Research

Our lab develops microtechnology tools to observe in vivo neuronal and behavioral responses to precise stimulation. We study the molecular and genetic basis of neural excitability, how it directs information flow within neural circuits, and its role in neuropsychiatric disorders.

We are an interdisciplinary group, combining biomedical and traditional engineering with neuroscience, genetics and optics. 

Project Areas:

Our projects are focused on understanding how neural excitability is modulated by chemicals, genes, experience (such as learning), and states (such as sleep or starvation).  Some current project realms include the following:

1. Functional screens for modulators of neural dynamics:

   C. elegans can be used as a model for human disorders related to voltage-gated calcium channels, like epilepsy and autism. To introduce human mutations in the worm, we are using CRISPR-Cas9 and standard genetic techniques, like cloning, transgenics, crosses, PCR and sequencing. When appropriate, we characterize our models by monitoring and quantifying calcium activity (GCaMP) during microfluidic or optogenetic (Chrimson) stimulation. In parallel, we are combining these established techniques with our recently developed automated high-throughput screening methods to discover potential therapeutics that modulate calcium activity in C. elegans neurons. Altogether, we predict that our research will elucidate novel genetic etiology in human diseases and identify potential neuromodulators for secondary screens in vertebrates.

2. Light sheet microscopy for long-term multi-neuronal imaging with chemical and optogenetic stimulation:

   Our lab has developed inverted selective plane illumination microscopy (diSPIM) methods to record high-resolution, isotropic, fluorescent 3-D volumetric images of multiple neurons for long periods of time (>12h). We use new protocols for the embedding and immobilization of small organisms (worm, fly, zebrafish, etc.) as well as cellular constructs and tissue sections (brain slices). We aim to study circuit computation in C. elegans when stimulated with natural sensory stimuli (e.g., chemicals) and with arbitrary optogenetic stimulation within compact and well-defined neural circuits. We use these methods to study neuronal response variability, decision-making, and to identify which neurons respond to novel stimuli.

3. Neural signaling changes across physiological and behavioral states:

   C. elegans neural activity and behavior depend on individual animal state and exposure conditions. Our lab aims to understand how neural signaling in C. elegans varies depending on state differences including starvation, sleep and learning, and how these neural variations lead to behavioral output. We assess the learning capability of C. elegans under various stimulation conditions and genetic perturbations using an automated associative learning paradigm. For example, we study changes in associative learning during development, aging and in neuropsychiatric disorders such as Alzheimer’s disease. Additionally, we study how neural responses change during awake and quiescent (potentially, sleep) states.

Technologies

Our current microfluidic technologies are able to record single neural responses from 20-40 animals at once, either moving or paralyzed, subjected temporal or spatial  patterns of chemicals, gases, vibration, temperature, light, or combinations of these.  These data have illustrated the reliability of some sensory neural responses and the variability of other interneuron responses give rise to probabilistic behaviors.

We continually develop and refine:

• hardware systems to image behavior, deliver liquids from multiwell plates
• automation systems to coordinate microscopy, stimulation, and robotic systems
• software tools to coordinate multivariate data, track behavior, and track neural activity

Funding

We are currently funded by the Burroughs Wellcome Fund, the National Science Foundation, the National Institutes of Health, WPI, and UMASS Medical School.

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