Mapping spatiotemporal electrochemical responses in vivo, especially within the brains of awake vertebrates, can elucidate the role of neuromodulation in brain activity. However, present tools in neuroscience are insufficient for the task. In the past decade, advances in the technology of multiplexed neural probes for electrophysiology has improved both the complexity and the spatial resolution of simultaneous electrical recordings that are now possible within brain tissue. The state-of-the-art is represented by silicon-based neural nanoprobes that we are developing to enable simultaneous in vivo electrical recording from 1000 sites. Probes that enable local electrochemical sensing in vivo, by comparison, have not kept apace with these advances in electrophysiology. Nonetheless, improvements have been made to electrochemical sensors for in vivo detection of individual neuromodulators of interest, such as dopamine and acetylcholine -- and local sensing at physiologically relevant levels is now possible with spatial and temporal resolution of ~400?m and ~1 second, respectively. We propose to leverage the expertise we've gained in engineering highly multiplexed nanoprobes for electrophysiology, and to build upon the recent improvements of in vivo electrochemical sensing, to develop a new generation of highly multiplexed, multi-site neural nanoprobes for simultaneous electrochemical sensing of multiple neuromodulator targets in vivo. The probes will be fabricated as long (~5mm), narrow (~50?m) silicon shanks that prove optimal for brain recording; onto these will be integrated a multiplicity of chemical sensing triads. Each triad will comprise three distinct sites for amperometric sensing of neurochemical targets -- for example, dopamine, acetylcholine, and choline -- and linear arrays of these triads, separated with less than 100m pitch, will be assembled along the probe shanks. These sensor arrays will enable simultaneous detection of the spatiotemporal variation of multiple different neuromodulator targets across extended regions in the brain. An important application is sampling neuromodulator variations along the multiple cortical and hippocampal layers of the brains of rats, mice and other small animals, where individual layer thicknesses can be ~100?m. The advanced, probe-based electrochemical sensing technology we will develop in this effort will open a new window into the spatiotemporal evolution of functional neurochemical heterogeneities across distributed brain regions.
Many neurological diseases arise from altered neuromodulation - for example, dopamine plays a critical role in Parkinson's and schizophrenia - and understanding the effects across the brain may provide insights that lead to novel treatments. The focus of this project is development and validation of multi-site neurochemical nanoprobes that will provide, for the first time, a window into the spatiotemporal variation of in vivo neuromodulator concentrations across distributed regions of the brain at physiologically relevant levels. The spatiotemporal resolution attained will enable simultaneous measurement of multiple neurotransmitters across distributed brain structures, for example, across the multiple cortical or hippocampal layers of vertebrates.
