Cell Subtype Transcriptional Mechanisms in Cocaine Addiction

描述（由申请人提供）：目前，没有可行的治疗精神兴奋剂成瘾的治疗方法。很可能，因为在异质性中枢神经系统中，治疗候选物对选择的细胞亚型的作用机制是未知的。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方法是必要的。最近的研究表明，在精神兴奋剂成瘾中，纹状体中型棘神经元（MSN）亚型的功能和分子失衡，这些亚型富含多巴胺（DA）D1与D2受体。然而，没有系统的研究检查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介导精神兴奋剂成瘾。我们将研究一种转录因子，早期生长反应3（Egr 3），这是由可卡因在腹侧纹状体（nucleus numbens-NAc）中以细胞类型特异性方式调节的，反过来又调节可卡因成瘾表型中关键分子参与者的转录。Egr 3通过多巴胺（DA）-D1和脑源性神经营养因子（BDNF）-TrkB信号通路调节。这些位于腹侧被盖区（VTA）-NAc回路中的信号通路对于介导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分析，研究Egr 3转录因子途径如何通过可卡因滥用中的VTA-NAc信号通路在MSN亚型中介导。然后，我们将研究MSN中Egr 3转录因子途径在介导可卡因复发（成瘾的标志性症状）中的功能作用，使用遗传工具选择性地干扰Egr 3或Egr 3共抑制因子Nab 2的水平。我们的研究结果可能会导致针对MSN亚型的精神兴奋剂成瘾的新颖有效的治疗策略，这将极大地影响患有这种慢性疾病的个人的生活。

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.