This application will seed the research program of an Early Stage Investigator recently hired at Rutgers University (Asst. Prof., January 2015), Dr. Kasia M. Bieszczad (bee-YESH-chad). The ultimate goal is to establish research to determine critical behavioral, molecular and genetic neural mechanisms of auditory learning and memory. A particular focus is on cortical plasticity. Learning to understanding the meaning of sounds by their linkage to other events and significant stimuli enables auditory comprehension. Abilities of auditory comprehension in normal adults, or in adults after rehabilitation following hearing loss or cochlear implantation, all depend on enduring auditory memory - that is, the stable information storage about sound. To understand processes underlying auditory memory function, it is important to identify neuroplasticity that enables the formation of long-term auditry memory and information storage. Auditory cortex is key for auditory memory. Even early auditory cortex can undergo experience-dependent physiological plasticity throughout a lifetime. The relationship between auditory memory and cortical plasticity is open to investigation from molecules, to genes, cells, circuits in systems, and behavior. This proposal is to determine molecular and genetic neural mechanisms that control cortical plasticity and, thereby, the transformation of auditory experiences into auditory memory. Future multi-level approaches will discover how these molecules and which particular genes function in their neural circuits and systems to ultimately establish robust auditory memory. The initial plan is to investigate in two Specific Aims epigenetic mechanisms of auditory memory formation and experience-dependent auditory cortical plasticity. Experience-dependent mechanisms that underlie auditory cortical plasticity require transcription - that is, the expression of genes that enable stable changes in neuronal function, and ultimately animal behavior. An exciting new avenue to approach the role of transcription for auditory cortical plasticity and memory is through the power of epigenetic control. A primary epigenetic mechanism is histone modification, specifically histone acetylation, which generally promotes transcription. Histone deacetylases (HDACs) repress transcription by down-regulating this process, so are critical and powerful negative regulators of experience-dependent neural plasticity. Currently completely unknown, is whether HDACs regulate auditory cortical plasticity and, thereby, change the formation of auditory memory in ways that may make memories stronger and more specific. To address this important question, the role of HDAC3 will be initially determined over the course of this proposal at molecular, neurophysiological and behavioral levels, using pharmacological (AIM 1) and targeted viral (AIM 2) techniques to manipulate HDAC3 in a rodent model of auditory associative learning. These studies promote the entry of Dr. Bieszczad and her research on auditory memory processes to the new field of behavioral epigenetics. Future R01s will extend this work to establish independence in a high-caliber, important, and completely novel niche of laboratory research.
It is broadly relevant to human health for research in auditory neuroscience to identify the neural mechanisms that allow auditory memories to form. The goal of this project is to investigate how molecules and genes in the auditory areas of the brain control neuroplasticity that transforms our transient auditory learning experiences into enduring auditory memories that are rich with specific acoustic information important for hearing, listening, understanding and communicating.
| Phan, Mimi L; Gergues, Mark M; Mahidadia, Shafali et al. (2017) HDAC3 Inhibitor RGFP966 Modulates Neuronal Memory for Vocal Communication Signals in a Songbird Model. Front Syst Neurosci 11:65 |
| Phan, Mimi L; Bieszczad, Kasia M (2016) Sensory Cortical Plasticity Participates in the Epigenetic Regulation of Robust Memory Formation. Neural Plast 2016:7254297 |
| Bieszczad, Kasia M; Bechay, Kiro; Rusche, James R et al. (2015) Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation. J Neurosci 35:13124-32 |
