权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Histamine Regulation of the Basal Ganglia and the Pathophysiology of Tics

基底神经节的组胺调节和抽动的病理生理学

基本信息

批准号：
9288634
负责人：
Christopher John Pittenger
金额：
$ 41.12万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288634
关键词：
Acute Adult Affect Alleles Anabolism Animal Model Animals Arbitration Basal Ganglia Behavior Behavioral Brain Brain region Cells Clinical Comorbidity Corpus striatum structure Data Development Disease Disinhibition Dissociation Dopamine Etiology Face Family Financial compensation Functional disorder Genes Genetic Genetic study Gilles de la Tourette syndrome Grooming Growth Heritability Histamine Histamine H1 Receptors Histamine H3 Receptors Histamine Receptor Histidine Histidine Decarboxylase Homeostasis Human Hypothalamic structure Incidence Infusion procedures Interneurons Knock-out Knockout Mice Lead Light Microdialysis Modeling Molecular Target Motor Tics Movement Mutation Neurobiology Neurons Nonsense Mutation Paper Pathogenesis Pathology Pattern Pharmacology Phase Population Prevalence Process Publishing Regulation Research Role Signal Transduction Source Stress Substantia nigra structure System Testing Tic disorder Vocal Tics Wild Type Mouse acute stress cell type clinically significant dopaminergic neuron gamma-Aminobutyric Acid genetic variant in vivo indexing innovation insight knock-down mutation carrier neuropsychiatry new therapeutic target novel novel therapeutics pars compacta phenomenological models presynaptic programs receptor repetitive behavior small hairpin RNA stereotypy therapeutic target

项目摘要

ABSTRACT Tourette syndrome (TS) and other tic disorders affect up to 5% of the population and are frequently comorbid with other neuropsychiatric conditions. Their neurobiology is poorly understood, and current treatments are often inefficacious. Recent genetic findings implicate dysregulation of histamine (HA) signaling as a rare cause; in a recent paper in Neuron we established the HA-deficient histidine decarboxylase (Hdc) knockout mouse as a model of tic pathophysiology that has etiologic, face, and predictive validity. Convergent evidence implicates the cortico-basal ganglia circuitry in tic disorders. In particular, dysregulation of dopamine (DA) in the striatum is thought to be an important contributing factor. HA receptors are highly expressed in the basal ganglia circuitry. HA regulates DA levels in the striatum: HA infusion in a wild-type mouse reduces striatal DA in vivo, and the HA-deficient Hdc-KO model has elevated basal DA levels. In our first Aim we will elucidate the mechanisms of this poorly understood regulatory interaction. We hypothesize that HA acts on H1R receptors found on inhibitory interneurons in the substantia nigra pars compacta (SNc). We will test this using in vivo pharmacology and microdialysis. We will then test the necessity and sufficiency of HA-induced SNc interneuronal activity for striatal DA regulation, using a novel chemogenetic strategy. Baseline DA dysregulation and repetitive behavioral pathology in the Hdc-KO tic model are subtle, but they are dramatically increased by behavioral or pharmacological perturbations. For example, stress induces repetitive behaviors in the model. Local neuronal disinhibition in the striatum produces a dramatic spike in DA, not seen in WT animals. This suggests a loss of DA homeostasis, rendering the system subject to phasic instability – a pattern that resembles the phasic phenomenology of tic disorders. We hypothesize that loss of H1R tone on SNc interneurons removes a source of homeostatic regulation; we will test this in our second Aim. We find much more dramatic repetitive behavioral pathology after HA neurons are chemogenetically silenced in vivo. This suggests that mitigating mechanisms constrain behavioral pathology in the KO animal. Identification of such mechanisms is of both basic and translational importance; enhancing them may represent a novel therapeutic strategy, both in tic disorders and in other hyperdopaminergic pathologies. We will arbitrate between two possible explanations for this observation in Aim #3. First, behavioral pathology may be more profound after acute silencing of HA neurons because it also disrupts GABA cotransmission, which is intact in the KO animals. Second, KO animals may develop compensations over ontogeny. We will use a combination of chemogenetics and shRNA knockdown to test these two hypotheses. In the long term, this innovative research program is of both basic and translational importance, aiming to elucidate the normal role of HA in the basal ganglia, establish how its perturbation can lead to tics, and identify potential new treatment targets.

摘要图雷特综合征（TS）和其他抽动障碍影响高达5%的人口，并经常共病其他神经精神疾病他们的神经生物学知之甚少，目前的治疗方法是往往是无效的。最近的遗传学发现暗示组胺（HA）信号调节异常是一种罕见的在最近的一篇Neuron论文中，我们建立了HA缺陷型组氨酸脱羧酶（Hdc）敲除小鼠作为抽动病理生理学模型，具有病因学、面部和预测有效性。会聚证据表明抽动障碍中的皮质-基底神经节回路。特别是，纹状体中多巴胺（DA）的释放被认为是一个重要的影响因素。HA受体高度在基底神经节回路中表达。HA调节纹状体中的DA水平：野生型中的HA输注小鼠体内纹状体DA降低，HA缺陷型Hdc-KO模型基础DA水平升高。在我们第一个目的我们将阐明这种知之甚少的调节相互作用的机制。我们假设 HA作用于在黑质丘脑部（SNc）的抑制性中间神经元上发现的H1 R受体。我们将使用体内药理学和微透析来测试这一点。然后我们将测试的必要性和充分性 HA诱导的SNc神经元间活动纹状体DA调节，使用一种新的化学遗传学策略。在Hdc-KO抽动模型中，基线DA失调和重复行为病理学是微妙的，但它们是通过行为或药理学扰动而显著增加。例如，压力会导致重复模型中的行为。纹状体中的局部神经元去抑制产生DA的显著尖峰，未观察到在WT动物中。这表明DA稳态的丧失，使系统处于阶段性不稳定状态- 类似于抽动障碍的阶段性现象的模式。我们假设H1 R张力的丧失 SNc中间神经元消除了自我平衡调节的来源;我们将在第二个目标中测试这一点。我们发现HA神经元化学沉默后， in vivo.这表明缓解机制限制了KO动物的行为病理学。确定这些机制具有基础和转化的重要性;加强这些机制可以代表了一种新的治疗策略，无论是在抽动障碍和其他高多巴胺能病理学。我们对于目标3中的观察结果，我将在两种可能的解释之间进行仲裁。首先，行为病理学可能在HA神经元急性沉默后更深刻，因为它也破坏了GABA共传递，在KO动物中保持完整。第二，KO动物可能在个体发育上发展补偿。我们将使用一个我们将化学遗传学和shRNA敲低相结合来测试这两种假设。从长远来看，这一创新研究计划具有基础和转化的重要性，旨在阐明HA在基底神经节中的正常作用，确定其扰动如何导致抽搐，并确定潜在的新治疗目标。