Auditory-Arousal Circuits in Normal and Disordered Hearing

About This Grant

Unlike other sensory modalities, the auditory system maintains its sensitivity at all times, modulating vigilance across brain states, from active wakefulness to deep sleep. Through their widespread connectivity with arousal centers, auditory circuits can rapidly and potently mobilize us to act on potential threats, making sound perception inextricable from arousal state. However, most of what we know about auditory encoding and perception comes from experiments performed in awake subjects, particularly in the case of hearing loss and hearing perceptual disorders. Meanwhile, sleep disruption is one of the primary complaints of patients with hearing disorders such as tinnitus, and is common among people with sensorineural hearing loss. Decades of research on the consequences of hearing loss for the brain point to a possible mechanism—central auditory hyperactivity. Following the loss of peripheral inputs, central circuits compensate by increasing spontaneous activity, synchrony, and sound response gain. Our core hypothesis is that after hearing loss, hyperactive auditory neurons more readily recruit arousal via auditory-arousal circuits in the brain, where sound information is relayed to neurons that wake us rapidly and robustly from sleep. For the first time, central auditory function will be characterized across all brain states, including sleep, and arousal dysregulation will be related to the degree of auditory perceptual gain measured with a behavioral task. Sleep quality and quantity, including markers of sleep- related cognition, before and after hearing loss, will be systematically studied in the noise-induced hearing loss (NIHL) model, which produces a permanent threshold shift at high sound frequencies while leaving lower frequency hearing intact. This profile of steeply sloping high frequency hearing loss is common in the human population and is associated with tinnitus. Aim 1 of this project seeks to characterize a comprehensive sleep/wake profile of a mouse model of NIHL using freely moving electrophysiology and quantitative videography. A loudness categorization task will enable us to relate the degree of auditory perceptual gain to the degree of arousal dysregulation, motivating the usage of objective sleep metrics as potential biomarkers and outcome measures for the diagnosis and treatment of hearing perceptual disorders such as hyperacusis and tinnitus. Preliminary data shows that after NIHL, mice exhibit significantly fragmented non-rapid eye movement (NREM) sleep and wake more readily to moderate intensity sounds. Aims 2 and 3 are based on the hypothesis that auditory circuit hyperactivity is to blame, and uses a combination of viral- genetic circuit dissection methods, optogenetics and chronic single-unit recordings available in mice to investigate the auditory-arousal circuitry where NIHL-induced hyperactivity and increased sound response gain may recruit wake- promoting neurons. Given the rising prevalence hearing loss, dementia and insomnia among the world’s population, it is the long- term objective of this project to investigate the interconnected causes and consequences of these disorders in a mouse model with measures that are readily translatable to parallel human patient studies.