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The development of in vivo analytical tools and methods for recording electrical signals and accurately quantifying chemical signals is a key issue for a comprehensive understanding of brain events. The electrophysiological microelectrode was invented to monitor electrical signals in free-moving brains. On the other hand, electrochemical assays with excellent spatiotemporal resolution provide an effect way to monitor chemical signals in vivo. Unfortunately, the in vivo electrochemical biosensors still have three limitations. First, many biological species such as reactive oxygen species (ROS) and neurotransmitters demonstrate large overpotentials at conventional electrodes. Thus, it is hard to convert the chemical/electrochemical signals of these molecules into electric signals. Second, the interfacial properties of the recognition molecules assembled onto the electrode surfaces have a great influence on the transmission of electric charge through the interface and the stability of the modified recognition molecules. Meanwhile, the surface of biosensors implanted in the brain is easily absorbed by many proteins present in the brain, resulting in the loss of signals. Finally, activities in the brain including neuron discharges and electrophysiological signals may be affected by electrochemical measurements due to the application of extra potentials and/or currents.This Account presents a deep view of the fundamental design principles and solutions in response to the above challenges for developing in vivo biosensors with high performance while meeting the growing requirements, including high selectivity, long-time stability, and simultaneously monitoring electrical and chemical signals. We aim to highlight the basic criteria based on a double-recognition strategy for the selective biosensing of ROS, H 2 S, and H n S through the rational design of specific recognition molecules followed by electrochemical oxidation or reduction. Recent developments in designing functionalized surfaces through a systematic investigation of self-assembly with Au-S bonds, Au-Se bonds, and Au≡C bonds for facilitating electrochemical properties as well as improving the stability are summarized. More importantly, this Account highlights the novel methodologies for simultaneously monitoring electrical and chemical signals ascribed to the dynamic changes in K + , Na + , and Ca 2+ and pH values in vivo. Additionally, SERS-based photophysiological microarray probes have been developed for quantitatively tracking chemical changes in the live brain together with recording electrophysiological signals.The design principles and novel strategies presented in this Account can be extended to the real-time tracking of electrical signals and the accurate quantification of more chemical signals such as amino acids, neurotransmitters, and proteins to understand the brain events. The final part also outlines potential future directions in constructing high-density microarrays, eventually enabling the large-scale dynamic recording of the chemical expression of multineuronal signals across the whole brain. There is still room to develop a multifiber microarray which can be coupled with photometric methods to record chemical signals both inside and outside neurons in the live brains of freely moving animals to understand physiological processes and screen drugs.

Developing a novel tool capable of real-time monitoring and simultaneous quantitation of multiple molecules in mitochondria across the whole brain of freely moving animals is the key bottleneck for understanding the physiological and pathological roles that mitochondria play in the brain events. Here we built a Raman fiber photometry, and created a highly selective non-metallic Raman probe based on the triple-recognition strategies of chemical reaction, charge transfer, and characteristic fingerprint peaks, for tracking and simultaneous quantitation of mitochondrial O 2 .- and pH at the same location in six brain regions of free-moving animal upon hypoxia. It was found that mitochondrial O 2+ and pH at the same location in six brain regions of free-moving animal upon hypoxia. It was found that mitochondrial O 2 and pH changed from superficial to deep brain regions upon hypoxia. It was discovered that hypoxia-induced mitochondrial O .- , Ca 2+ and pH changed from superficial to deep brain regions upon hypoxia. It was discovered that hypoxia-induced mitochondrial O 2 .- burst was regulated by ASIC1a, leading to mitochondrial Ca 2+ overload and acidification. Furthermore, we found the overload of mitochondrial Ca 2+ was mostly attributed to the influx of extracellular Ca 2+ ., (© 2021 Wiley-VCH GmbH.)

Understanding physiological and pathological processes in the brain requires tracking the reversible changes in chemical signals with long-term stability. We developed a new anti-biofouling microfiber array to real-time quantify extracellular Ca 2+ concentrations together with neuron activity across many regions in the mammalian brain for 60 days, in which the signal degradation was < ca. 8 %. The microarray with high tempo-spatial resolution (ca. 10 μm, ca. 1.3 s) was implanted into 7 brain regions of free-moving mice to monitor reversible changes of extracellular Ca 2+ upon ischemia-reperfusion processes. The changing sequence and rate of Ca 2+ in 7 brain regions were different during the stroke. ROS scavenger could protect Ca 2+ influx and neuronal activity after stroke, suggesting the significant influence of ROS on Ca 2+ overload and neuron death. We demonstrated this microarray is a versatile tool for investigating brain dynamic during pathological processes and drug treatment., (© 2021 Wiley-VCH GmbH.)

Herein, we present an electrochemophysiological microarray (ECPM) for real-time mapping and simultaneous quantification of chemical signals for multiple ions in the deep brain of a freely moving rat, in which microelectrode arrays were developed for direct determination of multiple ions using open-circuit potentiometry. Specific recognition ionophores were synthesized and optimized for determination of K + , Ca 2+ , Na + and pH. A reference electrode was also developed to avoid interferences in the brain. The microarrays were successfully applied in real-time monitoring and quantification of ions in a live brain. The extra current-free potentiometry allowed mapping and biosensing of chemical signals, together with recording of electrical signals in the whole brain without cross-talk, for the first time. Furthermore, the ECPM provided a platform for real-time monitoring of the dynamic changes of multiple ions in the deep brain of freely moving rat during a seizure., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Developing a novel tool capable of real‐time monitoring and simultaneous quantitation of multiple molecules in mitochondria across the whole brain of freely moving animals is the key bottleneck for understanding the physiological and pathological roles that mitochondria play in the brain events. Here we built a Raman fiber photometry, and created a highly selective non‐metallic Raman probe based on the triple‐recognition strategies of chemical reaction, charge transfer, and characteristic fingerprint peaks, for tracking and simultaneous quantitation of mitochondrial O2.−, Ca2+ and pH at the same location in six brain regions of free‐moving animal upon hypoxia. It was found that mitochondrial O2.−, Ca2+ and pH changed from superficial to deep brain regions upon hypoxia. It was discovered that hypoxia‐induced mitochondrial O2.− burst was regulated by ASIC1a, leading to mitochondrial Ca2+ overload and acidification. Furthermore, we found the overload of mitochondrial Ca2+ was mostly attributed to the influx of extracellular Ca2+. [ABSTRACT FROM AUTHOR]

Understanding physiological and pathological processes in the brain requires tracking the reversible changes in chemical signals with long‐term stability. We developed a new anti‐biofouling microfiber array to real‐time quantify extracellular Ca2+ concentrations together with neuron activity across many regions in the mammalian brain for 60 days, in which the signal degradation was < ca. 8 %. The microarray with high tempo‐spatial resolution (ca. 10 μm, ca. 1.3 s) was implanted into 7 brain regions of free‐moving mice to monitor reversible changes of extracellular Ca2+ upon ischemia‐reperfusion processes. The changing sequence and rate of Ca2+ in 7 brain regions were different during the stroke. ROS scavenger could protect Ca2+ influx and neuronal activity after stroke, suggesting the significant influence of ROS on Ca2+ overload and neuron death. We demonstrated this microarray is a versatile tool for investigating brain dynamic during pathological processes and drug treatment. [ABSTRACT FROM AUTHOR]

Herein, we present an electrochemophysiological microarray (ECPM) for real‐time mapping and simultaneous quantification of chemical signals for multiple ions in the deep brain of a freely moving rat, in which microelectrode arrays were developed for direct determination of multiple ions using open‐circuit potentiometry. Specific recognition ionophores were synthesized and optimized for determination of K+, Ca2+, Na+ and pH. A reference electrode was also developed to avoid interferences in the brain. The microarrays were successfully applied in real‐time monitoring and quantification of ions in a live brain. The extra current‐free potentiometry allowed mapping and biosensing of chemical signals, together with recording of electrical signals in the whole brain without cross‐talk, for the first time. Furthermore, the ECPM provided a platform for real‐time monitoring of the dynamic changes of multiple ions in the deep brain of freely moving rat during a seizure. [ABSTRACT FROM AUTHOR]