On the Role of Sensory Cancellation and Corollary Discharge in Neural Coding and Behavior

Studies of cerebellum-like circuits in fish have demonstrated that synaptic plasticity shapes the motor corollary discharge responses of granule cells into highly-specific predictions of self- generated sensory input. However, the functional significance of such predictions, known as negative images, has not been directly tested. Here we provide evidence for improvements in neural coding and behavioral detection of prey-like stimuli due to negative images. In addition, we find that manipulating synaptic plasticity leads to specific changes in circuit output that disrupt neural coding and detection of prey-like stimuli. These results link synaptic plasticity, neural coding, and behavior and also provide a circuit-level account of how combining external sensory input with internally-generated predictions enhances sensory processing. In addition, the mammalian dorsal cochlear nucleus (DCN) integrates auditory nerve input with a diverse array of sensory and motor signals processed within circuity similar to the cerebellum. Yet how the DCN contributes to early auditory processing has been a longstanding puzzle. Using electrophysiological recordings in mice during licking behavior we show that DCN neurons are largely unaffected by self-generated sounds while remaining sensitive to external acoustic stimuli. Recordings in deafened mice, together with neural activity manipulations, indicate that self-generated sounds are cancelled by non-auditory signals conveyed by mossy fibers. In addition, DCN neurons exhibit gradual reductions in their responses to acoustic stimuli that are temporally correlated with licking. Together, these findings suggest that DCN may act as an adaptive filter for cancelling self-generated sounds. Adaptive filtering has been established previously for cerebellum-like sensory structures in fish suggesting a conserved function for such structures across vertebrates

Role of the Cochlear Nucleus Circuitry in Tinnitus and Hyperacusis

Tinnitus is the disorder of phantom sound perception, while hyperacusis is abnormally increased loudness growth. Tinnitus and hyperacusis are both associated with hearing loss, but hearing loss does not always occur with either condition, implicating central neural activity as the basis for each disorder. Furthermore, while tinnitus and hyperacusis can co-occur, either can occur exclusively, suggesting that separate pathological neural processes underlie each disorder. Mounting evidence suggests that pathological neural activity in the cochlear nucleus, the first central nucleus in the auditory pathway, underpins hyperacusis and tinnitus. The cochlear nucleus is comprised of a ventral and dorsal subdivision, which have separate principal output neurons with distinct targets. Previous studies have shown that dorsal cochlear nucleus fusiform cells show tinnitus-related increases in spontaneous firing with minimal alterations to sound-evoked responses. In contrast, sound-evoked activity in ventral cochlear nucleus bushy cells is enhanced following noise-overexposure, putatively underlying hyperacusis. While the fusiform-cell contribution to tinnitus has been well characterized with behavioral and electrophysiological studies, the bushy-cell contribution to tinnitus or hyperacusis has been understudied. This dissertation examines how pathological neural activity in cochlear nucleus circuitry relates to tinnitus and hyperacusis in the following three chapters. In the first chapter, I characterize the development of a high-throughput tinnitus behavioral model, which combines and optimizes existing paradigms. With this model, I show that animals administered salicylate, a drug that reliably induces tinnitus at high doses in both humans and animals, show behavioral evidence of tinnitus in two separate behavioral tests. Moreover, in these same animals, I show that dorsal-cochlear-nucleus fusiform cells exhibit frequency-specific increases in spontaneous firing activity, consistent with the increased spontaneous firing observed in animal models of noise-induced tinnitus. In the second chapter, I show that following noise-overexposure, ventral-cochlear-nucleus bushy cells demonstrate hyperacusis-like neural firing patterns, but not tinnitus-specific increases in spontaneous activity. I contrast the bushy-cell neural activity with established fusiform-cell neural signatures of tinnitus, to highlight the bushy-cell, but not fusiform-cell contribution to hyperacusis. These analyses suggest that tinnitus and hyperacusis likely arise from distinct neural substrates. In the third chapter, I use computational modelling of the auditory periphery and bushy-cell circuitry to examine potential mechanisms that underlie hyperacusis-like neural firing patterns demonstrated in the second chapter. I then relate enhanced bushy-cell firing patterns to alterations in the auditory brainstem response, a sound-evoked electrical potential generated primarily by bushy cells. Findings in this chapter suggest that there are multiple hyperacusis subtypes, arising from separate mechanisms, which could be diagnosed through fine-tuned alterations to the auditory brainstem response.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163087/1/damartel_1.pd

Auditory-Somatosensory Integration in Dorsal Cochlear Nucleus Mediates Normal and Phantom Sound Perception.

The dorsal cochlear nucleus (DCN) is the first auditory brainstem nucleus that processes and relays sensory information from multiple sensory modalities to higher auditory brain structures. Converging somatosensory and auditory inputs are integrated by bimodal DCN fusiform neurons, which use somatosensory context for improved auditory coding. Furthermore, phantom sound perception, or tinnitus, can be modulated or induced by somatosensory stimuli including facial pressure and has been linked to somatosensory-auditory processing in DCN. I present three in vivo neurophysiology studies in guinea pigs investigating the role of multisensory mechanisms in normal and tinnitus models. 1) DCN fusiform cells respond to sound with characteristic spike-timing patterns that are controlled by rapidly inactivating potassium conductances. I demonstrated here that somatosensory stimulation alters sound-evoked firing rates and temporal representations of sound for tens of milliseconds through synaptic modulation of intrinsic excitability. 2) Bimodal plasticity consists of alterations of sound-evoked responses for up to two hours after paired somatosensory-auditory stimulation. By varying the interval and order between sound and somatosensory stimuli, I demonstrated stimulus-timing dependent bimodal plasticity that implicates spike-timing dependent synaptic plasticity (STDP) as the underlying mechanism. The timing rules and time course of stimulus-timing dependent plasticity closely mimic those of STDP at synapses conveying somatosensory information to the DCN. These results suggest the DCN performs STDP-dependent adaptive processing such as suppression of body-generated sounds. 3) Finally, I assessed stimulus-timing dependence of bimodal plasticity in a tinnitus model. Guinea pigs were exposed to a narrowband noise that produced temporary shifts in auditory brainstem response thresholds and is known to produce tinnitus. Sixty percent of guinea pigs developed tinnitus according to behavioral testing by gap-induced prepulse inhibition of the acoustic startle response. Bimodal plasticity timing rules in animals with verified tinnitus were broader and more likely to be anti-Hebbian than those in sham animals or noise-exposed animals that did not develop tinnitus. Furthermore, exposed animals with tinnitus had weaker suppressive responses than either sham animals or exposed animals without tinnitus. These results suggest tinnitus development is linked to STDP, presenting a potential target for pharmacological or neuromodulatory tinnitus therapies.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97934/1/skoehler_1.pd

A Cerebellum-like Circuit in the Auditory System Cancels Self-Generated Sounds

The first stage of mammalian auditory processing occurs within the dorsal and ventral divisions of the cochlear nucleus. The dorsal cochlear nucleus (DCN) is remarkable in that it shares striking similarities with the cerebellum in terms of its development, gene expression patterns, and anatomical organization. Notably, principal cells of the DCN integrate auditory nerve input with a diverse array of signals conveyed by a mossy fiber- granule cell system. Yet how the elaborate cerebellum-like circuitry of DCN contributes to early auditory processing has been a longstanding puzzle. The work in this thesis shows that, in mice, that the DCN functions to cancel responses to self-generated sounds. While the DCN and ventral cochlear nucleus (VCN) neurons respond similarly to externally-generated acoustic stimuli, sounds generated by licking behavior evoke much weaker responses in DCN than in VCN. Recordings in deafened mice revealed non- auditory signals related to licking in Purkinje-like neurons of DCN. Moreover, silencing somatosensory mossy fiber inputs revealed prominent DCN responses to sounds generated by licking, suggesting that these inputs normally function to cancel responses to self-generated sounds. Finally, I show that this cancellation is not fixed, but involves an adaptive process whereby neural responses correlated with the animal’s own behavior are gradually reduced. Together, these findings suggest that the fundamental process of distinguishing self-generated from external stimuli begins at the very first stage of mammalian auditory processing. Related adaptive filtering functions have been described for cerebellum-like sensory structures in fish and hypothesized for the mammalian cerebellum. Hence our findings also suggest that, despite their wide phylogenetic separation, different cerebellum-like structures and the cerebellum itself may all perform a similar computation

Sound processing in the mouse auditory cortex: organization, modulation, and transformation

The auditory system begins with the cochlea, a frequency analyzer and signal amplifier with exquisite precision. As neural information travels towards higher brain regions, the encoding becomes less faithful to the sound waveform itself and more influenced by non-sensory factors such as top-down attentional modulation, local feedback modulation, and long-term changes caused by experience. At the level of auditory cortex (ACtx), such influences exhibit at multiple scales from single neurons to cortical columns to topographic maps, and are known to be linked with critical processes such as auditory perception, learning, and memory. How the ACtx integrates a wealth of diverse inputs while supporting adaptive and reliable sound representations is an important unsolved question in auditory neuroscience. This dissertation tackles this question using the mouse as an animal model. We begin by describing a detailed functional map of receptive fields within the mouse ACtx. Focusing on the frequency tuning properties, we demonstrated a robust tonotopic organization in the core ACtx fields (A1 and AAF) across cortical layers, neural signal types, and anesthetic states, confirming the columnar organization of basic sound processing in ACtx. We then studied the bottom-up input to ACtx columns by optogenetically activating the inferior colliculus (IC), and observed feedforward neuronal activity in the frequency-matched column, which also induced clear auditory percepts in behaving mice. Next, we used optogenetics to study layer 6 corticothalamic neurons (L6CT) that project heavily to the thalamus and upper layers of ACtx. We found that L6CT activation biases sound perception towards either enhanced detection or discrimination depending on its relative timing with respect to the sound, a process that may support dynamic filtering of auditory information. Finally, we optogenetically isolated cholinergic neurons in the basal forebrain (BF) that project to ACtx and studied their involvement in columnar ACtx plasticity during associative learning. In contrast to previous notions that BF just encodes reward and punishment, we observed clear auditory responses from the cholinergic neurons, which exhibited rapid learning-induced plasticity, suggesting that BF may provide a key instructive signal to drive adaptive plasticity in ACtx

Interaural time difference processing in the mammalian medial superior olive

The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed

Change in Acoustic Startle as an Indicator of Continuous Tonal Tinnitus

Currently, there is no accepted objective measure of tinnitus in humans. The gap prepulse inhibition of acoustic startle (GPIAS) paradigm is an objective measure that has been used in the animal model to identify tinnitus based on the theory of tinnitus filling in the silent gap that would normally promote startle inhibition. The current study applied the GPIAS paradigm in human subjects with normal hearing thresholds without hyperacusis. Individuals with continuous tonal tinnitus (N=31) characterized their tinnitus by adjusting a signal to match the frequency, bandwidth, and intensity. These individual parameters were used to create maximally matched background sounds in the GPIAS paradigm for each subject. A group without tinnitus (N=8) also participated using the averaged parameter values of the background sound from the group with tinnitus. Startle inhibition percentage was calculated by comparing ocular EMG blinking amplitudes between gap embedded conditions and the condition without a gap. As expected, the group with no tinnitus revealed startle inhibition as evidenced by reduced EMG blink amplitudes when the background sound was interrupted by a silent gap prior to the startle impulse (100 dB SPL white noise). The group with tinnitus did not have a significant startle inhibition in this same condition supporting the theory that the background sound carefully matched to their tinnitus eliminated the perception of a silent gap, thereby removing the cue that would produce startle inhibition. Gradually increasing the contrast between the individual’s continuous tonal tinnitus and ongoing background sound leads to a nonlinear change in startle inhibition percentage, providing guidelines for how closely the background sound needs to match the tinnitus of an individual in order to get the expected result of no startle inhibition when tinnitus is filling in the gap. Collectively, these findings support the use of the GPIAS paradigm for objectively identifying continuous tonal tinnitus in humans. Further, certain deviations in frequency, intensity, or bandwidth in the ongoing background sound from the tinnitus match result in startle inhibition, which may help explain the inconsistent findings across human GPIAS studies and allow more confidence for animal researchers to use GPIAS for animal tinnitus studies