Thursday, May 2, 2024
5/2/2024
¿ DESCRIPTION (provided by applicant): Age-related hearing loss is a complex disorder affecting at least 30-50% of the United States population aged 65 or older. In public settings, seniors frequently have difficulty understanding speech, which can lead to withdrawal from social activities and depression. Elderly individuals also show deficits in their ability to attendto speech in complex auditory environments. Aging studies suggest that the elderly can maintain speech understanding as they age despite degraded ascending temporal information by using attentional and cognitive resources. Studies completed during the previous grant period detailed the makeup and function of receptors mediating inhibition in young and aged thalamocortical circuits likely to underpin coding of acoustic information. Using in vitro slice recordings and in vivo recordings from awake rat medial geniculate body (MGB), these studies found significant age-related changes in the makeup, function, and pharmacology of GABAA receptors in MGB and in auditory cortex. In young adults, difficult-to-understand speech and novel stimuli result in downstream signals sent from cortical areas, including auditory cortex and hippocampus, to activate brainstem cholinergic arousal/attentional circuits. In turn, brainstem cholinergic neurons project to auditory structures including MGB. In sensory thalamus, the neurotransmitter acetylcholine plays a critical role in waking attention and in establishing the salience of important stimuli. High levels of nicotinic cholinergic receptors (nAChRs) are found in MGB, yet much remains to be learned about their subunit composition, location within MGB circuits and how aging impacts these systems. Humans and rats show a 30+% age-related loss of one key nAChR subunit in whole thalamus. Our preliminary MGB assays support and extend these findings. These data suggest, for the first time, the presence of significant age-related changes in the subunit makeup of nAChRs resulting in an age-related loss in receptor affinity. Preliminary patch-clamp slice data show reduced pre- and postsynaptic nAChR responses supporting this age-related loss in affinity. In vitro and in vivo approaches will: SA1. Characterize heteromeric nAChRs in the major subdivisions and cell types of young-adult MGB via: 1A) pharmacology, subunit composition and location, and 1B) physiology and cellular location. SA2. Characterize age-related changes that occur in nAChRs for the major subdivisions and cell types in MGB via: 2A) pharmacology, subunit composition and location, and 2B) physiology and cellular location. SA3. 3A) Determine age-related changes that occur in processing novel, temporally rich stimuli recorded from MGB units in awake animals. 3B) Iontophoretic studies will examine the impact of nAChR agonist and antagonists on these temporal responses properties. Understanding pharmacologic and functional nAChR changes associated with aging would inform development of selective pharmacotherapy that could ameliorate age-related loss of speech understanding.
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