Delta FosB differentially modulates nucleus accumbens direct and indirect pathway function

作者：Grueter Brad A; Robison Alfred J; Neve Rachael L; Nestler Eric J; Malenka Robert C^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(5): 1923-1928.

DOI：10.1073/pnas.1221742110

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 Delta 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 Delta 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, Delta 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 Delta 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 Delta FosB, we selectively overexpressed Delta 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 Delta FosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.

• 出版日期2013-1-29