PROJECT SUMMARY & ABSTRACT This goal of this project is to investigate epigenetic neural mechanisms that can ensure meaningful sounds are faithfully and adaptively represented in the adult auditory brain. One important aspect of this research concerns the precision of acoustic content in memory, which is important for learning and performing fine-tine auditory discriminations. A second, concerns long-term maintenance of experience via learning-induced neuroplasticity for strong auditory memory, which is relevant to maintain learned auditory abilities for life. Animals (including humans) use associative learning to link sound cues to salient events (like rewards or other significant outcomes). When neural mechanisms of memory formation are activated following these experiences—mechanisms that span from molecules to genes to circuits and systems—associative memory is formed, which in turn provides otherwise arbitrary sound with acquired significance. For example, in audition, communication abilities require that sounds are precisely linked with their learned meaning, which depends on neuroplasticity and enduring auditory memory that lasts from minutes, to hours and days, or a lifetime. Decades of research indicate that associative learning systematically changes the sensory cortex to alter representation of sensory cues with learned behavioral salience. How? This proposal is to determine with multi-level approaches how molecules that regulate the genome—in particular epigenetic mechanisms that control chromatin acetylation by histone deacetylases (HDACs)—function to control genes that ultimately establish changes to the auditory system that contribute to its plasticity and subsequent long-term auditory memory. Indeed, HDACs are capable of enabling the auditory cortex to change with meaningful learning experiences, which may provide an instructive control on the auditory system as a whole for adaptive (or sometimes maladaptive) function. Currently unknown are the downstream gene and circuit mechanisms with which HDACs regulate auditory cortical plasticity. This is important as it could explain from a genetic level why some individuals naturally form auditory memories stronger and more specifically than others. Electrophysiological, pharmacological (AIM1) and viral (AIM2) techniques to manipulate HDAC3 in a rodent behavioral model of auditory associative learning will help determine how HDACs alter the acquisition and initial storage of robust auditory memory. Potential cholinergic determinants of HDAC effects will be tested using gene-targeted and genome-wide sequencing techniques (AIM1&2). Transgenic ChAT::Cre rats with activated DREADDs in cholinergic circuitry will challenge HDAC function (AIM3). The studies will explain how HDACs regulate neuroplasticity from genes, molecules, circuits and systems for robust auditory behaviors with a system better “tuned-in” to important sounds. This research promotes neuroepigenetics and gene-discovery as an important new niche for auditory neuroscience.

PROJECT NARRATIVE Approaching a comprehensive account of behavioral, neural and genetic mechanisms for the precision and lastingness of learning-induced auditory system reorganization will lead the future of hearing-related medical practices to achieve effects of auditory training that are acoustically rich as well as long-lasting. Use of a small- molecule epigenetic approach is a tool for gene discovery that will also aid precision medicine to its full potential for therapeutics that can coordinate complex effects that likely involve families of interacting genes. HDAC- inhibitors may further succeed in producing robust auditory remediation on an individual-person basis, especially when sound exposure therapies alone fail to induce relief, as in cases of long-standing hearing problems, in the aged brain where cholinergic signaling is known to be disrupted, or in rehabilitation following extreme auditory disturbances including cochlear implants.