Date of Award

12-1-2015

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Caspary, Donald

Second Advisor

Faingold, Carl

Abstract

Age-related hearing loss, presbycusis, is a complex disorder involving the interaction of both peripheral and central neurological deficits. Central auditory dysfunction may contribute to poor temporal discrimination of complex sounds such as speech. This research is timely since our population over 60 years old is increasing rapidly due to advances in medicine and nutrition as well as the advancing age of baby boomers. This study was designed to provide a better understanding of age-related changes in dorsal cochlear nucleus (DCN) physiology. DCN was chosen because it receives direct input from the auditory nerve and much is known about its neuronal morphology, physiology and circuitry. In young animals, DCN output neurons, fusiform cells, receive excitatory inputs from the acoustic nerve, which is modulated and shaped by inhibitory glycinergic inputs from nearby vertical cells. A number of studies in rodents suggested an age-related impairment of glycinergic neurotransmission. To access the functional impact of reduced putative glycinergic input in the central auditory system, this study compared the physiological responses of DCN neurons from young adult and aged rats in response set of simple and more complex acoustic stimuli. Single-unit extracellular recordings were made from two groups of DCN neurons: fusiform cells and cartwheel cells. Fusiform cells reflect the culmination of DCN processing, therefore were good candidates for studying the effect of aging on one ascending auditory stream. Two specific aims were directed at fusiform cell: SA1) Examine the effects of aging on fusiform cell response properties to simple tone burst stimuli; SA2) Examine the effect of aging on DCN output neuron response to complex temporal stimuli. A third aim, SA3) Examine the impact of aging on the response properties of cartwheel cells, a DCN inhibitory interneuron. Fusiform cells recorded from aged rats displayed significantly higher maximum discharge rates to characteristic frequency (CF) tones, fewer nonmonotonic CF rate-level functions and more wide-chopper type post-stimulus time histograms (PSTHs) when compared to neurons from young adult rats. These findings were consistent with an age-related loss of inhibitory glycinergic input. To elucidate how loss of inhibition could lead to functional deficits in temporal processing, fusiform cells were challenged to encode sinusoidally amplitude modulated (SAM) tones. DCN output neurons were presented with SAM tones at three modulation depths at 30 dB above hearing level/response threshold with the carrier frequency set to each unit’s CF. Temporal synchronicity to the SAM envelope was measured using vector strength from temporal modulation transfer functions (tMTFs). Firing rate to SAM tones was also assessed in rate modulation transfer functions (rMTFs). DCN output neurons from aged rats showed no loss of rate response (rMTF) but displayed a selective loss of temporal precision to SAM tones with significant age-related changes in peak vector strength (best modulation frequency), and the shape and category of tMTF. Wide-chopper PSTH types had significantly lower vector strength values than buildup and pauser PSTHs in both young and aged fusiform cells. Since a significantly greater proportion of aged neurons exhibited wide-chopper responses, this could explain, in part, the loss of temporal processing. The age-related response changes in the present study mimicked results from earlier studies were glycine inhibition onto young adult fusiform cells was pharmacologically blocked. Cartwheel cells receive excitatory inputs from granule cell parallel fibers as well as somatosensory dorsal column nucleus and project glycinergic inputs onto DCN output neurons. They appear to play a role in the integration of auditory and somatosensory inputs such as sensing head position. Aged cartwheel neurons exhibited signs of disinhibition showing increased spontaneous activity, increased maximum discharge rates and altered rate-level functions. The observed age-related changes in cartwheel cells are consistent with deafferentation studies using acoustic trauma. Collectively, the changes in DCN output neurons and cartwheel cells reflect a potentially maladaptive age-related neuroplasticity in response to a loss of excitatory acoustic nerve input. These in vivo extracellular findings were consistent with a global downregulation of glycinergic input within the DCN of aged rats. This reduced inhibition may contribute to functional deficits, particularly in activities that require precise timing of events such as response to speech-like stimuli.

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