ABSTRACT/SUMMARY Significance of auditory system processes in dementia is validated by over 20 years of research showing links between hearing loss, cognitive decline and cortical atrophy1,2,3. Reports show that the risk of dementia increases by 36% for those over the age of 60 years with a hearing loss greater than 24dB SPL4. Furthermore, relationships known to exist between hearing abilities and AD, mild cognitive impairment (MCI) or related dementias (RD), also extend to the failing reticular activating system5. The reticular arousal system may be a mechanistic link between hearing loss and dementia because its activation is required to induce learning-dependent plasticity in the auditory cortex (ACx) that underlies memory formation6. Arousal and learning effects of the reticular formation are mediated by the basal forebrain (primary source of cholinergic (ACh) input) on ACx, which is necessary and sufficient to induce cortical re-tuning7,8 and behavioral long-term memory9 for learned sounds. Indeed, an explanation for why hearing loss is related to accelerated cortical loss in AD/RD10,11 may be failing learning-induced processes mediated by ACh that fail to integrate the ACx into larger, and perhaps neuroprotective, memory networks. An exciting potential solution is to target mechanisms of the epigenome12,13 to restore and maintain activity-dependent transcriptional processes integral to cortical functions for memory. If successful, our prior work has shown ACx plasticity can also reduce sound-evoked threshold by 20-30 dB SPL (thus increasing central sensitivity to significant sounds), which when applied therapeutically, could additionally offset peripheral hearing losses associated with the risk for developing AD14. The parent R01 is aimed to study the synergy between epigenetic and cholinergic mechanisms on auditory learning, memory and learning-induced cortical plasticity. Here, we propose to study this synergy in a next-generation model (NexGenMo) of early-onset AD in CRISPR/Cas9 genetically modified rats that harbor a Swedish familial mutation of amyloid precursor protein (APPs)15. Data in the parent R01 showed that a pharmacological histone-deacetylase 3 (HDAC3)-inhibitor could improve performance in an auditory associative discrimination task and facilitate the formation of highly sound-specific long-term memory in wildtype rats. Facilitated learning and memory acuity appears to be mediated by epigenetic regulation of key genes for cholinergic modulation in ACx that enable its “re-tuning” to learned (and subsequently remembered) sounds. Here, we propose to use the HDAC3-inhibitor on the APP “disease” background in homozygous APPs/s vs. control APPh/h rats. If HDAC3-inhibition can rescue observed auditory learning and memory deficits to successfully enhance cortical representations of important sounds, it may be protective against future memory loss of those significant sounds, or of entire memory networks, which may ultimately protect ...