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。然而， 这些联系背后的机制仍然未知。对纹状体功能的一种可能的影响是 外周免疫介质组胺。组胺不仅是过敏性免疫反应的关键介质， 但也是一种中枢神经递质。神经递质组胺仅由后脑产生 下丘脑的结节乳头核（TMN）。组胺能神经元共同释放 GABA；他们 支配纹状体，维持强直抑制以抑制纹状体过度活跃。 对缺乏组胺的基因小鼠系（组氨酸脱羧酶 (Hdc) 敲除小鼠）的观察， 表明全身组胺和纹状体活动之间可能存在联系。 HDc-KO小鼠展示 组胺自身受体 H3R 的上调，特别是在 TMN 中，并且具有更大的基线神经元 纹状体的活动。 H3R 受体的全身激活促进纹状体活性进一步增强。在 在野生型小鼠中，TMN 的化学遗传学沉默也增强了纹状体活性。下丘脑是 周围有室周器官，允许全身免疫信号相对自由地通过，例如 如组胺。我们假设全身组胺通过 H3R 直接调节 TMN 活性，从而 调节纹状体的下游活动。 第一个目标测试 Hdc-KO 小鼠 TMN 中 H3R 的上调是否介导全身性的影响 H3R 激动剂 RAMH 对纹状体活动的影响。这将为未来探索其影响的工作提供信息 组胺源自下丘脑 TMN 和纹状体内的肥大细胞和其他过敏性免疫细胞 活动。将 RAMH 靶向递送至 TMN 将测试 TMN H3R 激活是否足以诱导纹状体 过度活跃和 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 小鼠中介导全身 RAMH 后纹状体过度活跃。第二次目标测试 TMN 中 H3R 的过度表达是否足以概括观察到的纹状体活动表型 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，在目标 3 中，我测试过敏性炎症是否影响 TMH 和 纹状体，以及这是否由下丘脑 H3R 介导。 这项工作将为进一步研究 TMN 及其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潜在相关。