# Neuromodulatory Control of Cerebellar Synaptic Processing and Sensory Input

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $347,813

## Abstract

Sensorimotor integration in the cerebellum is essential for refining motor output. Much of this
integration occurs at the initial stage of cerebellar processing, in the granule cell layer where
mossy fibers carrying diverse sensory and motor information converge. While these
computations have been thought to occur through rigid, anatomically defined circuits, recent
evidence suggests that granule cell layer integration can be contextually modified.
Neuromodulators represent a strong candidate for such regulation, and anatomical studies have
revealed prominent cholinergic and serotonergic projections into the cerebellar granule cell
layer. However, it is unknown how these neuromodulators act at the cellular and circuit level to
control sensory and motor integration. Our preliminary data reveal that Golgi cells, interneurons
that provide the sole source of inhibition to the granule cell layer, express receptors for both
acetylcholine (ACh) and serotonin (5-HT). We find that these neuromodulators bi-directionally
regulate the excitability of Golgi cells: ACh suppresses Golgi cell spiking while 5-HT elevates
spiking. In addition, we find that granule cells are depolarized by ACh. This suggests that ACh
may generally act to increase excitability in the granule cell layer. Using a combination of
modern physiological, genetic and anatomical approaches in the mouse, we will test the
following aims: In Aim 1 we will use an in vitro brain slice preparation to identify the sites of ACh
and 5-HT receptor expression on the major cell classes of the granule cell layer: the granule
cells, Golgi cells and mossy fibers. Using targeted application of neuromodulatory agonists and
specific pharmacology, we will determine how these neuromodulators directly impact cellular
excitability both acutely and after prolonged exposure. In Aim 2, we will use retrograde tracing to
identify the sources of cerebellar cholinergic and serotonergic inputs. This will allow us to
identify whether these neuromodulatory inputs are part of a larger, brain-wide system, and
under what conditions they are active. Localizing the afferent neuromodulatory nuclei will also
allow viral delivery of optogenetic proteins, and thus investigation of the effect of endogenously
released neuromodulators on the intact granule cell circuit. In particular, we will test the
hypothesis that ACh acts to increase excitability in the granule cell layer while 5-HT acts to
decrease it. Then in Aim 3, we will test how these neuromodulatory effects on excitability
regulate granule cell layer integration of sensory and motor input in vivo. We will use multi-unit
electrophysiology and two-photon imaging to determine how activation of cholinergic and
serotonergic inputs alter the activity of the population of granule cells. In particular, we will
present sensory stimuli with graded intensity to test the hypothesis that ACh and 5-HT change
the gain of the granule cell network. Together, these experiments will reveal th...

## Key facts

- **NIH application ID:** 9898477
- **Project number:** 5R01NS096289-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** COURT A HULL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,813
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898477

## Citation

> US National Institutes of Health, RePORTER application 9898477, Neuromodulatory Control of Cerebellar Synaptic Processing and Sensory Input (5R01NS096289-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898477. Licensed CC0.

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