Brain, as the source of neural activities such as perceptions and emotions, consists of the dynamic and complex networks of neurons that implement brain functions through electrical and chemical interactions. Therefore, analyzing and monitoring neurochemicals in living brain can greatly contribute to uncovering the molecular mechanism in both physiological and pathological processes, and to taking a further step in developing precise medical diagnosis and treatment against brain diseases. Through collaborations across disciplines, a handful of analytical tools have been proven to be befitting in neurochemical measurement, spanning the level of vesicles, cells, and living brains. Among these, electrochemical methods endowed with high sensitivity and spatiotemporal resolution provide a promising way to precisely describe the dynamics of target neurochemicals during various neural activities. In this review, we expand the discussion on strategies to address two key issues of in vivo electrochemical sensing, namely, selectivity and biocompatibility, taking our latest studies as typical examples. We systematically elaborate for the first time the rationale behind engineering electrode/brain interface, as well as the unique advantages of potentiometric sensing methods. In particular, we highlight our recent progress on employing the as-prepared in vivo electrochemical sensors to unravel the molecular mechanism of ascorbate in physiological and pathological processes, aiming to draw a blueprint for the future development of in vivo electrochemical sensing of brain neurochemicals.
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