title: Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation.
abstract: Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. Significance statement: Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually "tuned-in" to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control "informational capture" at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories.
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and Center for Hearing Research, University of California, Irvine, California 92697, College for Life Sciences, Wissenschaftskolleg zu Berlin, 14193 Berlin, Germany, Psychology Department, Behavioral and Systems Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, and kasia.bie@rutgers.edu mwood@uci.edu.
authors.forename: Kasia M
authors.initials: KM
authors.lastname: Bieszczad
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and.
authors.forename: Kiro
authors.identifier: http://orcid.org/0000-0002-8897-2431
authors.initials: K
authors.lastname: Bechay
authors.affiliation: Repligen Corporation, Waltham, Massachusetts 02453.
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.affiliation: Repligen Corporation, Waltham, Massachusetts 02453.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.affiliation: Repligen Corporation, Waltham, Massachusetts 02453.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kudugunti
authors.affiliation: Repligen Corporation, Waltham, Massachusetts 02453.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and Center for Hearing Research, University of California, Irvine, California 92697.
authors.forename: Norman M
authors.initials: NM
authors.lastname: Weinberger
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and.
authors.forename: James L
authors.initials: JL
authors.lastname: McGaugh
authors.affiliation: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and Center for Hearing Research, University of California, Irvine, California 92697, kasia.bie@rutgers.edu mwood@uci.edu.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Wood
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D001303:Auditory Cortex / Q000187:drug effects / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D005071:Evoked Potentials / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018709:Statistics, Nonparametric; D013997:Time Factors; D014868:Water Deprivation
chemical_list: D000178:Acrylamides; D056572:Histone Deacetylase Inhibitors; D010655:Phenylenediamines; C000603861:RGFP966; D006655:Histone Deacetylases
keywords: auditory cortex; chromatin modification; cortical plasticity; epigenetics; histone acetylation; memory