title: Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.
abstract: Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.
authors.affiliation: 1] Divisions of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY, USA [2] Department of Biological Sciences, Columbia University, New York, NY, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Yu
authors.affiliation: 1] Divisions of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY, USA [2] Sackler Institute for Developmental Psychobiology, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Teixeira
authors.affiliation: 1] Divisions of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY, USA [2] Sackler Institute for Developmental Psychobiology, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mahadevia
authors.affiliation: Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute and Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1] Divisions of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY, USA [2] Sackler Institute for Developmental Psychobiology, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Balsam
authors.affiliation: Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute and Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Mann
authors.affiliation: 1] Divisions of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY, USA [2] Sackler Institute for Developmental Psychobiology, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gingrich
authors.affiliation: 1] Divisions of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, NY, USA [2] Sackler Institute for Developmental Psychobiology, Columbia University and The New York State Psychiatric Institute, New York, NY, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Ansorge
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000339:Affect / Q000187:drug effects / Q000502:physiology*; D000374:Aggression / Q000187:drug effects / Q000502:physiology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D003863:Depression / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D057507:Mice, 129 Strain; D008995:Monoamine Oxidase / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D000661:Amphetamine; D008995:Monoamine Oxidase; D004298:Dopamine