Research Area II: Molecular and Chemical Probes for Neuroscience

From BRAIN 2025: A Scientific Vision Report

Chemistry and Molecular Technology: Optical Sensors of Neuronal Activity

The ability to monitor activity in large numbers of neurons has been accelerated over the past two decades by using optical methods and tools from chemistry and genetics. Optical sensors, whether chemical or genetic, have the potential to report sub‐cellular dynamics in dendrites, spines, or axons; to probe non‐electrical facets of neural dynamics such as the neurochemical and biochemical aspects of cells’ activities; and to sample cells densely within local microcircuits. The capacity for dense sampling holds particular promise for revealing collective activity modes in local microcircuits that might be missed with sparser recording methods.

Genetic tools can also target cells by genetic type or connectivity, and maintain large‐scale chronic recordings of identified cells or even individual synapses over weeks and months in live animals. Such large‐scale chronic recordings are especially beneficial for long‐term studies of learning and memory, circuit plasticity, development, animal models of brain disease and disorders, and the sustained effects of candidate therapeutics.

Although the acceleration in optical sensor development is relatively recent, it has already had a great impact on the field. Presently, most in vivo optical recordings are studies of neuronal or glial calcium dynamics. Neuronal calcium tracks action potentials as well as presynaptic and postsynaptic calcium signals at synapses, providing important information about both input and output signals. However, its ability to report sub­threshold or inhibitory signals is variable, and while existing indicators have achieved single‐spike sensitivity in low firing rate regimes, they cannot yet follow spikes in fast‐spiking neurons.

The future of this field is not just improving calcium sensors, but generating a broad suite of optical sensors. Voltage indicators are ripe for development: by following voltage, one could in principle follow spikes and sub­threshold signals, including inhibition. Several genetically encoded voltage indicators have appeared, but they do not yet have the desired combination of signal strength and speed, and could benefit greatly from disciplined, iterative improvements. Improved voltage indicators may well be genetically encoded, but other approaches from chemistry and nanotechnology should also be considered. The experience of optimizing the calcium indicators should be directly applicable to improving voltage indicators. Indicators with ultra­low background emissions hold particular importance for reliable event detection and timing estimation.