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Histamine Regulation of Basal Ganglia Function

组胺对基底神经节功能的调节

基本信息

批准号：
9349594
负责人：
Christopher John Pittenger
金额：
$ 18.38万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-08 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9349594
关键词：
Agonist Animal Model Attention Attenuated Basal Ganglia Behavior Behavioral Cell Nucleus Cells Corpus striatum structure Cyclic AMP DRD2 gene Data Dimensions Disease model Dopamine Dopamine D2 Receptor Dopamine Receptor Dorsal Drug Delivery Systems Enzymes Feedback Functional disorder Future G-Protein-Coupled Receptors Genetic Gilles de la Tourette syndrome Glutamates HRH2 gene Haloperidol Heterodimerization Histamine Histamine H3 Agonist Histamine H3 Receptors Histamine Production Histamine Receptor Histidine Decarboxylase Infusion procedures Investigation Knock-out Knockout Mice Lead Light LoxP-flanked allele MAP Kinase Gene Mediating Modeling Molecular Motor Activity Mus Mutation Neuraxis Neurons Neurotransmitters Obsessive-Compulsive Disorder Penetrance Pharmaceutical Preparations Pharmacology Phosphorylation Posterior Hypothalamus Process Property Protein Dephosphorylation Proto-Oncogene Proteins c-akt Reagent Receptor Activation Receptor Signaling Regulation Reporter Reporting Role Series Signal Transduction Testing Time Tissues Transgenic Mice Transgenic Organisms Varicosity Work behavior change cell type experimental study in vivo mouse model neglect neurochemistry neuropsychiatric disorder neuropsychiatry novel postsynaptic presynaptic receptor receptor-mediated signaling synergism tool

项目摘要

ABSTRACT The basal ganglia circuitry – including the primary input nucleus, the striatum – critically regulates numerous behavioral processes and is implicated in the pathophysiology of multiple neuropsychiatric conditions, including Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Regulation of the basal ganglia by the modulatory neurotransmitter dopamine (DA) has been extensively studied. Much less is known about the regulation of this circuitry by histamine (HA). Recent findings have highlighted the contribution of dysregulated HA modulation of the basal ganglia to neuropsychiatric disease, especially TS and OCD. A mutation in histidine decarboxylase (Hdc), the key biosynthetic enzyme required for HA production, was identified as a rare cause of TS and, with lower penetrance, of OCD. Our studies in Hdc knockout mice confirm that HA disruption can lead to TS-relevant behaviors and changes in striatal neurochemistry and function. Preliminary data from the mouse model focus attention on the histamine receptor H3R, which is highly expressed in the striatum. Signaling by H3R in the basal ganglia is not well understood. Recent work, most of it ex vivo, has documented heterodimerization between H3R and both D1R and D2R dopamine receptors and shown that H3R and D1R interact in counterintuitive ways in the regulation of MAPK. Such heterodimerization of G- protein-coupled receptors is increasingly reported, but its functional significance has been difficult to pin down. We have replicated H3R-D1R functional interactions in vivo and identified a behavioral correlate. We have also identified a novel, cell-type specific effect of H3R on signaling through AKT-GSK3β: in striatal medium spiny neurons that express D1R (D1R-MSNs), H3R leads to phosphorylation (and thus inactivation) of GSK3β, while in D2R-MSNs it leads to GSK3β dephosphorylation. This differential regulation of both MAPK and GSK3β highlights the ability of H3R-DR functional interactions to modulate signaling and the importance of better understanding this dimension of striatal regulation. We propose to use existing transgenic mouse lines to characterize functional interactions between H3R and dopamine receptors in D1R- and D2R-MSNs of the dorsal striatum. We predict nonlinear interactions in the regulation of both MAPK and GSK3β, and that these will lead to interactions in the regulation of locomotor activity. We will test the causal importance of H3Rs in specific striatal cell types by generating inducible H3R knockout mice, which we will cross with cell type-specific cre-expressing transgenic mice to produce D1R- and D2R-MSN-specific disruption of H3R signaling. We predict differential effects at the level of both signaling and behavior when H3R is disrupted in different MSN subtypes. These experiments will shed new light on the underappreciated role of HA in the modulation of basal ganglia function and lay the groundwork for future studies in animal models of pathophysiology.

摘要基底神经节回路-包括初级输入核，纹状体-严格调节许多行为过程，并涉及多种神经精神疾病的病理生理学包括抽动秽语综合征（TS）和强迫症（OCD）。调控基底神经节通过调节性神经递质多巴胺（DA）的作用已被广泛研究。之甚少已知组胺（HA）对该回路的调节。最近的调查结果强调，基底神经节HA调节失调对神经精神疾病，尤其是TS的作用，强迫症组氨酸脱羧酶（Hdc）的突变，HA生产所需的关键生物合成酶，被认为是TS的罕见病因，也是强迫症的罕见病因。我们在Hdc基因敲除小鼠中的研究证实HA破坏可导致TS相关行为和纹状体神经化学变化，功能来自小鼠模型的初步数据将注意力集中在组胺受体H3 R上，在纹状体中高度表达 H3 R在基底神经节中的信号传导还不清楚。最近的研究，大部分是离体研究，记录了H3 R与D1 R和D2 R多巴胺受体之间的异源二聚化，并显示， H3 R和D1 R在MAPK的调节中以违反直觉的方式相互作用。这种G- 蛋白偶联受体的报道越来越多，但其功能意义一直难以确定。我们已经在体内复制了H3 R-D1 R功能相互作用，并确定了行为相关性。我们有还确定了H3 R对通过AKT-GSK 3 β信号传导的一种新的细胞类型特异性作用：表达D1 R（D1 R-MSNs）的棘神经元，H3 R导致GSK 3 β磷酸化（从而失活），而在D2 R-MSN中，它导致GSK 3 β去磷酸化。这种MAPK和 GSK 3 β强调了H3 R-DR功能相互作用调节信号传导的能力以及H3 R-DR功能相互作用的重要性。更好地理解纹状体调节的这个维度。我们建议使用现有的转基因小鼠品系来表征H3 R之间的功能性相互作用。和背侧纹状体的D1 R-和D2 R-MSNs中的多巴胺受体。我们预测非线性相互作用， MAPK和GSK 3 β的调节，这些将导致运动调节的相互作用，活动我们将通过产生诱导型H3 R来测试H3 R在特定纹状体细胞类型中的因果重要性敲除小鼠，我们将与细胞类型特异性表达cre的转基因小鼠杂交，产生D1 R-和 D2 R-MSN特异性破坏H3 R信号传导。我们预测在信号传导和当H3 R在不同的MSN亚型中被破坏时的行为。这些实验将为我们了解 HA在调节基底神经节功能中的作用未被充分认识，并为将来的研究奠定基础。病理生理学动物模型的研究。