Sound reward learning induces distinct auditory cortical transcriptional changes
Creators: name: Graham, Guan-En
Publisher: name: No Publisher Supplied
Year: 2025

description: Gene expression is dynamically regulated in the adult brain during learning and memory formation across multiple brain systems including the sensory cortex. Over the past decade, epigenetic mechanisms that regulate transcription have been implicated in modulating adult learning-induced sensory cortical plasticity. Of the sensory cortices, the auditory cortex has been best described for its capabilities to gate the encoding of sensory features in the production of persistent and vivid long-term memories of sensory experiences. Learning induces neurophysiological plasticity in the adult auditory cortex at multiple timescales to support both short-term (at a scale of seconds to minutes) and long-term (at a scale of hours or potentially one’s lifetime) memory. Long-term memories that persist over days, weeks, or even a lifetime, require learning to induce de novo activity-dependent gene expression in the brain. As learning-induced transcription is the molecular determinant for long-term auditory memory consolidation and emergent sound-related behaviors, epigenetic mechanisms that control transcription offer an opportunity to investigate key genes in auditory memory processes. Here we use a known memory-modulating epigenetic molecule, histone deacetylase 3 (HDAC3), as a tool to investigate learning-induced gene expression within the auditory cortex that supports auditory learning, memory, physiological neuroplasticity, and its consequences on learned sound-specific behavior. Doing so has provided the opportunity to characterize learning-induced transcription within the adult auditory cortex. Chapter 1 reports the first identified genome-wide changes in learning-induced gene expression within the auditory cortex using an auditory memory model in adult, male Sprague-Dawley rats. Auditory cortical samples were collected from animals in the initial learning phase of a two-tone discrimination sound-reward task previously reported to induce exceptionally sound-specific neurophysiological cortical plasticity and behavioral memory under conditions that inhibited HDAC3 activity during training. Genome-wide changes in auditory cortical transcription are now candidate to underlie neurophysiological changes in the auditory cortex for the formation of long-lasting discriminative memory of acoustic frequency cues. Bioinformatic analyses identified molecules and mechanisms including cholinergic synapse (KEGG rno04725), extra-cellular matrix receptor interaction (KEGG rno04512), and neuroactive ligand receptor interaction (KEGG rno04080). These candidate pathways are potential therapeutic targets to enable experiences to induce long-lasting changes to sound-specific auditory function in adulthood and prime for future gene-targeted investigations. Chapter 2 examines the anatomical relevance of genes of interest (GOIs) identified the transcriptional profiles induced by successful auditory learning mediated by blocking HDAC3 described in Chapter 1. Changes in GOI expression were examined within the auditory cortex in a separate cohort of adult animals that underwent the same two-tone discrimination task described in Chapter 1. RNAscope was used to reveal that learning experiences can shift the amount of GOI transcripts uniquely within cellular subpopulations (e.g. CamkIIa+ or Rorb+ cells). Additionally, GOIs shift their magnitude of expression uniquely between hemispheres of the same subject. These findings indicate that there are gene-specific changes in transcription that depend on cellular context and functional hemispherical asymmetries in the auditory cortex that may support molecular mechanisms that underly neurophysiological plasticity and the expression of learned sound-reward behaviors. Analysis of GOI expression and how it contributes to behavioral performance indicate that relative GOI expression within both hemispheres are strong predictors of how well an individual will learn and acquire a sound discrimination task. Together, these findings indicate a highly specialized set of cellular changes at the transcriptional level that are now relevant for investigation of their physiological consequences at the circuit and systems levels. Chapter 1 and 2 use pharmacological HDAC3-inhiition as a tool to examine gene expression within the auditory cortex related to successful sound reward learning, plasticity, and auditory memory. In contrast, Chapter 3 determines how local to the auditory cortex the memory enhancing effects of HDAC3 are on epigenetic regulation of auditory cortical transcription, neurophysiological plasticity, and sound-cued behavior. By specifically delivering an adeno-associated virus (AAV) containing a single point mutation of HDAC3 (mtHDAC3) to the auditory cortex, we aimed to limit the effects of HDAC3 inhibition to just the auditory cortex and to target only the deacetylase function of HDAC3. In contrast to prior reports using pharmacological inhibition of HDAC3, animals expressing mtHDAC3 in the auditory cortex showed no behavioral differences compared to eGFP controls learning a single tone detection sound-reward task or in a later auditory memory test. However, electrophysiological recordings of the auditory cortex revealed potential differences in sound representation between groups. Learning appeared to induce tonotopic expansions in both groups but was more sound-specific to the learned tone in animals expressing mtHDAC3 compared to those expressing eGFP. The data did not fully replicate prior HDAC3 manipulations using a pharmacological inhibitor, leaving room for several interpretations. For example, the data could support a role for the non-deacetylase function of HDAC3 in auditory cortical and behavioral effects. In addition, the data could suggest a larger network within and beyond the auditory cortex that can be regulated by epigenetic players like HDAC3 to influence learning-induced gene expression in the auditory cortex that subserve different forms of cortical plasticity with dedicated outcomes on sound-cued memory and behavior depending on task demands. As a whole, the results reported in this thesis highlight the unique and dynamic profiles of gene expression within the auditory cortex, and how their differential activation by learning experiences can modulate the success of auditory memory formation.