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.

抽象的图雷特综合征（TS）和其他抽动疾病影响多达5％的人口，并且经常合并与其他神经精神疾病有关。他们的神经生物学知之甚少，目前的治疗方法是通常不效率。最近的遗传发现暗示组胺（HA）信号的失调是罕见的原因;在神经元的最新论文中，我们建立了HA缺陷组氨酸脱羧酶（HDC）敲除小鼠是具有病因，面部和预测有效性的TIC病理生理学模型。收敛证据在抽动疾病中实现了皮质 - 基因神经节电路。特别是失调纹状体中的多巴胺（DA）被认为是重要的因素。 HA受体高度在巴萨神经节电路中表达。 HA调节纹状体中的DA水平：HA在野生型中输注小鼠在体内降低了纹状体DA，缺乏HA的HDC-KO模型的基本DA水平升高。在我们的首先，我们将阐明这种不理理的调节相互作用的机制。我们假设该HA作用于在黑质中的抑制性中间神经元（SNC）中发现的H1R受体。我们将使用体内药理学和微透析进行测试。然后，我们将测试必要的充分性 HA诱导的SNC中神经元活性用于纹状体DA调节，使用新型的化学遗传策略。 HDC-KO TIC模型中的基线DA失调和重复的行为病理是微妙的，但它们是通过行为或药物扰动动态增加。例如，应力引起重复模型中的行为。纹状体中局部神经元抑制作用会在DA中产生戏剧性的尖峰，未见在WT动物中。这表明DA稳态的丧失，使该系统受到质量不稳定的影响 - 类似于TIC疾病的阶段现象学的模式。我们假设H1R音调的损失 SNC中间神经元删除了稳态调节的来源；我们将在第二个目标中对此进行测试。我们发现HA神经元后，更引人注目的重复行为病理是化学遗传沉默的体内。这表明缓解机制限制了KO动物的行为病理。这种机制的识别既具有基本和转化的重要性；增强它们可能代表一种新型的热策略，无论是在抽动疾病还是其他高巴博金能病理学中。将在AIM＃3中对此观察的两个可能的解释进行仲裁。首先，行为病理可能在急性沉默HA神经元之后要更深刻在KO动物中完好无损。其次，KO动物可能会对个体发育产生补偿。我们将使用一个化学遗传学和shRNA敲低的结合以检验这两个假设。从长远来看，这项创新的研究计划既具有基本和转化的重要性，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动，并识别潜在的新治疗目标。