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为纹状体的神经精神障碍有关 调节失调，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不清楚。对纹状体功能的一个可能的影响是 外周免疫调节剂组胺。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 下丘脑结节乳头状核(TMN)。组胺能神经元共同释放GABA；它们 支配纹状体，在那里它们保持紧张性抑制，以抑制纹状体的过度活动。 在一种缺乏组胺的遗传性小鼠系，组氨酸脱羧酶(HDC)基因敲除小鼠中进行了观察， 提示全身性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上调，特别是在TMN，并具有更多的基线神经元 纹状体中的活动。H3R受体的全身性激活促进纹状体活动的进一步增强。在……里面 野生型小鼠的TMN化学发生沉默也增强了纹状体的活动。下丘脑是 被室周器官包围，这些器官允许系统免疫信号相对自由地通过，如 是组胺。我们假设全身性组胺通过H3R直接调节TMN活性，从而 调节纹状体中的下游活动。 第一个目的是测试HDC-KO小鼠TMN中H3R的上调是否介导了全身性 给予H3R激动剂RAMH对纹状体活动的影响。这将为今后探索的影响提供参考 下丘脑肥大细胞和其他过敏性免疫细胞在TMN和纹状体上的组胺 活动。靶向向TMN输送RAMH将测试TMN H3R激活是否足以诱导纹状体 过度活跃和shRNA靶向下调TMN中的H3R将测试这些受体的必要性 在调节WT和HDC-KO小鼠全身性RAMH后纹状体过度活动方面。第二个目标测试 H3R在TMN中的过度表达是否足以概括所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，我测试了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及其下游的免疫调控奠定基础 大脑靶点，与广泛的神经精神障碍有潜在的相关性。