Research Projects

Project Abstract Current common methods for measuring somatosensory function in preclinical rodent models generally rely on withdrawal responses to uncomfortable or painful stimuli. These tests can be stressful to the animal, while also yielding a high variability in measured responses, and repetitive testing in longitudinal models may even result in chronic pain states. To better understand the connection between physiology and perception of touch and proprioception, researchers need a modern, off-the-shelf assessment system to administer and quantify trained, volitional behaviors.

Over the past 15 years, new microscope technologies and methods for high throughput imaging have revolutionized structural biology by extending the resolution and scale of datasets in 3 dimensions. The resulting image volumes are more typically hundreds of GB to even tens of TB and for large volume electron microscope images of brain, can approach PB sizes. These file sizes pose challenges for image analysis, and communication of a representative set of raw data and quantification.

Project Summary The goal of this work is to achieve high-speed optical fluorescence imaging of 3D brain volume in moving, behaving mice, using miniature scanning mirrors in an implantable, fiber-coupled microscope. Existing implantable microscopes for neural imaging primarily image a single focal plane or may alter image depth using scanning mechanisms that are slow and/or reduce the optical resolution.

Electrostimulation (ES) is a versatile and efficient tool for interrogating, altering, and manipulating neural activities in health and disease. Deep brain ES delivered with implanted electrodes requires an elaborate neurosurgery and carries risks of tissue damage, bleeding, stroke, infection, and inflammation. This limits the use of deep brain ES for disease diagnostics and conditions that may not justify the risks. Non-invasive targeted deep brain ES has long been a major quest, with countless potential applications.

The exponential surge in the prevalence of neurological diseases/disorders, partly due to the rapid growth in the aged population, poses a significant challenge to the prevention and treatment of impairments in cognitive, sensory, and motor functions. However, our insufficient understanding of the mechanisms underlying the pathogenesis of many neurological diseases delays the development of effective treatments to address this challenge. Recent advances in optogenetics have provided novel tools to investigate complex neural circuits and brain functions.

Project Summary Noninvasive high precision neuromodulation technologies are crucial for probing mechanisms of neural circuits and enabling the non-pharmacological treatment of brain disorders. Transcranial-focused ultrasound (tFUS) neuromodulation has demonstrated its efficacy and precision in modulating the brain, from neuron to circuit level.

Abstract Optical methods provide high-resolution, non-invasive measurement of neural function, ranging from single neurons to entire populations, in the intact brain. Nevertheless, limited penetration depth, spatial scale and temporal resolution remain the main challenges for optical imaging. Laser scanning multiphoton microscopy is the main technology used for cellular-level imaging in scattering brains.

PROJECT SUMMARY Achieving a detailed understanding of the neural codes of sensation, action, and cognition will require technologies that can both sample and perturb neural activity with millisecond precision and cellular resolution across large populations of neurons. We will develop an all-optical holographic two-photon microscope that can simultaneously record and perturb population neural activity with cellular resolution and millisecond precision. To achieve this, we will leverage multispectral temporally focused three-dimensional (3D) wavefront shaping.

PROJECT SUMMARY / ABSTRACT Neuropeptide modulation of neuronal circuits is strongly linked to many crucial behaviors such as exploration, stress, memory formation, learning, and many pathophysiological conditions. Unfortunately, neuropeptides are notoriously difficult to understand because many methods are not well-positioned to isolate neuropeptide function accurately in space and time within the brain. Genetically-encoded fluorescent protein sensors could provide precise monitoring with high-spatial and temporal resolution and cell-type specificity.

Abstract This project aims to develop the first Inverse Activity Marker (IAM) for detecting neuronal inhibition (broadly defined as the decrease of neuronal activities). The transcription of immediate early genes (IEGs) like c-Fos and Arc has been the most widely used for translating neuronal activity into stable, trackable histological labels to allow structural and functional interrogations. Existing activity targeting methods, either through direct detection of IEGs or engineered IEG promoters, are optimized for detecting the sustained increase of neural activity.