ΔFosB differentially modulates nucleus accumbens direct and indirect pathway function
ΔFosB differentially modulates nucleus accumbens direct and indirect pathway function
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DOI：
10.1073/pnas.1221742110
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发表时间：
2013-01-29
影响因子：
11.1
通讯作者：
Malenka, Robert C.
中科院分区：
文献类型：
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作者：
Grueter, Brad A.;Robison, Alfred J.;Malenka, Robert C.
突触修饰在适应性和病理性奖赏依赖性学习中起着关键作用，包括药物成瘾中的适应不良反应。NAc MSNs参与两个平行的电路，直接和间接的途径，使不同的行为功能。NAc MSN突触的修饰可能部分通过某些基因转录潜能的改变以细胞类型特异性方式发生。转录因子Delta FosB是参与药物滥用引起的NAc基因表达变化的关键蛋白之一，但其对NAc MSNs突触功能的影响尚不清楚。在这里，我们表明，过表达三角洲FosB兴奋性突触强度下降，并可能增加沉默的突触到D1多巴胺受体表达直接途径MSN的NAC外壳和核心。相比之下，Delta FosB可能减少了NAc壳上的沉默突触，但不是核心，D2多巴胺受体表达间接途径MSN。NAc MSN树突棘形态学分析显示，Delta FosB增加了D1直接通路MSN中未成熟棘的密度，但不增加D2间接通路MSN中未成熟棘的密度。为了确定Delta FosB的细胞类型特异性作用的行为后果，我们在体内NAc中选择性地在D1直接或D2间接MSN中过表达Delta FosB，并发现直接（但不是间接）途径MSN表达增强了对可卡因的行为反应。这些结果表明，NAc中的Delta FosB以细胞类型和亚区域特定的方式差异调节突触特性和奖励相关行为。
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.