Epigenetic rescue of age-related deficits in auditory processing of vocal communication signals

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PROJECT SUMMARY A critical component of cognitive decline during aging is impairment in auditory processing and memory formation for speech and speaker identity. Because of its social nature, decline in this domain has been associated with increasing social avoidance, isolation, and other comorbidities that increase with age, such as depression and anxiety. Moreover, because of its nearly uniquely human nature, no animal model system has been established in which to study age-related decline in neural mechanisms underlying auditory processing of complex, learned vocal sounds. The model system best suited to address this need is the songbird, which learns its vocal signals in much the same manner as do humans. Here we propose to establish a songbird model system of aging and test a promising mechanism of targeted epigenetic manipulation in improving memories for auditory communication signals. We will also examine the effects of epigenetic manipulation on the age-related increased inflammation and decreased neurogenesis in the neural substrate underlying auditory processing of vocalizations. The songbird model has historically been central to our understanding of the dynamics of neurogenesis and new neuron incorporation into telencephalic circuits corresponding to varied and tractable behaviors and cognitive domains. Developmental models of songbirds have also been at the forefront of our understanding of critical periods in sensory, motor, and sensorimotor learning and memory. Surprisingly, songbirds have not been used much at the end of the lifespan to study behavioral and neural substrate changes, and interventions, during aging and senescence. In the few examples of such use, findings have led to new avenues of investigation adopted by researchers for studies in rodent aging. Thus, a songbird model of aging provides opportunities for discoveries relevant to understanding human aging that may not be available in rodent models. The use of epigenetic tools to regulate gene expression is at the forefront of research on brain aging and cognitive decline and is emerging as a promising treatment in a wide range of disease models of neurodegeneration. One means of epigenetic regulation targets histone deacetylases (HDACs), enzymes that suppress gene transcription by catalyzing the removal of histone acetyl groups, resulting in a closed chromatin structure. HDAC inhibitors (HDIs) block this process, promoting transcription. However, until recently, HDIs were limited in translational use because available HDIs targeted a broad range of HDACs, resulting in widespread side effects. A new generation of HDAC-specific HDIs is leading the way in establishing promising treatments with limited side effects. Here we will describe the effects of blocking HDAC3 specifically on gene expression profiles, neural inflammation, neurogenesis, and parameters of auditory memory for vocalizations in aging male and female zebra finches. The results of this work will advance our understanding of the role of epigenetics in modulating inflammation, neurogenesis, and memory with an aim toward establishing interventions for age-related memory loss.