Emerging tools and technologies, including optogenetics and pharmacology, have provided important avenues for neuroscience research. However, despite intensive work, it is still challenging to achieve closed-loop neuromodulation in a way that allows the free movement of animals, multimodal operation, and multiplexed monitoring of neurochemicals with high sensitivity, selectivity, spatiotemporal resolution, and cellular specificity, simultaneously. Our long-term goal is to develop advanced tools and approaches that support these capabilities for large-scale modulation and monitoring of the nervous system. Our immediate goal is to develop wireless, closed-loop neural probe systems for optogenetics, pharmacology, and neurochemical monitoring in freely moving mice and rats. We will achieve this goal by pursuing the following three specific aims: (1) to develop soft neural probes for the selective and sensitive monitoring of neurochemicals with high spatiotemporal resolution and cellular specificity; (2) to develop wireless, closed-loop neural probes for optogenetics, pharmacology, and neurochemical monitoring; and (3) to evaluate and characterize the efficiency and functionality of the wireless, closed-loop neural probes in vivo in freely moving mice and rats. The proposed research is innovative for five key reasons: First, the aptamer-enhanced graphene-field effect transistors (AeG- FETs) combine the high selectivity of the aptamer with the high sensitivity of G-FETs, thereby enabling sensitive (femtomolar) and selective (> 19-fold) detection of neurochemicals. Second, the nearly cellular-scale dimensions (50 ?m x 50 ?m), fast response time (~1 s), and site selective functionalization of AeG-FETs make it possible to monitor multiple neurochemicals, including dopamine, serotonin, norepinephrine, and neuropeptide Y, with high spatiotemporal resolution, sensitivity, and selectivity. Third, coupling state-of-the-art genetically encoded fluorescent sensors with a wireless multicolor photometer makes it possible to detect multiple neurochemicals in genetically defined neurons of freely moving animals. Fourth, multimodal operation and a customized graphical user interface (GUI) provide a robust, easy-to-use automated data analysis and control interface for closed-loop optogenetic and/or pharmacological manipulation, thereby enabling adjustable and on-demand neuromodulation. Finally, magnetic resonance coupling and wireless data communication allow fully wireless, battery-free operation, thereby enabling lightweight construction and eliminating concerns about battery life, charging status, and other issues that often arise during extended behavioral tests, while at the same time allowing animals to move freely. The successful completion of the proposed research will yield wireless, ?all- in-one? closed-loop neural probes with several innovative features for neurochemical monitoring and optogenetic and/or pharmacological stimulation during freely moving behaviors. We believe these neural probes will be of great interest to the neuroscience community for basic studies in neuroscience as well as for studies of disease-related processes in various contexts relevant to the BRAIN initiative.
The proposed research is relevant to public health because it focuses on developing new technologies to understand the operation of neural circuits and underlying causes of neurological diseases. This study will yield a wireless, closed-loop neural probe to monitor multiple neurochemicals and to conduct optogenetic and/or pharmacological stimulation during freely moving behaviors of animals, which will allow for rapid interrogations of neural circuits.