Cell Subtype Transcriptional Mechanisms in Cocaine Addiction

描述(申请人提供)：目前，没有可行的治疗精神刺激性成瘾的方法。很有可能，因为治疗候选者对异质中枢神经系统中选定的细胞亚型的作用机制尚不清楚。阐明不同细胞亚型中介导兴奋剂成瘾的不同分子途径事件，对于开发有效的治疗药物是必要的。最近的研究表明，在精神刺激成瘾中，纹状体中棘神经元(MSN)亚型存在功能和分子的失衡，这些亚型富含多巴胺(DA)D1vs.D2受体。然而，目前还没有系统的研究来研究哪些突触输入和信号通路调节MSN亚型的不同转录变化，以及这些分子变化最终如何调节精神刺激剂成瘾。我们将研究一种转录因子，早期生长反应3(Egr3)，它在可卡因成瘾表型中受可卡因以细胞类型特异性的方式调节腹侧纹状体(伏隔核-NAC)，进而调节关键分子成员的转录。Egr3通过多巴胺(DA)-D1和脑源性神经营养因子(BDNF)-TrkB信号通路进行调节。腹侧被盖区(VTA)-NAC回路中的这些信号通路对于调节对可卡因的行为反应至关重要。我们将使用光遗传学和药理学工具结合新的细胞类型选择性转录组图谱来研究Egr3转录因子途径是如何通过VTA-NAC信号通路在可卡因滥用中在MSN亚型中介导的。然后，我们将使用遗传工具选择性地扰乱Egr3或Egr3共抑制子Nab2的水平，研究MSN中Egr3转录因子途径在调节可卡因复发(成瘾的一个特征症状)中的功能作用。我们的发现可能会导致针对MSN亚型的精神刺激性成瘾的新颖和有效的治疗策略，这将极大地影响这种慢性病患者的生活。

DESCRIPTION (provided by applicant): Currently, there are no viable therapeutic treatments for psychostimulant addiction. Likely, because the mechanism of action of therapeutic candidates on select cell subtypes, in the heterogeneous central nervous system, is unknown. Shedding light on distinct molecular pathway events in distinct cell subtypes, that mediate stimulant addiction, is necessary for development of effective therapeutics. Recent studies demonstrate an imbalance of function and molecules in striatal medium spiny neuron (MSN) subtypes, those enriched in dopamine (DA) D1 vs. D2 receptors, in psychostimulant addiction. Yet, there are no systematic studies examining which synaptic inputs and signaling pathways regulate distinct transcriptional changes in MSN subtypes and how these molecular changes ultimately mediate psychostimulant addiction. We will investigate a transcription factor, early growth response 3 (Egr3), that is regulated by cocaine in a cell-type specific manner in the ventral striatum (nucleus accumbens-NAc) and in turn regulates transcription of key molecular players, in the cocaine addictive phenotype. Egr3 is regulated through dopamine (DA)-D1 and brain derived neurotrophic factor (BDNF)-TrkB signaling pathways. These signaling pathways, in the ventral tegmental area (VTA)-NAc circuit, are critical for mediating behavioral responses to cocaine. We will use optogenetic and pharmacological tools combined with novel cell-type selective transcriptome profiling to investigate how the Egr3 transcription factor pathway is mediated in MSN subtypes through VTA-NAc signaling pathways in cocaine abuse. We will then examine the functional role of the Egr3 transcription factor pathway in MSNs in mediating relapse for cocaine, a hallmark symptom of addiction, using genetic tools to selectively perturb levels of Egr3 or the Egr3 co-repressor, Nab2. Our findings could lead to novel and effective treatment strategies for psychostimulant addiction that target MSN subtypes, which would greatly impact the lives of individuals suffering from this chronic disease.