Here we propose to create a set of voltage imaging tools that dissect the neural response within the mammalian cortex. In the recent past, neuroscientists have better understood the barrel cortex of the rodent brain by using a variety of recording and genetically targeted strategies. These methods have identified whether neurons participate in a particular whisker sensing task and how neurons connect with each other in the columnar structure. These existing structural and functional views of the barrel cortex will be enhanced by my proposed voltage imaging tools. The novel tools will record previously inaccessible millisecond voltage dynamics that fall into two new regimes: (1) I will record at cellular resolution the spiking dynamics of multiple excitatory neurons in parallel; and (2) I will record at ensemble scale the voltage dynamics of multiple genetically defined populations of neurons in parallel. The enabling technology for these experiments is an integrated set of next generation voltage imaging tools, which includes a set of spectrally separable genetically-encoded voltage indicators that can be targeted to sub-cellular regions and a corresponding set of optical microscopy schemes to access these fluorescent indicators. Using this set of voltage imaging tools, I will provide an unprecedented view of the brain in action. I will be the first to record the voltage dynamics of tens of neurons within a single barrel field. This new view of neural activity will enable better understanding of how groups of individual neurons coordinate activity together during whisker sensing tasks. I will also be the first to record the dynamics of two interacting ensembles with millisecond precision. This new view of neural activity will identify the role of inhibitory neurons in controlling the propagation of information through multiple receptive fields of the barrel cortex. Together, the new views generated by the next generation of voltage imaging will dissect the fine details of mammalian cortical organization.
The knowledge and techniques developed in this work will generalize toward understanding perception in a variety of sensory modalities. Understanding the structure of neural representations of percepts will help create treatments for neural diseases of sensory impairment, either acute or degenerative. Specifically, the new knowledge obtained through this work will identify targeted manipulations that could restore lost tactile sensations.
