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.

抽象的抽动秽语综合征 (TS) 和其他抽动障碍影响高达 5% 的人口，并且经常合并患病人们对他们的神经生物学知之甚少，目前的治疗方法也很有限。最近的基因发现表明组胺 (HA) 信号传导失调是一种罕见的情况。在《Neuron》最近发表的一篇论文中，我们建立了 HA 缺陷型组氨酸脱羧酶 (Hdc) 敲除模型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。一致的证据表明皮质基底神经节回路与抽动障碍尤其是失调有关。纹状体中的多巴胺 (DA) 被认为是一个重要的促成因素。在基底神经节回路中表达的 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 减少，而 HA 缺陷的 Hdc-KO 模型的基础 DA 水平升高。第一个目标是，我们将阐明这种人们知之甚少的监管相互作用的机制。 HA 作用于黑质致密部 (SNc) 抑制性中间神经元上的 H1R 受体。我们将使用体内药理学和微透析来测试这一点，然后我们将测试必要性和充分性。使用一种新的化学遗传学策略，研究 HA 诱导的 SNc 间神经元活性对纹状体 DA 的调节。 Hdc-KO 抽动模型中的基线 DA 失调和重复行为病理学是微妙的，但它们是行为或药理学扰动会显着增加，例如，压力会导致重复。模型中的局部神经元去抑制会导致 DA 急剧增加，但未观察到。在 WT 动物中，这表明 DA 稳态丧失，导致系统出现阶段性不稳定——a 类似于抽动障碍的阶段性现象的模式我们追踪了 H1R 音调的丧失。 SNc 中间神经元消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。在 HA 神经元被化学遗传学沉默后，我们发现了更加戏剧性的重复行为病理学这表明缓解机制限制了 KO 动物的行为病理。识别这些机制具有基础性和转化性的重要性，可能会增强它们；我们代表了一种新颖的治疗策略，适用于抽动障碍和其他多巴胺能亢进病理学。将在目标#3 中对这一观察结果进行两种可能的解释之间的仲裁：首先，行为病理学可能。 HA 神经元急性沉默后影响更为深远，因为它还会破坏 GABA 共传递，即其次，KO 动物可能会在个体发育上产生补偿。结合化学遗传学和 shRNA 敲除来检验这两个假设。从长远来看，这一创新研究项目具有基础性和转化性的重要性，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，并确定潜在的新治疗目标。