Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
J Neurosci. 2024 Jun 5;44(23):e1327232024. doi: 10.1523/JNEUROSCI.1327-23.2024.
Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b (), a Ca/calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of in regulating the molecular, cellular, and behavioral responses to cocaine.
可卡因使用障碍是一个重大的公共卫生问题，但目前还没有有效的药物治疗方法。成功的治疗方法部分受到限制，原因是我们对导致持久适应不良性可塑性和类似成瘾行为的分子机制的理解还不完全。在这里，我们利用一个大型 RNA 测序数据集，生成了来自接受盐水或可卡因自我给药的小鼠的大脑奖励回路的六个相互连接区域的基因共表达网络。我们确定磷酸二酯酶 1b ()，一种 Ca/钙调蛋白依赖性酶，可增加 cAMP 和 cGMP 水解，作为与成瘾样行为在生物信息学上相关的伏隔核 (NAc) 基因模块中的核心枢纽基因。慢性可卡因暴露会增加雄性而非雌性小鼠 NAc 中 D2 中型棘突神经元 (MSNs)中的 表达。在 NAc 中通过病毒介导过表达 会减少雌性大鼠的可卡因自我给药，但会增加两性的觅药行为。在雌性小鼠中，过表达 D1 MSNs 中的 会减弱对可卡因的运动反应，而在 D2 MSNs 中则会产生相反的效果。在雄性小鼠中，过表达 D1/D2 MSNs 中的 对可卡因引起的运动反应没有影响。在电生理水平上，过表达会降低 D1 MSNs 中的 sEPSC 频率，并调节 NAc MSNs 的兴奋性。最后，过表达会显著减少慢性可卡因后 NAc 中差异表达基因 (DEGs) 的数量，且在性别之间对基因转录产生不一致的影响。总的来说，我们确定了与成瘾样行为相关的大脑奖励回路中的新型基因模块，并探索了 在调节对可卡因的分子、细胞和行为反应中的作用。
