Elizabeth Pollina M.D., Ph.D. 

ABSTRACT

Across a lifetime, neurons must retain a remarkable level of plasticity that facilitates learning, memory, and behavior. As animals encounter new sensory stimuli and learn complex behaviors, these experiences trigger changes in the activation of the state of neurons in the brain. In turn, increased neuronal activity induces the transcription of thousands of genes, the products of which dynamically modify the cells and circuits of the brain. Neuronal activity-induced transcription is, however, a costly and risky endeavor. During transcription, the DNA is cut, unwound, and eventually resealed in a process that has the potential to create permanent mutations. How then do animals balance the benefits of elevated neuronal activity for plasticity with the risks it poses to the stability of their genetic code? The goal of this proposal is to identify the molecular mechanisms that protect neuronal genomes from damage during periods of heightened neuronal activity. In our first aim, we will identify new mechanisms that repair activity-induced DNA damage, with an eye towards future work assessing how these protective mechanisms change with age in mouse models. In our second aim, we will identify the burden of mutations that accrue during aging at activity-induced genes in different types of brain cells. These studies will identify the cell types most susceptible to damage and will highlight gene candidates with high levels of mutations that may contribute to age-associated cognitive decline. Together, our work will provide foundational knowledge of how diverse neuronal cell types maintain transcriptional control and genome stability with age and how these genome control mechanisms go awry in aging and degenerative disease.

Lay Summary: 
Our aging population is expected to develop increased incidences of neurodegenerative disease and dementia, but the molecular mechanisms that underlie these complex processes remain poorly understood. This proposal aims to understand how neuronal activity-dependent gene expression and DNA damage repair can regulate brain aging by leveraging a newly identified, activity-inducible protein complex, NPAS4:NuA4. Our work will shed light on how changing levels of activity in the brain influence the accumulation of DNA damage across neuronal genomes as we age and the consequences of this damage for brain function. These experiments will lay critical groundwork for designing targeted strategies to slow or reverse decline in the neuronal cell types most susceptible to
age-dependent diseases.