title: IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity.
abstract: The neurobiological underpinnings of mood and anxiety disorders have been linked to the nucleus accumbens (NAc), a region important in processing the rewarding and emotional salience of stimuli. Using chronic social defeat stress, an animal model of mood and anxiety disorders, we investigated whether alterations in synaptic plasticity are responsible for the long-lasting behavioral symptoms induced by this form of stress. We hypothesized that chronic social defeat stress alters synaptic strength or connectivity of medium spiny neurons (MSNs) in the NAc to induce social avoidance. To test this, we analyzed the synaptic profile of MSNs via confocal imaging of Lucifer-yellow-filled cells, ultrastructural analysis of the postsynaptic density, and electrophysiological recordings of miniature EPSCs (mEPSCs) in mice after social defeat. We found that NAc MSNs have more stubby spine structures with smaller postsynaptic densities and an increase in the frequency of mEPSCs after social defeat. In parallel to these structural changes, we observed significant increases in IκB kinase (IKK) in the NAc after social defeat, a molecular pathway that has been shown to regulate neuronal morphology. Indeed, we find using viral-mediated gene transfer of dominant-negative and constitutively active IKK mutants that activation of IKK signaling pathways during social defeat is both necessary and sufficient to induce synaptic alterations and behavioral effects of the stress. These studies establish a causal role for IKK in regulating stress-induced adaptive plasticity and may present a novel target for drug development in the treatment of mood and anxiety disorders in humans.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Christoffel
authors.forename: Sam A
authors.initials: SA
authors.lastname: Golden
authors.forename: Dani
authors.initials: D
authors.lastname: Dumitriu
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: William G
authors.initials: WG
authors.lastname: Janssen
authors.forename: H Francisca
authors.initials: HF
authors.lastname: Ahn
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Reyes
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ables
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
authors.forename: John H
authors.initials: JH
authors.lastname: Morrison
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007398:Interpersonal Relations; D007546:Isoquinolines; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D009714:Nucleus Accumbens / Q000473:pathology*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013223:Statistics as Topic; D013315:Stress, Psychological / Q000473:pathology* / Q000503:physiopathology
chemical_list: D007546:Isoquinolines; D049452:Green Fluorescent Proteins; C017475:lucifer yellow; D051550:I-kappa B Kinase