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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

基本信息

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
项目类别：
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

项目摘要

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.

过敏性炎症与表现纹状体的许多神经精神疾病有关