# Synaptic modulation of mesopontine cholinergic neurons

> **NIH NIH R01** · NEW YORK MEDICAL COLLEGE · 2021 · $481,274

## Abstract

Chronic or intermittent sleep disorders including narcolepsy, REM behavior disorder, sleep apnea, and
insomnia afflict nearly 50-70 million people in the United States. Yet the neural mechanisms controlling both
normal sleep and its pathologies remain poorly understood. Considerable evidence indicates that
mesopontine cholinergic neurons and serotonergic dorsal raphe neurons along with other neurons at the
mesopontine junction are critical for this control and that their dysregulation is involved with numerous
disorders including narcolepsy, REM behavior disorder, Parkinson's disease, supranuclear palsy and
depression. The long term goal of this project is to understand the mechanisms regulating activity of these
neurons and their functions in regulating normal homeostatic brain functions including sleep and sleep
pathologies. Compelling evidence indicates that disruption of the Hypocretin/Orexin (Hcrt/Orx) peptide system
results in narcolepsy - a sleep disorder characterized by excessive daytime sleepiness, sleep fragmentation
and the intrusion of rapid eye movement sleep behaviors into wakefulness. Building on the findings from the
previous funding period, which discovered a novel mechanism by which orexin alters the intrinsic properties of
mesopontine cholinergic neurons and dorsal raphe serotonergic neurons, we will investigate the hypothesis
that Hcrt/Orx peptides have pleiotropic actions which in the short term tune somatic and dendritic excitability to
enhance phasic synaptic inputs while attenuating tonic synaptic inputs and in the long-term regulate the
strength of synaptic inputs and circuit function.
To do so we will 1) Identify the ion channels underlying the new class of orexin actions on the post-spike
afterhyperpolarization in mesopontine cholinergic neurons and dorsal raphe serotonergic neurons. 2)
Determine the role of these novel actions on modulating the dendrites of mesopontine cholinergic neurons and
dorsal raphe serotonergic neurons. 3) Investigate the hypothesis that orexin regulates the strength of synaptic
inputs to 5-HT and GABA neurons in the LDT and DR and that the orexin-enhanced AHP and noisy orexin
conductance preferentially boost high frequency synaptic inputs arising from prefrontal cortex and that these
processes are perturbed in narcolepsy. These experiments will use whole-cell patch clamp recording, calcium
imaging and dynamic clamp methods in brain slices from normal and orexin receptor knockout mice and will
utilize focal uncaging of glutamate and optogenetic stimulation methods in normal and narcoleptic mice.
Collectively, these results will advance our understanding of the molecular, cellular and circuit mechanisms
underlying sleep regulation and its pathology.

## Key facts

- **NIH application ID:** 10168655
- **Project number:** 5R01NS027881-25
- **Recipient organization:** NEW YORK MEDICAL COLLEGE
- **Principal Investigator:** CHRISTOPHER S LEONARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $481,274
- **Award type:** 5
- **Project period:** 1991-12-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168655

## Citation

> US National Institutes of Health, RePORTER application 10168655, Synaptic modulation of mesopontine cholinergic neurons (5R01NS027881-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168655. Licensed CC0.

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