Elizabeth Pollina, PhD

Molecular Mechanisms of Nervous System Longevity and Rejuvenation

A fundamental mystery of biology is how the myriad neurons of the mammalian brain persevere for the lifetime of an organism. A defining feature of long-lived neurons is their plastic nature: neurons continually adapt to environmental cues to facilitate learning, memory, and behavior. Neuronal activity is crucial for these adaptive responses but poses an inherent risk to the stability of the genome and epigenome across the lifespan of post-mitotic neurons.

In my postdoctoral work, I discovered a neuronal chromatin modifier that assembles in active neurons to protect the genome from accumulating DNA damage during periods of heightened synaptic activity. This finding has inspired the central questions that motivate our research: What mechanisms preserve the genome in active eurons, especially in long-lived species? Can we identify the molecular basis of environmental interventions that slow or reverse damage to restore youthful plasticity? These issues have remained obscure due to the extreme heterogeneity of cell types in the brain and the previous intractability of assessing in depth molecular mechanisms by biochemical and genome-wide approaches in vivo. Thus, how distinct types of neurons protect their genomes over time, particularly in the context of intact circuit function, is a fundamental unanswered question with major implications for both normal cognitive aging and neurodegenerative disease.

Overcoming these barriers, my lab applies techniques from molecular neuroscience, epigenetics, and genome integrity to make critical advances in our understanding of DNA repair and transcriptional fidelity in the nervous system of living organisms. Specifically,

1. We assess the mechanisms by which neurons achieve high-fidelity DNA repair and chromatin maintenance at the genomic loci that undergo repeated cycles of transcriptional activation, combining optogenetic activation of neurons with new methods for cell-type-specific gene manipulation.
2. We examine the mutagenic consequences of faulty repair for diverse neuronal cell types in both short and long-lived species.
3. Finally, we seek to understand how lifestyle factors modify genome control mechanisms in neurons. Among lifestyle factors (e.g. diet, exercise, sleep) known to promote long-term plasticity of the nervous system, sleep has intriguingly been linked to the maintenance of genome stability. We examine how perturbed sleep impacts neuronal genome integrity across neuronal ensembles of the brain and body.

Our hope that our studies in the nervous system will reveal paradigms for how specialized cell types coordinate both transcriptional control and genome stability across time.

More about the Pollina lab

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