Daniel B. Polley - US grants

Project Summary Ludwig van Beethoven poignantly expressed the perceptual and social burden of hearing loss in an 1801 letter to a friend stating, ?But that jealous demon, my wretched health, has put a nasty spoke in my wheel?for the last three years my hearing has become weaker and weaker. My ears continue to hum and buzz day and night. Sometimes I can scarcely hear a person who speaks softly?but if anyone shouts I can?t bear it. Heaven alone knows what is to become of me.? Beethoven?s self-described maladies can be identified as tinnitus, threshold shift and hyperacusis, respectively. Hyperacusis presents as two distinct neurological disorders: i) ?noxicusis?, in the form of excruciating sound-triggered ear pain or ii) a generalized auditory hypersensitivity that makes even moderately intense sounds seem uncomfortably loud. The neurobiological causes of this second, more common, type of hyperacusis have yet to be defined. This project will develop a mouse model of noise-induced hearing loss to reveal neural circuit changes that cause auditory perceptual hypersensitivity. Studies pursuant to Aim 1 will develop a suite of head-fixed operant behavioral assays to track the emergence of perceptual hypersensitivity following noise-induced high-frequency hearing loss. Studies in Aim 2 will use chronic 2-photon calcium imaging of genetically targeted excitatory and inhibitory neurons in auditory cortex to pinpoint the emergence of cortical hyperactivity relative to perceptual hypersensitivity. Complementary single unit electrophysiology studies will contrast cortical hyperexcitability elicited with acoustic stimuli versus optogenetic stimuli that bypass the ear and brainstem to directly activate neurons in the auditory thalamus. Aim 3 will test the hypothesis that auditory cortex hyperexcitability is necessary and sufficient for auditory perceptual hypersensitivity by expressing stabilized step function opsins to temporarily induce or reverse cortical hyperexcitability independent of hearing loss. Studies in Aim 4 will address the distributed downstream effects of excess central gain by tracking the emergence of noise- induced hyperexcitability in descending cortical efferents as well as local cell bodies in the amygdala and dorsal cortex of the inferior colliculus. By tracking the precise chronology of hyperexcitability within and beyond the auditory pathway alongside sound-triggered defensive behaviors such as freezing, it will be possible to identify a direct link between sensory plasticity and disorders of anxiety and stress that are commonly observed in individuals with hyperacusis. This association can be causally tested by inducing or reversing cortical hyperexcitability and noting a potential reversal in subcortical makers of excess loudness growth. Taken together, this proposal will leverage modern neuroscience tools to perform causal hypothesis testing on neural circuit changes that underlie a common hearing disorder. Sensory hypersensitivity is also a core phenotype of migraine as well as neurodevelopmental disorders including Autism and Fragile X syndrome. Identifying the biological signatures of over-powered cortical amplification would open up new treatment strategies, with far- ranging implications for hearing impairment and other related neurological disorders.

DESCRIPTION (provided by applicant): The long-term objective of the proposed work is to understand how the intrinsic electrical excitability of neurons in central auditory system contributes to auditory signal processing. The type and amount of voltage- gated potassium (Kv) channels expressed in the cell membrane determine the shape, probability and temporal patterning of action potentials and therefore principally determine a neuron's intrinsic electrical excitability. Detailed analyses of Kv channel biochemistry and biophysics indicate that two Kv channels, Kv3.1 and Kv1.3, exhibit properties that are particularly germane to the aims of this proposal. Kv1.3 and Kv3.1 have been observed to have significant - and often opposing - roles in regulating the neuronal response threshold, maximum sustained firing rate and maximum following rate. Alterations in these response features have clear implications for acoustic signal processing, which will be explored in depth through the combined use of neurophysiological and behavioral assays in Kv3.1 and Kv1.3 knockout mice. Aim 1 seeks to characterize the effects of Kv3.1 and Kv1.3 deletion at the level of the single unit within the inferior colliculus (IC). Neurophysiological selectivity for variations in sound frequency, temporal envelope properties, intensity and binaural interaction will be compared in awake Kv3.1 null, Kv1.3 null and wild-type mice. Aim 2 would relate variations in neurophysiological responses to commensurate shifts in hearing thresholds. These experiments will implement a conditioned avoidance protocol to measure detection and discrimination thresholds for variations in sound frequency, temporal structure and intensity. Through the combined application of genetic, neurophysiological and behavioral analyses, the proposed experiments would further our understanding of how the basic building blocks of excitability in the brain impact auditory processing and perception. Relevance: These experiments will further our understanding of the molecular determinants of brain function and behavior. By studying the effects of single gene deletions on the physiological response properties of single cells in the brain and the hearing abilities of animals actively engaged in listening tasks, the proposed experiments may allow us to frame the effects of genetic mutations in a more integrative context of auditory system function. Furthermore, the proposed experiments could shed additional light on the role of intrinsic neuronal excitability in the context of auditory information processing as well as pathological states such as audiogenic seizure.

DESCRIPTION (provided by applicant: Sensory representations are dynamically maintained by ascending and descending connections linking the cerebral cortex and the thalamus. Although the overall extent and topographic specificity of descending corticothalamic projections can equal or surpass that of thalamocortical projections, little is known about their role in perception or learning. Here, we propose a new chemical-genetic approach known as DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to parse the functional contribution of corticothalamic circuits that arise from layer 5 versus layer 6 of primay and secondary areas of the auditory cortex. By silencing specific cortical feedback circuits while recording from ensembles of thalamic neurons in mice that are either passively listening to sound or are actively engaged in listening tasks, we will gain deeper insight into the workings of multiple, parallel feedback systems that enable the cerebral cortex to modify its afferent input stream.

Project Summary Hearing impairment is a common chronic health condition of older age that has been linked to adverse changes in social and emotional well-being. Steeply sloping, high-frequency hearing loss (HFHL) is the most common sensorineural hearing loss profile for middle-aged and older adults with a past history of noise exposure. A common complaint of subjects with HFHL relates to a difficulty understanding speech in fluctuant background noise. Individual thresholds for recognizing speech in noise vary widely, are not well predicted from the audiogram, and are not reliably improved by amplification. The underlying motivation for this project is to identify physiological and perceptual biomarkers that more accurately predict speech in noise recognition in subject with HFHL, as compared to age-matched subjects with normal hearing (NH). Our underlying hypothesis is that impaired speech in noise processing for subjects with HFHL can be predicted from abnormal neural coding of low-frequency signals, where thresholds are normal. In Aim 1, we employ a series of physiological and psychophysical tests to identify the stage of neural processing (from auditory nerve to cortex) and mode of neural processing (from the auditory nerve compound action potential to subcortical encoding of stimulus fine structure) that most directly map onto speech in noise outcomes in HFHL and NH subjects. To further probe the linkage between neural processing of low-frequency signals and speech in noise recognition, we will employ a new approach to enhance speech in noise processing through an immersive, closed-loop audiomotor software training interface. Our preliminary data suggest that speech in noise recognition can be significantly improved in subjects with sensorineural hearing loss that were randomly assigned to closed-loop audiomotor training, as compared to subjects assigned to a placebo auditory training interface. However, it is not known which physiological and perceptual predictors of speech processing are also modified to support a change in speech recognition thresholds. Aim 2 will address this point through a randomized, double-blind placebo-controlled study design that will compare the neural and physiological predictors of speech processing before training, after training and at a follow-up test after training has been discontinued. By identifying the biomarkers of neural processing that not only predict speech outcomes in a baseline condition, but also track dynamic shifts in speech processing over the course of an intervention, these studies may identify the most robust neural predictors of speech in noise processing as well as possible targets for future therapies.

Project Summary During active listening, sound features that are distracting, irrelevant, or totally predictable are suppressed and do not rise to perceptual awareness. By contrast, inputs selected for amplification convey behaviorally relevant auditory signals used to guide ongoing perceptual decision making. The neural circuit mechanisms that selectively suppress or amplify bottom-up inputs to support active listening remain largely mysterious. Logically, neurons that support active listening would have inputs from cognitive signals that encode expectation, attentional selection and task demands, yet would also be able to adjust the gain and tuning of low-level auditory neurons that encode or compute bottom-up sound features. The massive network of descending auditory corticofugal neurons fit the bill because their cell bodies are embedded in highly plastic centers for cortical sound processing, yet their axons innervate subcortical auditory nuclei in the thalamus, midbrain and brainstem. Addressing the involvement of corticofugal neurons in active listening behaviors has been challenging due to the technical difficulty of isolating and manipulating specific classes of auditory cortex neurons in awake, actively listening animals. Here, we describe an approach to overcome these technical obstacles and address the hypothesis that a specific sub-class of auditory corticofugal neuron, the layer 6 corticothalamic neuron (L6 CT), plays an essential role in sculpting enhanced cortical and perceptual processing of expected sounds. In Aim 1, we will use cutting-edge methods for cell type-specific imaging and electrophysiology in awake, behaving mice to make targeted recordings from two classes of auditory subcerebral projection neurons: layer 5 corticocollicular neurons (L5 CCol) and L6 CTs. We expect to find stark differences in the auditory tuning, sensitivity to internal state variables, local outputs and monosynaptic inputs of L5 CCol and L6 CT neurons (Aim 1a-1d, respectively). In Aim 2, we will record from targeted subtypes of auditory cortex neurons as mice learn to form a spatiotemporal filter for processing expected sounds. We will address the hypothesis that L6 CT neurons modify their activity shortly before the onset of expected sounds to optimize cortical processing of behaviorally relevant signals. In Aim 3, we will test the causal involvement of L6 CT spike patterning for enhanced processing of expected sounds by optogenetically silencing their activity at key times in well-trained mice (to test necessity) or activating them in naïve mice (to test sufficiency). Collectively, these experiments will reveal neural circuit mechanisms that support the selection of bottom-up inputs for enhanced perceptual processing during active listening. By extension, improper regulation of this circuit could underlie the irrepressible awareness of unwanted or distracting sounds (e.g., attention deficit hyperactivity disorder) or the perception of sounds that do not exist in the environment (e.g., tinnitus and schizophrenia). ?