Efforts to understand how neurons within networks interact to control behavior will be greatly facilitated by a means with which to measure multiple neuroactive molecules in the brain simultaneously and in near-real time. Existing methods either offer rapid measurements of a single analyte (e.g., fast-scan cyclic voltammetry) or provide multiple analyte measurement with insufficient temporal resolution (microdialysis). Here, we will develop an implantable microprobe capable of simultaneous rapid monitoring of 3 ubiquitous neurotransmitters/neuromodulators: dopamine (DA), glutamate (Glut), and acetylcholine (ACh). Further, we will harness the power of optogenetics by incorporating an optical waveguide into the microprobe providing directional illumination of tissue juxtaposed to each sensing electrode on the microelectrode array. This will be achieved using an innovative silica-based microprobe design with embedded waveguides and light splitters, and with a micromirror embedded underneath each microelectrode for uniform directional light illumination. The resultant microprobe will combine local modulation of genetically isolated neuron terminals with measurement of transmitter release from those terminals, together with resultant changes in the release of other transmitters from neurons within the network, all in the context of a freel behaving animal. These sensors will be transformative in a wide range of neuroscience applications due to the involvement of DA, Glut and ACh as inter-neuronal signaling molecules in multiple brain regions controlling a plethora of functions from learning and memory to motor control. Our evaluation of their performance in vivo will focus on the striatum, a brain region involved in motor control and motivated behavior. Precise coupling of multiple transmitter release events to behavioral actions will provide valuable information pertinent to the search for therapeutic interventions for multiple neurological and psychiatric disorders.
This project will develop a micromachined microsensor for simultaneous near-real-time detection of three major neurotransmitters in the rat brain incorporating the capacity for local optogenetic manipulation of neurotransmitter release. This device will be broadly applicable to a wide range of neuroscience investigations of relevance in the search for treatments of an array of neurological and psychiatric conditions.