For hearing, as for the other senses, the perception of environmental stimuli improves with activation of nicotinic acetylcholine receptors (nAChRs) in the brain. For example, auditory-cognitive function is enhanced by administration of the drug nicotine, but impaired by blocking nAChRs (using other drugs) or by disease- induced loss of nAChRs (i.e., in neurodegenerative diseases, such as Alzheimer's Disease). It is widely thought, therefore, that nAChRs are important for optimal auditory-cognitive function. Although, as a result, nicotinic drugs are being developed to treat a variety of cognitive disorders, such approaches to date have not been used to treat auditory processing disorders. During auditory attention, activation of nAChRs is thought to improve attentional filtering-the enhanced processing of important stimuli and suppression of distracting stimuli that appears to involve narrowing of frequency receptive fields (RFs) in the auditory system. We hypothesize that activation of nAChRs will narrow RF tuning in primary auditory cortex (A1) and enhance processing within narrowed RFs, and that these cellular actions of nAChRs contribute to attentional filtering.
Aim 1 will determine how activation of nAChRs alters spectral integration in A1, using tone-evoked current- source density (CSD) profiles to determine frequency RFs.
Aim 2 will determine how nicotinic activation of intracellular signal transduction involving mitogen-activated protein kinase (MAPK) recruits subpopulations of neurons, especially interneurons, in A1.
Aim 3 will determine how activating nAChRs and MAPK in identified interneurons alters acoustic processing.
These Aims will identify mechanisms by which nAChRs in A1 can enhance auditory processing, and specify the contributions of nAChR subtypes and neuron subpopulations. Our long-term goal is to understand nicotinic mechanisms of auditory-cognitive function, and thereby aid the development of pharmacological treatments for auditory processing disorders.

Public Health Relevance

The drug nicotine enhances auditory-cognitive function because it 'hijacks' the brain's own system for paying attention to important sounds amid distractions, such as speech in a noisy environment. This project seeks to determine how nicotinic acetylcholine receptors in the brain contribute to the auditory-attention system. The long-term goal is to understand auditory-cognitive function and aid the development of pharmacological treatments for auditory processing disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013200-13
Application #
8846569
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Platt, Christopher
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
13
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Askew, Caitlin; Intskirveli, Irakli; Metherate, Raju (2017) Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions. eNeuro 4:
Samra, Gurleen K; Intskirveli, Irakli; Govind, Anitha P et al. (2017) Development of fluorescence imaging probes for nicotinic acetylcholine ?4?2? receptors. Bioorg Med Chem Lett :
Intskirveli, Irakli; Joshi, Anar; Vizcarra-Chacón, Bianca Julieta et al. (2016) Spectral breadth and laminar distribution of thalamocortical inputs to A1. J Neurophysiol 115:2083-94
Askew, Caitlin E; Metherate, Raju (2016) Synaptic interactions and inhibitory regulation in auditory cortex. Biol Psychol 116:4-9