# Synaptic Mechanisms of Mammalian Vestibular Efferent Responses

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $327,144

## Abstract

Project Summary
Vestibular organs, through their resident hair cells and afferent innervation, transmit information to the central
nervous system about the direction, speed, and magnitude of head and body movements, which are necessary
for maintaining posture, stabilizing gaze, and guiding navigational tasks. The vestibular organs are also
endowed with a robust efferent innervation that begins as a few hundred neurons within the dorsal brainstem
and extensively collateralizes in the periphery to end as thousands of bouton varicosities abutting hair cells and
afferents. In mammals, activation of the efferent vestibular system (EVS) ultimately excites primary vestibular
afferents along two distinct time scales. While acetylcholine (ACh) accounts for many EVS actions in other
vertebrates, the synaptic mechanisms underlying afferent responses to EVS stimulation in mammals have not
been identified. As a result, there is a clear gap in our knowledge in relating how the various EVS-mediated
actions are initiated, and what impact they exert on the subsequent responses of vestibular afferents to natural
stimuli. To facilitate an understanding of EVS function in mammalian vestibular physiology, three major
directions will be pursued in the peripheral vestibular system of mice. The first specific aim will establish the
pharmacological basis for the effects of EVS activation on spontaneous discharge of vestibular afferents. The
second specific aim will specify EVS postsynaptic mechanisms required for these EVS actions by using
transgenic animals where individual signaling components, implicated by our pharmacological data, are
absent. Finally, the last specific aim will identify how the activation of each EVS synaptic mechanism modifies
the responses of mammalian afferents to vestibular stimulation. To complete these specific aims, the discharge
properties of primary vestibular afferents in the anesthetized mouse will be characterized during EVS activation
with or without vestibular stimulation. Selective pharmacological agents will be applied to identify the receptors
and downstream effectors and to determine how they impact both stimulation paradigms. To identify and
localize specific signaling pathways, parallel electrophysiological and immunohistochemical studies will be
performed in transgenic animals where the function of proteins, integral to the synaptic mechanisms implicated
by the pharmacology in the first specific aim, are disrupted. The effects of EVS stimulation on afferent
responses to vestibular stimulation will be characterized by pairing rotational and translational stimuli with EVS
stimulation paradigms during pharmacological interrogation in both control and transgenic animals. These
studies are significant as they will provide much needed insights into the diverse synaptic mechanisms that the
EVS recruits to modulate afferent discharge in mammals. The data captured by this proposal is critical for
probing the functional roles of the EVS i...

## Key facts

- **NIH application ID:** 9861237
- **Project number:** 5R01DC016974-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Joseph Christopher Holt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $327,144
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861237

## Citation

> US National Institutes of Health, RePORTER application 9861237, Synaptic Mechanisms of Mammalian Vestibular Efferent Responses (5R01DC016974-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9861237. Licensed CC0.

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