# Early-onset narcolepsy: A role for histamine

> **NIH NIH F32** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $19,628

## Abstract

PROJECT SUMMARY/ABSTRACT
 Narcolepsy is a sleep disorder caused by the selective death of orexin neurons that commonly occurs
in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, an
abnormal behavioral state between REM sleep and wake. Cataplexy is much more severe in children who
develop narcolepsy than in adults, but the underlying mechanisms remain unknown.
 Histamine is a wake-promoting neuromodulator produced solely in the tuberomammillary nucleus.
Histamine neurons are active during cataplexy, possibly maintaining consciousness during this REM sleep-like
state. Mice lacking both orexins and histamine exhibit far less cataplexy than mice lacking only orexins,
suggesting that histamine is necessary for cataplexy. In children with narcolepsy, cerebrospinal fluid histamine
levels are higher than in healthy controls, whereas histamine levels are normal or low in adults with narcolepsy.
 Our pilot data indicate that orexin neuron loss in mice at age 4 weeks (young-onset) results in very
severe cataplexy, whereas orexin neuron loss at age 14 weeks (adult-onset) results in little cataplexy but more
REM sleep. We hypothesize that the abundant cataplexy in young mice is caused by a compensatory increase
in histamine signaling.
 We will test this hypothesis by first analyzing sleep-wake behavior in young-onset and adult-onset mice
acutely and chronically after orexin neuron loss to confirm that young-onset mice experience more cataplexy.
Then, we will use photometry to measure histamine neuron activity during cataplexy and across sleep/wake
states in young-onset mice to confirm whether histamine neurons are active during cataplexy. Finally, we will
chemogenetically inhibit or activate histamine neurons to test whether elevated histamine neuron activity
promotes cataplexy.
 These experiments will define the role of histamine neurons in the regulation of cataplexy in mice with
young-onset or adult-onset orexin neuron loss. Ultimately, elucidating this mechanism of severe cataplexy
should enable more targeted treatments for children with narcolepsy.

## Key facts

- **NIH application ID:** 10086329
- **Project number:** 5F32HD101193-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Alissa A Coffey
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $19,628
- **Award type:** 5
- **Project period:** 2020-01-17 → 2021-04-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086329

## Citation

> US National Institutes of Health, RePORTER application 10086329, Early-onset narcolepsy: A role for histamine (5F32HD101193-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086329. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*