# Nicotinic enhancement of auditory-cognitive processing

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $619,350

## Abstract

PROJECT SUMMARY / ABSTRACT
For hearing, as for other senses, higher-level processing improves with attention-related release of the
neurotransmitter acetylcholine and activation of nicotinic acetylcholine receptors (nAChRs) in the brain.
Similarly, auditory-cognitive function is enhanced by systemic administration of nicotine to activate nAChRs,
impaired by pharmacological blockade of nAChRs, and progressively diminished by disease-induced loss of
nAChRs (e.g., in Alzheimer’s disease) that reduces the efficacy of endogenous acetycholine. It is widely
agreed, therefore, that nAChRs are important for sensory-cognitive function. As a result, selective nicotinic
agonists are being developed as treatments for cognitive disorders; however, to date these are only
moderately successful and further progress requires a better understanding of how nAChRs regulate cortical
processing. This project will test the hypothesis that nicotine produces its cognitive-enhancing effects by
“sharpening” neural representations in two key regions, primary auditory (A1) and prefrontal (PFC) cortex, and
that nicotine’s effects depend on activating a2 nAChRs located on inhibitory neurons that can be identified by
the protein marker, vasoactive intestinal peptide (VIP). Aim 1 will determine how nAChRs regulate neural
circuits in mouse A1 and PFC using in vitro brain slices and in vivo electrophysiological recordings. The use of
transgenic mouse lines will enable recordings from identified neurons, including VIP neurons, and recordings
from mice with a2 nAChRs “knocked out” or made hypersensitive. Aim 2 will determine how nicotine alters the
activity of A1 and PFC neurons during auditory-cued behavior using high-density single-cell recordings in rats
and mice performing a novel auditory-sequence memory task. Again, nicotine effects will be compared across
wild-type, a2 knock-out and a2 hypersensitive mice. Aim 3 will use chemogenetic techniques to determine if
suppression of VIP neurons or a2 nAChRs blocks nicotine’s effects on neural processing, in vitro and in vivo,
and behavioral performance. This project will advance the understanding of nAChRs in auditory-cognitive
function and the specific involvement of VIP interneurons and a2 nAChRs in A1 and PFC. Confirmation of an
important role will guide development of more effective and selective drug therapies to enhance auditory-
cognitive function.

## Key facts

- **NIH application ID:** 9830635
- **Project number:** 5R01DC017687-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Raju Metherate
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $619,350
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830635

## Citation

> US National Institutes of Health, RePORTER application 9830635, Nicotinic enhancement of auditory-cognitive processing (5R01DC017687-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830635. Licensed CC0.

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