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Developing a novel tool capable of real-time monitoring and simultaneously quantifying of both intra/extracellular chemical signals across the large-scale brain is the key bottleneck for understanding the interactions between the molecules inside and outside neurons. Here we built up a high-density intra/extracellular optophysiology platform, together with developing two probes for specific recognition of L-cysteine (Cys) and dopamine (DA), for simultaneously quantifying of both intracellular Cys and extracellular DA with high selectivity and accuracy across the brain of freely moving animals, as well as recording electrical signals. Using this powerful tool, it was found that intracellular Cys regulated extracellular DA through inducing the expression of tyrosine hydroxylase in the depressed mice brain. We also established the functional networks of Cys and DA across 32 brain regions in freely moving animals. More importantly, it was discovered that depression reduced the correlations between adjacent brain regions, which was recovered by the treatment of N-acetyl-l-cysteine., (© 2023 Wiley-VCH GmbH.)

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.)

The imbalance of Cu + and Cu 2+ in the brain is closely related to neurodegenerative diseases. However, it still lacks of effective analytical methods for simultaneously determining the concentrations of Cu + and Cu 2+ . Herein, we created a novel SERS probe (CuSP) to real-time track and accurately quantify extracellular concentrations of Cu + and Cu 2+ in the live brain. The present CuSP probe demonstrated specific ability for recognition of Cu + and Cu 2+ in a dual-recognition mode. Then, a microarray consisting of 8 CuSP probes with high tempo-spatial resolution and good accuracy was constructed for tracking and simultaneously biosensing of Cu + and Cu 2+ in the cerebral cortex of living brain. Using our powerful tool, it was found that that the concentrations of Cu 2+ and Cu + were increased by ≈4.26 and ≈1.80 times upon ischemia, respectively. Three routes were first discovered for understanding the mechanisms of the increased concentrations of Cu + and Cu 2+ during ischemia., (© 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.)

Described here is that Au-C≡C bonds showed the highest stability under biological conditions, with abundant thiols, and the best electrochemical performance compared to Au-S and Au-Se bonds. The new finding was also confirmed by theorical calculations. Based on this finding, a specific molecule for recognition of Fe 2+ was designed and synthesized, and used to create a selective and accurate electrochemical sensor for the quantification of Fe 2+ . The present ratiometric strategy demonstrates high spatial resolution for real-time tracking of Fe 2+ in a dynamic range of 0.2-120 μM. Finally, a microelectrode array with good biocompatibility was applied in imaging and biosensing of Fe 2+ in the different regions of live mouse brains. Using this tool, it was discovered that the uptake of extracellular Fe 2+ into the cortex and striatum was largely mediated by cyclic adenosine monophosphate (cAMP) through the CREB-related pathway in the brain of a mouse with Alzheimer's disease., (© 2020 Wiley-VCH GmbH.)

Developing a novel tool capable of real‐time monitoring and simultaneously quantifying of both intra/extracellular chemical signals across the large‐scale brain is the key bottleneck for understanding the interactions between the molecules inside and outside neurons. Here we built up a high‐density intra/extracellular optophysiology platform, together with developing two probes for specific recognition of L‐cysteine (Cys) and dopamine (DA), for simultaneously quantifying of both intracellular Cys and extracellular DA with high selectivity and accuracy across the brain of freely moving animals, as well as recording electrical signals. Using this powerful tool, it was found that intracellular Cys regulated extracellular DA through inducing the expression of tyrosine hydroxylase in the depressed mice brain. We also established the functional networks of Cys and DA across 32 brain regions in freely moving animals. More importantly, it was discovered that depression reduced the correlations between adjacent brain regions, which was recovered by the treatment of N‐acetyl‐l‐cysteine. [ABSTRACT FROM AUTHOR]

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]

The imbalance of Cu+ and Cu2+ in the brain is closely related to neurodegenerative diseases. However, it still lacks of effective analytical methods for simultaneously determining the concentrations of Cu+ and Cu2+. Herein, we created a novel SERS probe (CuSP) to real‐time track and accurately quantify extracellular concentrations of Cu+ and Cu2+ in the live brain. The present CuSP probe demonstrated specific ability for recognition of Cu+ and Cu2+ in a dual‐recognition mode. Then, a microarray consisting of 8 CuSP probes with high tempo‐spatial resolution and good accuracy was constructed for tracking and simultaneously biosensing of Cu+ and Cu2+ in the cerebral cortex of living brain. Using our powerful tool, it was found that that the concentrations of Cu2+ and Cu+ were increased by ≈4.26 and ≈1.80 times upon ischemia, respectively. Three routes were first discovered for understanding the mechanisms of the increased concentrations of Cu+ and Cu2+ during ischemia. [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]

Described here is that Au−C≡C bonds showed the highest stability under biological conditions, with abundant thiols, and the best electrochemical performance compared to Au−S and Au−Se bonds. The new finding was also confirmed by theorical calculations. Based on this finding, a specific molecule for recognition of Fe2+ was designed and synthesized, and used to create a selective and accurate electrochemical sensor for the quantification of Fe2+. The present ratiometric strategy demonstrates high spatial resolution for real‐time tracking of Fe2+ in a dynamic range of 0.2–120 μM. Finally, a microelectrode array with good biocompatibility was applied in imaging and biosensing of Fe2+ in the different regions of live mouse brains. Using this tool, it was discovered that the uptake of extracellular Fe2+ into the cortex and striatum was largely mediated by cyclic adenosine monophosphate (cAMP) through the CREB‐related pathway in the brain of a mouse with Alzheimer's disease. [ABSTRACT FROM AUTHOR]