Monitor Neural Activity

Limited recovery of function after stroke remains a major problem for millions. Disability persists in many, especially when hand function is limited. Existing therapies are limited and many have difficulties with activities of daily living, even after rehabilitation. Electrical stimulation of the brain has been proposed and used in early studies to try and aid recovery. In animals, stimulation delivered to the brain at precise times may improve the effect of stimulation.

PROJECT SUMMARY/ABSTRACT Two-photon all-optical electrophysiology in behaving mice Neurons communicate through electrical signals, so the ability to record membrane potential from dozens or hundreds of points simultaneously within the brain of a behaving animal would be a transformative capability for neuroscience. This proposal is to develop advanced tools-molecular reporters and microscopes for genetically targeted all-optical electrophysiology in behaving mice.

SUMMARY The brain processes sensory inputs and contextualizes this information with internal brain states, generating the signals that drive motor and cognitive behaviors. The underlying computations are distributed across several anatomically and functionally distinct brain regions. Therefore, neuroscience requires tools to simultaneously investigate multiple brain regions at high spatial and temporal resolution in animals performing naturalistic behaviors.

PROJECT SUMMARY/ABSTRACT Optogenetics provides a precise deconstruction of neural circuits by optically manipulating the activity of opsin-expressing neurons with fast temporal responses and neuron-type specificity. A critical challenge of delivering light in the brain for in vivo optogenetics arises from the poor penetration of photons in biological tissue due to the scattering and absorption of light. As a result, in vivo optogenetic stimulation in the deep brain usually requires invasive procedures, such as craniotomy and intracranial implantation of optical fibers.

Project Summary Pharmacological probes are widely used to study the nervous system. Despite often exhibiting exquisite specificity for target receptors, due to diffusion, traditional small molecule drugs act slowly and with spatial imprecision. This impedes neuropharmacological studies in vivo, particularly those involving high-resolution electrophysiological, imaging, and behavioral tracking methods. Such studies greatly benefit from the ability to correlate measurements with well-defined, time-locked stimuli that can be readily varied in intensity and duration.

Abstract Precisely timed activation of genetically targeted cells is a powerful tool for studying neural circuits. Neuronal modulation (activating or inhibiting select neurons) allows us to investigate how neural activity causes changes in animal behavior. Recent work has led to many tools for genetically targeted neuromodulation; however, the ideal technology should be: 1) Wireless – to enable unrestricted animal behavior and social interactions. 2) Injectable – to minimize tissue damage and ease implementation associated with implants.

PROJECT SUMMARY/ABSTRACT Miniaturized silicon neurochemical probe to monitor brain chemistry. Monitoring local concentrations of neurochemicals in specific parts of the brain in vivo is critical for correlating neural circuit functionality to behavior as long-range neuromodulation can significantly alter information processing. Current methods for detecting neuromodulators have limited temporal and/or spatial resolution, limited sensitivity, and/or are prohibitively invasive.

SUMMARY Acoustic technologies such as optoacoustic (OA) imaging and ultrasound neuromodulation (USNM) are poised to revolutionize deep tissue, high-resolution, large-scale, in vivo imaging, and neurostimulation in mammalian organisms. These advances are enabled by the high tissue penetrability of ultrasound (US) waves, and present untapped and exciting opportunities for accessing structures throughout the mammalian brain for precise control and measurement of neural activity.

The neural circuitry of the spinal cord has a unique, repetitive structure that forms an especially promising target for control via electrical stimulation. Furthermore, this structure allows the essential circuits for generation of movements to be preserved below the level of a spinal cord injury (SCI).

Project Summary Ultrasound has been explored as a modality to modulate nerves and muscles back in the 1920s. A number of recent studies have demonstrated the feasibility of using ultrasound to stimulate peripheral nerves, spinal cord, and brain. Yet, it has been difficult to determine whether ultrasound stimulation is via direct modulation of the membrane voltage or via indirect synaptic or network pathways.