture and synaptic organization of DA circuitry. I will use in vivo microdialysis and electrophysiology to capture the functional consequences of the neuroanatomical alterations. I will use mice that lack dcc specifically within DA neurons to assess whether DCC receptors play a role in AMPH-induced disruption of mPFC development. I will perform loss- and gain-of-function experiments by manipulating netrin-1 expression in DA targets to discern how AMPH-induced changes in DCC-mediated netrin-1 signaling alter mPFC development. I will examine the effects of AMPH exposure in adolescence, and the contribution of DCC receptors, on cognitive processing in adulthood by performing tests of behavioral flexibility and behavioral inhibition, and working memory.

Public Health Relevance

Drug use during adolescence is a strong predictor of lifetime abuse. The goal of this application is to identify the developmental processes that occur in the adolescent brain and how these events are affected by exposure to drugs of abuse during this critical age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA037911-03
Application #
9220775
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$194,404
Indirect Cost
$14,400
Name
Mcgill University
Department
Type
DUNS #
205667090
City
Montreal
State
QC
Country
Canada
Zip Code
H3 0-G4
Reynolds, Lauren M; Yetnikoff, Leora; Pokinko, Matthew et al. (2018) Early Adolescence is a Critical Period for the Maturation of Inhibitory Behavior. Cereb Cortex :
Salameh, Samer; Nouel, Dominique; Flores, Cecilia et al. (2018) An optimized immunohistochemistry protocol for detecting the guidance cue Netrin-1 in neural tissue. MethodsX 5:1-7
Vosberg, Daniel E; Zhang, Yu; Menegaux, Aurore et al. (2018) Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers. J Neurosci 38:4655-4665
Hoops, Daniel; Reynolds, Lauren M; Restrepo-Lozano, Jose-Maria et al. (2018) Dopamine Development in the Mouse Orbital Prefrontal Cortex Is Protracted and Sensitive to Amphetamine in Adolescence. eNeuro 5:
Cuesta, Santiago; Restrepo-Lozano, José Maria; Silvestrin, Steven et al. (2018) Non-Contingent Exposure to Amphetamine in Adolescence Recruits miR-218 to Regulate Dcc Expression in the VTA. Neuropsychopharmacology 43:900-911
Reynolds, Lauren M; Pokinko, Matthew; Torres-Berrío, Angélica et al. (2018) DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence. Biol Psychiatry 83:181-192
Torres-Berrío, Angélica; Lopez, Juan Pablo; Bagot, Rosemary C et al. (2017) DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218. Biol Psychiatry 81:306-315
Hoops, Daniel; Flores, Cecilia (2017) Making Dopamine Connections in Adolescence. Trends Neurosci 40:709-719
Madularu, Dan; Mathieu, Axel P; Kumaragamage, Chathura et al. (2017) A non-invasive restraining system for awake mouse imaging. J Neurosci Methods 287:53-57
Walker, Deena M; Bell, Margaret R; Flores, Cecilia et al. (2017) Adolescence and Reward: Making Sense of Neural and Behavioral Changes Amid the Chaos. J Neurosci 37:10855-10866

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