Functions of Nicotine Receptors in Sensory Neocortex

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DESCRIPTION (provided by applicant): 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.