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.
