title: Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ΔFosB.
abstract: Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Department of Physiology, Michigan State University, Lansing, Michigan 48824, Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, New York 14214, Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada, Department of Psychiatry, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, and Institut National de la Santé et de la Recherche Médicale, U1130, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8246, and Université Pierre et Marie Curie, UM CR18, Sorbonne Université, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vialou
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Bagot
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.forename: Barbara
authors.initials: B
authors.lastname: Fallon
authors.forename: Michelle
authors.initials: M
authors.lastname: Mazei-Robison
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ku
authors.forename: Eileen
authors.initials: E
authors.lastname: Harrigan
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Winstanley
authors.forename: Tej
authors.initials: T
authors.lastname: Joshi
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.forename: Olivier
authors.initials: O
authors.lastname: Berton
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001008:Anxiety Disorders / Q000473:pathology / Q000503:physiopathology*; D001931:Brain Mapping; D002766:Cholecystokinin / Q000502:physiology*; D002908:Chronic Disease; D003866:Depressive Disorder / Q000473:pathology / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008032:Limbic System / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000502:physiology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology*; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012930:Social Dominance; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology
chemical_list: D014151:Anti-Anxiety Agents; C483819:Fosb protein, mouse; D007211:Indoles; D016760:Proto-Oncogene Proteins c-fos; D043887:Receptor, Cholecystokinin B; C065599:PD 134308; D008536:Meglumine; D002766:Cholecystokinin
keywords: CCK; accumbens; amygdala; anxiety; depression; mPFC