Date of Award

8-1-2017

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Tischkau, Shelley

Second Advisor

Caspary, Donald

Abstract

The medial geniculate body (MGB) is the thalamic nucleus situated between the inferior colliculus (IC) and auditory cortex (AC) in the ascending auditory pathway. It has classically been thought of as a relay station for auditory stimuli; however, we now know that is capable of significantly influencing incoming auditory information. As aging occurs, there is a loss of auditory signal fidelity as well as a disruption in the accurate coding of acoustic information. In order to compensate for the age-related loss of auditory signal quality, additional cortical resources play a role in knowledge-based optimization of input. This top-down processing is mediated in part by cholinergic systems, which direct attention to relevant incoming sensory information. The primary cholinergic input to the MGB is a large cholinergic projection from the pontomesencephalic tegmentum. The PMT is a brainstem structure composed of the pedunculopontine nucleus and laterodorsal tegmental nuclei. These structures provide acetylcholine (ACh) to the auditory thalamus and midbrain thereby playing a role in sustaining attention, sensory gating, and arousal. Acetylcholine may then act at pre- and postsynaptic receptors at the level of MGB and function to assign salience to auditory stimuli. The central goal of these studies is to examine the location of nAChRs in the local MGB circuitry, their subunit composition, physiology, and how these properties are impacted with age. We have found that ACh produces significant excitatory postsynaptic actions on young MGB neurons, likely mediated by β2-containing heteromeric nAChRs. Use of the β2-selective nAChR antagonist, dihydro-β-erythroidine, suggests that loss of cholinergic efficacy may also be due to an age-related subunit switch from high affinity β2-containing nAChRs to low affinity β4-containing nAChRs, in addition to a loss of total nAChR number. This age-related nAChR dysfunction may partially underpin the attentional deficits which contribute to the loss of speech understanding in the elderly. Activation of presynaptic nAChRs potentiated responses evoked by stimulation of excitatory corticothalamic terminals and inhibitory tectothalamic terminals. Conversely, application of ACh appeared to have no consistent effects on paired-pulse responses evoked from stimulation of excitatory tectothalamic terminals and inhibitory projections from the thalamic reticular nucleus. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were attenuated by aging. The present findings suggest that the increased output from the cholinergic pedunculopontine neurons onto MGB neurons following presentation of difficult to identify stimuli or arousal increases the strength of tectothalamic inhibitory projections likely improving signal-to-noise ratio and enhancing signal detection, while increasing gain on corticothalamic excitatory signals facilitating top-down identification of the unknown stimulus. Thus, cholinergic inputs to MGB are positioned to maximize sensory processing by dynamically adjusting both top-down and bottom-up mechanisms in conditions of attention/arousal.

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