Mesocortical dopamine connectivity continues to mature during adolescence. This protracted development confers increased vulnerability for environmental and genetic factors to disrupt mesocortical wiring and subsequently influence responses to drugs of abuse in adulthood. The netrin-1 receptor, DCC, orchestrates medial prefrontal cortex dopamine input during adolescence and dictates the functional organization of local circuitry. Haploinsufficiency of dcc results in increased dopamine innervation to the medial prefrontal cortex, which in turn leads to resilience against the behavioral activating effects of stimulant drugs. However, whether sensitivity to the rewarding effects of drugs of abuse is also altered in dcc haploinsufficiency remains to be resolved. Here, we used the curve-shift method to measure cocaine-induced facilitation of intracranial self-stimulation (ICSS) in adult dcc haploinsufficient mice and wild-type littermates. We found that dcc haploinsufficient mice acquire ICSS behavior at comparable stimulation parameters to wild-type controls. However, cocaine-induced potentiation of ICSS is significantly blunted in dcc haploinsufficient mice. These results are consistent with decreased sensitivity to the rewarding effects of cocaine and/or decreased proclivity to invest effort in the pursuit of reward in dcc haploinsufficient mice. Moreover, these findings suggest that DCC signaling determines adult susceptibility to drug abuse most likely by controlling prefrontal cortex development in adolescence.
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Disproportionate neuroanatomical effects of haploinsufficiency in adolescence compared with adulthood: links to dopamine, connectivity, covariance, and gene expression brain maps in mice.
J Psychiatry Neurosci
May 2024
From the Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ont. (Hoops, Yee, Hammill, Wong, Lerch, Sled); the Department of Medical Biophysics, University of Toronto, Ont. (Hoops, Yee, Lerch, Sled); the Department of Psychiatry, McGill University, Montréal, Que. (Hoops, Flores); the Douglas Mental Health University Institute, Montréal, Que. (Hoops, Manitt, Flores); the Department of Chemistry, Memorial University, St. John's, N.L. (Hoops, Cahill); the Department of Neurology and Neurosurgery, McGill University, Montréal, Que. (Bedell, Flores); the Wellcome Centre for Integrative Neuroimaging, Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neuroscience, University of Oxford, U.K. (Lerch); the Ludmer Centre for Neuroinformatics & Mental Health, McGill University, Montréal, Que. (Flores)
Background: Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced on neuroanatomy in the adolescent and adult mouse brain.
Methods: We examined neuronal connectivity, structural covariance, and molecular processes in a -haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute.
Reduced dopamine release in Dcc haploinsufficiency male mice abolishes the rewarding effects of cocaine but not those of morphine and ethanol.
Psychopharmacology (Berl)
March 2023
Douglas Mental Health University Institute, Montréal, Québec, Canada.
Rationale: The Netrin-1/DCC guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug.
Objective: Here, we tested whether the protective effects of Dcc haploinsufficiency are specific to stimulant drugs of abuse or instead extrapolate to opioids and ethanol.
Dopamine Axon Targeting in the Nucleus Accumbens in Adolescence Requires Netrin-1.
Front Cell Dev Biol
June 2020
Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
The fine arrangement of neuronal connectivity during development involves the coordinated action of guidance cues and their receptors. In adolescence, the dopamine circuitry is still developing, with mesolimbic dopamine axons undergoing target-recognition events in the nucleus accumbens (NAcc), while mesocortical projections continue to grow toward the prefrontal cortex (PFC) until adulthood. This segregation of mesolimbic versus mesocortical dopamine pathways is mediated by the guidance cue receptor DCC, which signals dopamine axons intended to innervate the NAcc to recognize this region as their final target.
View Article and Find Full Text PDFNeural function in DCC mutation carriers with and without mirror movements.
Ann Neurol
March 2019
Department of Psychology, University of Montreal, Montreal, Quebec, Canada.
Objective: Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC mutation carriers without mirror movements might exhibit some of these features.
View Article and Find Full Text PDFMesocorticolimbic Connectivity and Volumetric Alterations in Mutation Carriers.
J Neurosci
May 2018
Department of Psychiatry,
The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in -haploinsufficient mice.
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