Susan Shore, Ph.D. - US grants

DESCRIPTION: (Adapted from applicant's abstract): We have demonstrated that the trigeminal ganglion sends a projection to the auditory brain stem and to the cochlear vasculature. The terminations in the brainstem end in granular and magnocellular regions of the ventral cochlear nucleus (VCN) and at the locations of olivocochlear neurons in the superior olivary complex. The cochlear portion of the innervation modulates blood flow within the cochlea. However, the function of the brainstem projection is unknown. Preliminary findings suggest that the projection to the VCN is excitatory. The axons of granule' cells (parallel fibers) project to the dorsal cochlear nucleus (DCN). Therefore, excitation by the trigeminal innervation could affect most of the output neurons of the cochlear nucleus (CN). A series of studies is designed to elucidate the function of the CN portion of this new projection and define its neurotransmitters: The trigeminal ganglion will be electrically stimulated while observing the responses of single units in the CN. The candidate neurotransmitters, Substance P and Nitric Oxide, will be evaluated using immunocytochemistry and neuropharmacology. A role for the trigeminal ganglion in the generation and modulation of tinnitus will be explored: As many as two thirds of tinnitus patients are able modulate their tinnitus by clenching the jaw or touching the skin on the face, areas innervated by the trigeminal ganglion. Others can attribute the onset of tinnitus to a somatic insult in the head and neck region ("somatic tinnitus"). On the assumption that increased spontaneous rate is a manifestation of tinnitus, its modulation by somatosensory input to the CN could play a role in the generation and modulation of tinnitus. The hypothesis wifi be tested by electrically stimulating the trigeminal ganglion while recording spontaneous activity in single units of the CN. Identifying the neurotransmitter used in this pathway could then set the stage for later drug treatments.

DESCRIPTION (provided by applicant): Glutamatergic somatosensory projections to the cochlear nucleus (CN) originate in trigeminal and dorsal column systems and terminate primarily in the CN granule cell domain (GCD). Stimulating these inputs alters spontaneous and sound-driven responses in principal neurons of the dorsal and ventral CN for extended periods of time. This long-term bimodal alteration is enhanced after unilateral deafness and could explain why patients are able to modulate their tinnitus by somatic maneuvers such as jaw clenching. The aims of this proposal are to determine the physiological and molecular mechanisms underlying long-term suppression and enhancement of CN responses by somatosensory projection neurons and their implications for tinnitus generation and modulation. Aim 1a will examine long-term synaptic plasticity as a mechanism underlying bimodal enhancement and suppression in fusiform and bushy cells in normal and noise-damaged guinea pigs. We hypothesize that bimodal enhancement will predominate in noise-damaged animals with physiological correlates (increased spontaneous rates and synchrony) and behavioral evidence of tinnitus using the gap-detection tinnitus screening method (Aim 1b). Aim 2 will examine the hypothesis that the predominance of bimodal enhancement in animals with tinnitus (preliminary data) is a result of up-regulation of specific Vglut2- positive somatosensory endings in the CN after deafness. In Aim 2a, tract-tracing and immunocytochemical studies will determine the precise origins and endings of the upregulated inputs in mouse. Aim 2b will utilize Vglut2-deficient mice to test the hypothesis that Vglut2+/- mice will be resistant to tinnitus induction. Mice will be tested for tinnitus using gap-detection before and after narrow-band noise overexposure. Preliminary data indicate that compared to matched wild-types, the Vglut2+/- mice show significantly less evidence of tinnitus, supporting this hypothesis. Aim 2c will then explore the involvement of the fibroblast growth factor, FGF22, as a postsynaptic signal for presynaptic upregulation of somatosensory mossy fibers to the CN after deafness. Our studies strongly implicate the somatosensory system, not only in the modulation, but also in the generation of tinnitus. Not surprisingly, more than half of tinnitus patients (~20 million) can modulate their tinnitus with somatic maneuvers, or attribute its onset to a somatosensory injury. Investigating underlying mechanisms in somatosensory-auditory integration after cochlear damage will allow us to elucidate the changes that contribute to tinnitus, and thus provide insights leading to successful interventions.

Abstract The dorsal cochlear nucleus (DCN) integrates auditory and somatosensory information through circuitry that modulates activity of the principal output neurons of the circuit, the fusiform cells. Fusiform cells receive somatosensory information via synapses on their apical dendrites and acoustic information via their basal dendrites. When somatosensory activation is combined with sound, the circuit can be strengthened or weakened depending on the order of the bimodal stimuli. This process is called stimulus timing dependent plasticity. In the condition of phantom sound perception, or tinnitus, the DCN circuitry is strengthened to increase the firing rates and synchrony of fusiform cells. This proposal seeks to investigate the effects of manipulations on the circuitry of this first auditory brainstem nucleus by implementing a bimodal sound + electrical stimulus paradigm to alter the circuit in normal and pathological conditions. Animal and human studies will be conducted to optimize the stimulation parameters/dosages necessary to weaken the circuit and thus ameliorate the pathological condition. This will ultimately lead to treatments for neural disorders involving hyperactive or hyper synchronous circuits such as those identified for tinnitus or Parkinson's disease.

Abstract The concept of ?hidden? hearing loss challenges the idea that temporary threshold shifts (TTS) reflect a return to normal hearing. Recent studies indicate that after noise-exposure that produces TTS, and thus clinically 'normal' audiograms, there is nonetheless permanent damage to auditory nerve fiber (ANF) synapses with cochlear inner hair cells. Hidden hearing loss is a potential major health issue, as human temporal bone and ABR studies suggest it is common in humans. The remaining perceptual deficits in humans with clinically normal audiograms reflect temporal coding problems likely due to loss of the high threshold, low spontaneous rate ANFs, which are preferentially affected after TTS. The primary central targets of high-threshold ANFs reside in the small cell cap (SCC) of the cochlear nucleus (CN). High-threshold ANFs and their SCC targets display large dynamic ranges and superior suprathreshold tuning and temporal coding, which are essential for speech perception in noisy environments. The SCC occupies a large proportion of the CN in humans and is therefore poised to play a major role in central mechanisms of hidden hearing loss. The SCC is unique also as a putative recipient and projection area of medial olivocochlear (MOC) neurons. The overall hypothesis of this proposal is that the SCC plays a major role in suprathreshold sound coding and that this coding is highly susceptible to degradation by hidden hearing loss. The goal of this series of studies is to elucidate the cochlea- SCC-MOC circuit in normal and noise-damaged animals with hidden hearing loss, using state-of-the-art optogenetics, multichannel single unit physiology, tract tracing and sophisticated immunohistochemical methods.