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. The objective of this grant is to develop a versatile silicon technology platform for the design and fabrication of implantable nanodialysis probes that enable fast (1sec) and sensitive (100nM) sampling of multiple neurochemicals from the alive and behaving mammalian brain. The Application-Specific Integrated Nano-Dialysis (ASIND) technology allows collection in a time-sequential manner a series of isolated pL-volume analytes from the brain extracellular fluid (ECF) with high chemical information content. Once collected and stored on-chip, these analytes are delivered for subsequent ultra-sensitive mass spectrometry (MS) analysis to monitor temporal profiles of several important neurochemicals (from 100Da up to 5KDa). To extend the applicability of the ASIND technology to a large number of diverse neurobiology experiments, we develop, validate and integrate advanced microfluidic components with add-on functionalities (multiplexed chemical sampling, local drug delivery, electrophysiology, electrochemistry, optogenetics, and nano-electrospray) into a system-on-chip on a silicon implantable neural probe with a significantly reduced cross-section (<1000 µm2) equivalent to just a few neuron bodies across. To stress-test the technology and demonstrate its advanced capabilities to study the chemical brain, we adapt the platform to three different neurobiological experiments to address important open questions that are difficult or impossible to explore with traditional approaches. Such development extends the technology readiness level from a demonstration of basic capabilities to proof-of-concept validation for both scientific and translational applications in various areas of neuroscience This contribution is significant since the instrumental platform will allow monitoring concentration gradients of various neuromodulators and drugs from precise brain locations time-synchronized with recordings of neural activity and behavior that should enable advances in fundamental systems neuroscience as well as accelerate the development of new treatments for neurological diseases. The proposed research is innovative because we will develop highly sensitive nanodialysis probes on a silicon platform that allows us to attain unprecedented temporal and spatial resolution. The developed and verified ASIND silicon platform will significantly facilitate the broad dissemination of this manufacturable technology.

Miniaturized silicon neurochemical probe to monitor brain chemistry NARRATIVE The project aims to develop a highly sensitive, multiplexed silicon platform technology for monitoring simultaneously a broad range of neurochemicals in the brain of awake and behaving animals with high spatio- temporal resolution and minimal tissue damage. Silicon microfluidics, ultra-thin dialysis membrane, on-chip sub- nL droplet generation, and off-line mass spectrometry are used to record neurochemicals transients that are time-synchronized with recordings of neural activity and behavior.