The Role of Hypothalamic H3 Histamine Receptors in Regulation of Striatal Function

下丘脑 H3 组胺受体在纹状体功能调节中的作用

• 批准号: 10534998
• 负责人: Christopher Fields
• 金额: $ 6.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534998
• 关键词: Affect; Agonist; Allergic; Allergic inflammation; Autoreceptors; Behavioral; Biological Response Modifiers; Brain; Cells; Corpus striatum structure; Disease; Down-Regulation; Exhibits; Future; Genetic; Histamine; Histamine H3 Receptors; Histamine Receptor; Histidine Decarboxylase; Hyperactivity; Hypothalamic structure; Immune; Immune response; Immune signaling; Investigation; Knockout Mice; Link; Mediating; Mediator of activation protein; Mus; Neurons; Neurotransmitters; Obsessive-Compulsive Disorder; Organ; Pathology; Peripheral; Phenotype; Process; Receptor Activation; Regulation; Role; Schizophrenia; System; Testing; Up-Regulation; Wild Type Mouse; Work; autism spectrum disorder; epidemiology study; gamma-Aminobutyric Acid; mammilloinfundibular nucleus structure; mast cell; neuropsychiatric disorder; overexpression; receptor; receptor upregulation; relating to nervous system; small hairpin RNA; targeted delivery

Allergic inflammation is associated with a number of neuropsychiatric disorders exhibiting striatal dysregulation, including autism, obsessive-compulsive disorder, and schizophrenia. However, the mechanisms underlying these links remain unknown. One possible influence on striatal function is the peripheral immune mediator histamine. Histamine is not only a key mediator of the allergic immune response, but is also a central neurotransmitter. Neurotransmitter histamine is produced solely by the posterior tuberomammillary nucleus (TMN) of the hypothalamus. Histaminergic neurons co-release GABA; they innervate the striatum, where they maintain tonic inhibition to suppress striatal hyperactivity. An observation in a genetic mouse line lacking histamine, the histidine decarboxylase (Hdc) knockout mouse, suggests a possible connection between systemic histamine and striatal activity. Hdc-KO mice exhibit upregulation of the histamine autoreceptor H3R, particularly in the TMN, and have greater baseline neuronal activity in the striatum. Systemic activation of the H3R receptor promotes further enhanced striatal activity. In wild-type mice, chemogenetic silencing of the TMN also enhanced striatal activity. The hypothalamus is surrounded by circumventricular organs which allow relatively free passage of systemic immune signals, such as histamine. We hypothesize that systemic histamine directly modulates TMN activity via H3R and thereby regulates downstream activity in the striatum. The first Aim tests whether H3R upregulation in the TMN in Hdc-KO mice mediates the effects of systemic administration of the H3R agonist RAMH on striatal activity. This will inform future work exploring the effects of histamine derived from mast cells and other allergic immune cells within the hypothalamus on TMN and striatal activity. Targeted delivery of RAMH to the TMN will test the sufficiency of TMN H3R activation to induce striatal hyperactivity, and shRNA-targeted downregulation of H3R in the TMN will test the necessity of these receptors in mediating striatal hyperactivity after systemic RAMH in both WT and Hdc-KO mice. The second Aim tests whether overexpression of H3R in the TMN is sufficient to recapitulate the striatal activity phenotype observed in Hdc-KO mice, which would further support the importance of hypothalamic H3R in modulating striatal activity phenotypes. Finally, in Aim 3, I test whether allergic inflammation affects neural activity in the TMH and the striatum, and whether this is mediated by hypothalamic H3R. This work will lay the groundwork for further investigations of immune control of the TMN and downstream brain targets, with potential relevance to a wide spectrum of neuropsychiatric disorders.

过敏性炎症与许多表现出纹状体的神经精神疾病有关 失调，包括自闭症，强迫症和精神分裂症。但是， 这些联系的基础机制仍然未知。对纹状体功能的一种可能影响是 外周免疫介质组胺。组胺不仅是过敏反应的关键介体，而且是 但也是中央神经递质。神经递质组胺仅由后部产生 下丘脑的结核核核（TMN）。组胺能神经元共释gaba;他们 支配纹状体，在那里它们保持滋补抑制以抑制纹状体多动。 在缺乏组胺的遗传小鼠系中观察到组氨酸脱羧酶（HDC）基因敲除小鼠， 表明系统性组胺和纹状体活性之间可能存在联系。 HDC-KO小鼠展览 组胺自身受体H3R的上调，特别是在TMN中，具有更大的基线神经元 纹状体的活性。 H3R受体的全身激活促进了进一步增强的纹状体活性。在 野生型小鼠，TMN的化学发生沉默也增强了纹状体活性。下丘脑是 周围环绕着室内器官，允许相对自由地通过全身免疫信号，例如 作为组胺。我们假设系统性组胺直接通过H3R调节TMN活性 调节纹状体中的下游活动。 第一个目的测试HDC-KO小鼠中TMN中的H3R上调是否介导了全身性的影响 H3R激动剂RAMH对纹状体活性的施用。这将为未来的工作提供探讨的影响 源自肥大细胞和其他过敏性免疫细胞的组胺在TMN和纹状体上 活动。将RAMH靶向TMN的靶向输送将测试TMN H3R激活的充分性以诱导纹状体 多动症和TMN中H3R的shRNA靶向下调将测试这些受体的必要性 在WT和HDC-KO小鼠中全身性RAMH后介导纹状体多动症中。第二个目标测试 TMN中H3R的过表达是否足以概括观察到的纹状体活性表型 在HDC-KO小鼠中，这将进一步支持下丘脑H3R在调节纹状体活动中的重要性 表型。最后，在AIM 3中，我测试过敏性炎症是否影响TMH和 纹状体，以及这是否是由下丘脑H3R介导的。 这项工作将为进一步调查TMN和下游的免疫控制奠定基础 大脑目标，与广泛的神经精神疾病具有潜在相关性。