ESE Spring Seminar – “All-Optical Recording and Control of the Mammalian Cortex”

The mammalian cortex is the most effective and efficient electronic device we know of, yet its immense complexity and large spatial extent make interfacing with it extraordinarily difficult, limiting our understanding of its operation. To help address this challenge, we are developing tools that enable interrogation of cortical dynamics both in concert with the natural behaviors the cortex evolved to facilitate and with the spatiotemporal precision and coverage needed to capture the entire structure.

In the first half of my talk, I will present our work on recording and controlling cortex-wide networks during freely moving behavior. To accomplish this, we developed a lightweight (4.8 g) miniaturized macroscope that combines large-field (10 × 10 mm) optical imaging with random-access, cell-type-specific optogenetic control across the dorsal cortex of freely moving mice. This miniOEG scope has the sensitivity to resolve single-trial neural activity, the spatial resolution to capture subregional structure, and the spectral flexibility to simultaneously record and optogenetically control neural activity across the brain, together enabling unbiased global screening of natural and causal activity during mammalian behavior.

In the second half of my talk, I will present our work recording and stimulating the whole murine cortex at unprecedented spatiotemporal scales using genetically encoded voltage indicators. To do this, we developed cortex-wide flat-field immersion microscopy, which enables imaging of the entire curved mouse cortex with a single custom-designed objective achieving an effective NA of 0.6. In combination with a fast genetically encoded subthreshold voltage indicator, this approach enabled imaging of the entire dorsal cortex at 100 µm spatial resolution and millisecond temporal resolution, with sufficient signal-to-noise ratio to resolve single-trial activity into the gamma band. This global view spans more than five orders of magnitude in time and four (2 × 2) in space, and enabled unbiased exploration of previously inaccessible spatiotemporal scales. With this new view, we characterized and causally tested the network architecture of the cortex.

Finally, I will give my perspective on how we can leverage these technologies, along with additional tools that we plan to develop, to generate fundamental insights into cortical function.