Nicotinic Effect on Auditory Processing: an Unexpected Role of the alpha2 Nicotinic Acetylcholine Receptor
ABSTRACT OF THE DISSERTATIONNicotine Effect on Auditory Processing: an Unexpected Role of the alpha-2 Nicotinic Acetylcholine Receptor by Susan Gil Doctor of Philosophy in Biological Sciences University of California, Irvine, 2021 Dr. Raju Metherate, Chair Nicotine enhances cortical neurophysiology and higher cognitive functions, such as attention, learning and memory. This enhancement is presumably mediated by activation of nicotinic acetylcholine receptors (nAChRs), located within central cholinergic systems that mediate attention and other higher brain functions. Subsequently, nAChR agonists are being considered as prospective therapeutics for treating cognitive disorders. However, the nAChR family is comprised of many subtypes, which differ in composition, expression density, distribution, and nicotinic action. A prudent approach to better inform drug development is to investigate the unique contribution(s) of individual nAChR subtypes to nicotinic cognitive enhancement. Moreover, it is important to consider the possible involvement of less common (and underexamined) nAChR subunits and the role they may play in the overall outcomes of nAChR activation. Using the mouse auditory system, the following experiments explore the physiological role and laminar expression of the alpha2 nicotinic acetylcholine receptor (a2nAChR). xiii In Chapter 1, I used in-vivo electrophysiology within mouse primary auditory cortex (A1), to investigate the role of the underexamined a2nAChR in nicotinic effects on auditory processing. Current-source density recordings within A1 of anesthetized mice revealed that activation of a2nAChRs is involved in the nicotinic enhancement of responses to pure tone stimuli. In fact, compared to wild-type (WT) mice, nicotinic enhancement of A1 responses is altered in mice where the a2 gene has been deleted (a2KO). In Chapter 2, in order to survey respective laminar distributions, and co-expression within the auditory cortex (ACx), I used immunolabeling of parvalbumin (PV), vasoactive intestinal peptide (VIP), and somatostatin (SOM) interneuron markers on brain sections of mice expressing the enhanced green-fluorescent reporter protein (eGFP). Driven by the a2 promoter, eGFP fluoresced in cells containing the a2nAChR subunit (resulting mice are referred to as a2eGFP mice). We found that a2nAChRs were almost exclusively expressed in Layer V, and generally localized with SOM-expressing interneurons. Together these chapters represent the initial physiological and anatomical investigations of a2nAChRs in the ACx. They serve to further our understanding of a2nAChRs function in auditory processing.