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

> **NIH NIH F32** · YALE UNIVERSITY · 2023 · $73,772

## Abstract

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.

## Key facts

- **NIH application ID:** 10685282
- **Project number:** 5F32MH129052-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Christopher Fields
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $73,772
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685282

## Citation

> US National Institutes of Health, RePORTER application 10685282, The Role of Hypothalamic H3 Histamine Receptors in Regulation of Striatal Function (5F32MH129052-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10685282. Licensed CC0.

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