Lauren M Reynolds1, Matthew Pokinko1, Angélica Torres-Berrío1, Santiago Cuesta2, Laura C Lambert2, Esther Del Cid Pellitero2, Michael Wodzinski2, Colleen Manitt2, Paul Krimpenfort3, Bryan Kolb4, Cecilia Flores5. 1. Integrated Program in Neuroscience, McGill University, Douglas Mental Health University Institute, Montréal, Québec, Canada; Departments of Psychiatry and Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montréal, Québec, Canada. 2. Departments of Psychiatry and Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montréal, Québec, Canada. 3. Division of Molecular Genetics, Centre for Biomedical Genetics, Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 4. Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada. 5. Departments of Psychiatry and Neurology and Neurosurgery, McGill University, Douglas Mental Health University Institute, Montréal, Québec, Canada. Electronic address: cecilia.flores@mcgill.ca.
Abstract
BACKGROUND: Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. METHODS: We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. RESULTS: We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. CONCLUSIONS: The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex.
BACKGROUND:Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. METHODS: We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFCdopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. RESULTS: We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. CONCLUSIONS:The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex.
Authors: B J Casey; R J Trainor; J L Orendi; A B Schubert; L E Nystrom; J N Giedd; F X Castellanos; J V Haxby; D C Noll; J D Cohen; S D Forman; R E Dahl; J L Rapoport Journal: J Cogn Neurosci Date: 1997-11 Impact factor: 3.225
Authors: Vibeke S Catts; Samantha J Fung; Leonora E Long; Dipesh Joshi; Ans Vercammen; Katherine M Allen; Stu G Fillman; Debora A Rothmond; Duncan Sinclair; Yash Tiwari; Shan-Yuan Tsai; Thomas W Weickert; Cynthia Shannon Weickert Journal: Front Cell Neurosci Date: 2013-05-15 Impact factor: 5.505
Authors: Lauren M Reynolds; Leora Yetnikoff; Matthew Pokinko; Michael Wodzinski; Julia G Epelbaum; Laura C Lambert; Marie-Pierre Cossette; Andreas Arvanitogiannis; Cecilia Flores Journal: Cereb Cortex Date: 2019-08-14 Impact factor: 5.357
Authors: Deena M Walker; Margaret R Bell; Cecilia Flores; Joshua M Gulley; Jari Willing; Matthew J Paul Journal: J Neurosci Date: 2017-11-08 Impact factor: 6.167
Authors: Santiago Cuesta; José Maria Restrepo-Lozano; Steven Silvestrin; Dominique Nouel; Angélica Torres-Berrío; Lauren M Reynolds; Andreas Arvanitogiannis; Cecilia Flores Journal: Neuropsychopharmacology Date: 2017-11-20 Impact factor: 7.853