title: ∆FosB differentially modulates nucleus accumbens direct and indirect pathway function.
abstract: Synaptic modifications in nucleus accumbens (NAc) medium spiny neurons (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modification of NAc MSN synapses may occur in part via changes in the transcriptional potential of certain genes in a cell type–specific manner. The transcription factor ∆FosB is one of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. Here, we demonstrate that overexpression of ∆FosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor–expressing direct pathway MSNs in both the NAc shell and core. In contrast, ∆FosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor–expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that ∆FosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. To determine the behavioral consequences of cell type-specific actions of ∆FosB, we selectively overexpressed ∆FosB in D1 direct or D2 indirect MSNs in NAc in vivo and found that direct (but not indirect) pathway MSN expression enhances behavioral responses to cocaine. These results reveal that ∆FosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.
authors: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
authors: Brad A
authors: BA
authors: Grueter
authors: Alfred J
authors: AJ
authors: Robison
authors: Rachael L
authors: RL
authors: Neve
authors: Eric J
authors: EJ
authors: Nestler
authors: Robert C
authors: RC
authors: Malenka
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; C483819:Fosb protein, mouse; D008164:Luminescent Proteins; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D003042:Cocaine