Development of molecular imaging tools for understanding the mechanisms of neuromodulation
Embargo Date
2028-01-29
OA Version
Citation
Abstract
One fundamental principle in cellular neuroscience is that a neuron’s membrane voltage (Vm) is the sum of its intrinsic dynamics and active synaptic inputs. Neuronal Vm activities consist of subthreshold dynamics and suprathreshold spiking. When Vm depolarization is sufficient, a spike is generated. The temporal precision of spikes is critical for neural computation. However, single neurons and neural circuits are constantly shaped by plasticity mechanisms involving cellular signaling. To understand the relationship between ongoing neural dynamics and cellular signaling, we describe the development of molecular imaging tools for multimodality imaging of cellular Vm and cytosolic Ca2+, and their application in understanding the mechanisms of clinical electrical neuromodulation. In this dissertation, we first developed novel viral vectors, which enabled simultaneous recording of Vm and cytosolic Ca2+ dynamics in the brains of awake behaving mice. We provide the first direct evidence that prolonged neuronal Vm depolarization is better related to cellular changes via Ca2+-mediated pathways than transient spiking. Different types of spikes lead to distinct cellular consequences depending on the concurrent subthreshold Vm dynamics, demonstrating the distinct impact of different spiking outputs on intracellular environment. Finally, Vm coupling to Ca2+ was sensitive to intracranial electrical stimulation, broadly used in clinical neuromodulation, highlighting the translational potential to differentially regulate neuronal output versus cellular learning.
To enable longer term recordings of Vm, we further developed a fully genetically encoded, bright and photostable voltage indicator, which we named ElectraOFF. ElectraOff enabled long-term, single-neuron recordings during behavior over many tens of minutes with minimal signal loss across neuron types and brain regions. We applied electrical stimulation parameters comparable to clinical ones, and the extended recording capability of ElectraOFF revealed previously uncharacterized plasticity effects induced by intracranial electrical neuromodulation, highlighting the novel insights facilitated by prolonged voltage imaging.
The novel genetically-encoded molecular imaging tools developed here can be broadly applied to various neuroscience studies. Using these tools, we revealed important insights into the relationship between neuronal excitability and cellular plasticity, and the impact of neuromodulations across broad time scales.
Description
2026
License
Attribution-NonCommercial-NoDerivatives 4.0 International