title: Basal forebrain projections to the lateral habenula modulate aggression reward.
abstract: Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Sam A
authors.initials: SA
authors.lastname: Golden
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Mitra
authors.initials: M
authors.lastname: Heshmati
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Flanigan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Palo Alto, California 94305, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Christoffel
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Guise
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Madeline L
authors.initials: ML
authors.lastname: Pfau
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Menard
authors.affiliation: Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Georgia E
authors.initials: GE
authors.lastname: Hodes
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Bregman
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Khibnik
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tai
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Rebusi
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Graduate Program in Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Krawitz
authors.affiliation: Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Dipesh
authors.initials: D
authors.lastname: Chaudhury
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Palo Alto, California 94305, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Walsh
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Pharmacology and Systems Therapeutics and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Matt L
authors.initials: ML
authors.lastname: Shapiro
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
mesh_terms: D000200:Action Potentials; D000374:Aggression / Q000502:physiology*; D000818:Animals; D066187:Basal Forebrain / Q000166:cytology / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism; D019262:Habenula / Q000166:cytology / Q000502:physiology*; D025602:Halorhodopsins / Q000378:metabolism; D007206:Individuality; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009042:Motivation; D009433:Neural Inhibition; D009434:Neural Pathways / Q000502:physiology*; D012054:Reinforcement, Psychology; D012201:Reward; D012243:Rhodopsin / Q000378:metabolism; D012919:Social Behavior
chemical_list: D025602:Halorhodopsins; D012243:Rhodopsin