Jason T. Ritt, Ph.D. - US grants

? DESCRIPTION (provided by applicant): With the continuing expansion of optogenetic tools, the central importance of optical measurement of neural activity has and will continue to grow. However, large scale optical approaches, such as pursued by the BRAIN Initiative, must overcome high light scattering in brain tissue. Moreover, optical approaches should be feasible in behaving animals, including freely moving mice. We will develop an ultra-miniature microendoscope, termed a needle optrode, made with a bare fiber bundle beveled to a fine tip. The smaller size and beveling improves tissue penetration and lowers tissue damage compared to existing technology, and arranges the field of view for imaging across layered structures such as neocortex. The core project contribution is achieving miniaturization through a lensless design, using an innovative coupling of array detector to enable fluorescence background rejection and remote focusing. We will demonstrate the power of our approach for collecting large scale, multiregion data by recording simultaneously from aligned cortical and thalamic regions of the mouse somatosensory system, in anesthetized mice. Completion of these aims will prepare us to record simultaneously throughout an entire thalamocortical whisker processing network, including both feedforward and feedback projections, and be a first step towards performing these recordings in an awake animal actively engaging objects of interest in a tactile task. Moreover, our approach --- providing multiregion, cellular resolution recording of genetically identified cell types, with possible extension to behaving animals --- will support similar experiments across brain regions and systems, as one of the high priority components of the BRAIN initiative.

Project Summary The long terms goal of this project is to enable the control of large networks in the brain using neurostimulation technologies, a key focus of the BRAIN initiative. These technologies, including optogenetics, are developing at unprecedented rates and, consequently, are allowing scientists to make increasingly specific extrinsic perturbations to the activity in neural circuits. However, the nature of these perturbations remains largely limited so that the stimulated neuronal population is activated or deactivated en masse. As scientists seek to uncover the finer mechanisms of brain function, methods will be needed that allow more complex spatiotemporal activity patterns ? neural trajectories ? to be induced in these networks. The immense scale and interconnectedness of networks in the brain make this problem highly nontrivial. One may liken this problem to a musician on stage attempting to elicit a specific, unique response from each member of their audience individually, while playing to the group as a whole. To better understand these challenges and attempt to surpass them, our proposal introduces early concepts at the intersection of neuroscience and control theory, the mathematical study of how to optimally ?steer? complex systems subject to their dynamics, possible constraints, and an objective function that measures differences between the desired and induced trajectories. Our specific research aims are grounded in our team's interdisciplinary experience at the interface of dynamical systems, control theory and neuroscience. In Aim 1, we will study how the architecture and dynamics of networks in the brain enable control with respect to natural inputs, i.e., excitation through sensory pathways. In other words, we seek insights into how brain networks control themselves, towards better designing extrinsic stimulation. In Aim 2, we will develop a new toolkit, adapted from modern optimal control engineering, for designing neurostimulation input waveforms that are capable of creating high-dimensional trajectories (e.g., patterns of spikes) in large neuronal networks. In support of Aims 1 and 2, we will develop an innovative benchmark model containing structural and dynamical features pervasive in many salient neuronal networks. Finally, in Aim 3, we will perform in vivo experiments in which we will deploy our theoretical innovations to induce high-dimensional neuronal trajectories in a mouse somatosensory network using optogenetics. The proposed research will yield tangible outcomes in the form of new neurostimulation design methodologies and a benchmark control model that will be disseminated to the broader neuroscience community. Further, our theoretical developments are an important complement to continued growth in stimulation technology and cellular manipulation methods, facilitating a more complete approach to uncovering the mechanisms of the human brain.