Our brain is an astounding organ, composed of greater than 80 billion neurons that make myriad connections to hundreds or thousands of other neurons throughout the brain, resulting in an estimated ~1012 neuronal junctions, or synapses. From this incredible complexity arises the panoply of experiences, thoughts, feelings, perceptions, and actions that comprise the human condition. Understanding the relationship between structure and function within the brain remains one of the great uncharted scientific frontiers. To address this challenge, the Miller Lab will pursue research along two broad lines.
neuron 2

Voltage Imaging

While the last several decades have seen dramatic increases in our understanding of the human brain and related neural systems, available tools have limited our ability to investigate the emergent properties arising from the concerted activity of neurons within circuits. Current techniques have relied heavily upon either the direct measurement of electrical activity with an electrode, which limits the spatial information one can collect; or upon the indirect measurement of neuronal activity via Ca2+ imaging, in which changes in intracellular Ca2+ act as a surrogate for monitoring transmembrane potential. Because neither method provides a direct measure of electrical dynamics with both spatial and temporal fidelity, our ability to faithfully record activity dynamics within interacting circuits of neurons remains incomplete. To address the challenge of directly recording neuronal activity without the use of an electrode and across multiple cells, the Miller Lab is developing new voltage sensitive fluorescent indicators. This approach will explore synthetic and genetically encoded platforms for voltage sensing and further our understanding of brain and circuit function in health and disease states. At the same time, we will address basic questions in physical organic chemistry, biophysics, and protein design.

Activity Tracing

A second approach to charting brain activity is to make use of “activity tracers,” which integrate neuronal activity over time. The challenge of recording activity from thousands of neurons in parallel during activity presents a unique obstacle that is difficult to overcome with current imaging technologies. One solution is to use an integrating, rather than sensing, approach, in which neuronal activity is “recorded” or “captured” by the integrating molecule, independent of observation by the experimentalist. An integrating approach leaves a permanent record of biochemical events, enabling high-fidelity spatial reconstruction of neuronal activity. The Miller Lab is developing activity integrators to trace neuronal activity at multiple scales—from sub-cellular to circuits—using a variety of modalities, including fluorescence imaging, super-resolution optical microscopy, and electron microscopy.