Project Details
Description
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.
Status | Active |
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Effective start/end date | 9/15/20 → 8/31/25 |
Funding
- National Institute on Deafness and Other Communication Disorders: $331,500.00
- National Institute on Deafness and Other Communication Disorders: $391,773.00
- National Institute on Deafness and Other Communication Disorders: $331,500.00
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