Cooperative Agreements

We propose to develop a novel electrode array (`NeuroGrid') for large-scale recording of spikes and improved miniaturized, multiplexed devices for recording of neural activity in freely behaving rodents, while minimizing the loss of cellular/sub-cellular and temporal resolution. We will develop neuron-size density (10x10 µm with 30 µm pitch), ultra-conformable (4-µm thick) and scalable parylene-based probes (MRI compatible) that can be placed on the brain's surface to record spiking activity of individual neurons and their aggregate activity (local field potentials, LFP).

Developing enhanced methods for reporting and manipulating brain activity is a major focus of the BRAIN Initiative. A major aspect of these efforts is aimed at developing genetically encoded probes for large-scale sensing and/or manipulation of neural activity in vivo.

The objective of the proposed three-year research project is to develop high-speed, high-spatial- resolution, deep-penetration photoacoustic computed tomography (PACT) for real-time imaging of neuro-activities in mouse brains in vivo. The proposed hardware imaging system will be unprecedented in the field of PACT in terms of its volumetric rate and spatial resolving power, which benefit from the use of the largest ever number of sensing elements with one-to-one mapped digitization channels.

The overarching goal of this proposal is to develop an optical-genetic toolbox for reading and writing neural population codes in functional maps of awake, higher mammals. Such tools could ultimately be used to restore perceptual capabilities in patients with damage to peripheral sensory pathways by direct stimulation of early sensory cortex. Advanced optical methods for reading and writing neural codes using genetically-encoded reporters and actuators have become powerful tools for studying neural circuits in rodents.

Studying complex neurological function and disease requires imaging technologies that can provide a comprehensive view of the mammalian brain with high spatiotemporal resolution. Ideally, these technologies should be scalable from small brain regions in rodents to whole-brain imaging in larger organisms such as non- human primates. They should provide access to endogenous signals such as hemodynamics, and be able to image neuron-specific signals such as calcium and activity-dependent gene expression using targeted reporters.

 DESCRIPTION (provided by applicant): The development of minimally invasive direct readouts of neural activity is one of the greatest challenges facing neuroscience today. Our recent work has shown that it is possible to perform high resolution functional magnetic resonance imaging (fMRI) of molecular-level phenomena using MRI contrast agents sensitive to hallmarks of neurotransmitter release. An even more valuable contribution would be the creation of calcium sensors suitable for molecular fMRI of intracellular neural signaling processes.

 DESCRIPTION (provided by applicant): This project seeks to develop a high density, minimally invasive electrode array for long-term recording and control of brain activity. Multielectrode arrays are an essential tool in experimental and clinical neuroscience, yet current arrays are severely limited by a mismatch between large or stiff electrodes and the fragile environment of the brain. Chronically implanted electrodes cause ongoing damage to the brain, and an active process of rejection eventually silences neural signals.

 DESCRIPTION (provided by applicant): Determining the levels of neurotransmitters present in the living brain in real time is a matter of current scientific interest for research and clinicl reasons. Among these reasons is the need for understanding and mapping brain function and for improvement in the clinical application of deep brain stimulation (DBS). One analytical technique that holds potential promise in this application is fast-scan cyclic voltammetry (FSCV), however technical limitations have hindered its adoption for chronic in vivo use.

Significance: A number of scientific questions, especially in local circuit analysis, require manipulating neurons in vivo at multiple sites independently at high spatial and temporal resolutions by perturbing a controlled number and simultaneously recorded neurons. Optogenetic stimulation is cell-type specific which has proven to be the most powerful means of circuit control. Several laboratories have developed solutions to deliver optical stimulation to deep brain structures whilst simultaneously recording neurons.

 DESCRIPTION (provided by applicant): The goal of this research program is to optimize three-photon fluorescence microscopy (3PM) for large scale, noninvasive, volumetric imaging of neuronal activity.