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1. A 512-Ch Dual-Mode Microchip for Simultaneous Measurements of Electrophysiological and Neurochemical Activities

   https://doi.org/10.3390/bios13050502  

   Mulberry, Geoffrey; White, Kevin A.; Crocker, Matthew A.; Kim, Brian N. (May 2023, Biosensors)

   In the study of the brain, large and high-density microelectrode arrays have been widely used to study the behavior of neurotransmission. CMOS technology has facilitated these devices by enabling the integration of high-performance amplifiers directly on-chip. Usually, these large arrays measure only the voltage spikes resulting from action potentials traveling along firing neuronal cells. However, at synapses, communication between neurons occurs by the release of neurotransmitters, which cannot be measured on typical CMOS electrophysiology devices. Development of electrochemical amplifiers has resulted in the measurement of neurotransmitter exocytosis down to the level of a single vesicle. To effectively monitor the complete picture of neurotransmission, measurement of both action potentials and neurotransmitter activity is needed. Current efforts have not resulted in a device that is capable of the simultaneous measurement of action potential and neurotransmitter release at the same spatiotemporal resolution needed for a comprehensive study of neurotransmission. In this paper, we present a true dual-mode CMOS device that fully integrates 256-ch electrophysiology amplifiers and 256-ch electrochemical amplifiers, along with an on-chip 512 electrode microelectrode array capable of simultaneous measurement from all 512 channels. 

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2. Design of 256-ch neurochemical MEA probe

   https://doi.org/10.1109/BioCAS54905.2022.9948577  

   White, Kevin A.; Kim, Brian N. (October 2022, 2022 IEEE Biomedical Circuits and Systems Conference (BioCAS))

   Dopamine constitutes a significant portion of the catecholamine content in the brain and plays a distinct role in neuromodulation including directing motor control, motivation, reward, and cognitive function. For future neuroprobe technology, not only is simultaneous high-density neurochemical recording vital, temporal resolution plays a key part in the roles of the spatiotemporal distributions of catecholamines in the brain. In this work, we present a new probe design that contains a 256 microelectrode array with an integrated 256 transimpedance amplifier array capable of both amperometry and fast-scan cyclic voltammetry. Each amplifier in the array is capable of both modes of electrochemical detection with three gain settings for the voltammetry mode and occupies an area of 60 μm × 60 μm. The new probe enables a high-resolution spatiotemporal mapping of neurochemicals in the brain. 

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3. On-chip Detection of Single Vesicle Release from Neuroblastoma Cells using Monolithic CMOS Bioelectronics

   https://doi.org/10.1109/EMBC.2018.8513219  

   White, Kevin A.; Mulberry, Geoffrey; Sugaya, Kiminobu; Kim, Brian N. (July 2018, 2018 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC))

   Neuroblastoma cells are often used as a cell model to study Parkinson's disease, which causes reduced dopamine release in substantia nigra, the midbrain that controls movements. In this paper, we developed a 1024-ch monolithic CMOS sensor array that has the spatiotemporal resolution as well as low-noise performance to monitor single vesicle release of dopamine from neuroblastoma cells. The CMOS device integrates 1024 on-chip electrodes with an individual size of 15 μm × 15 μm and 1024 transimpedance amplifiers for each electrode, which are each capable of measuring sub-pA current. Thus, this device can be used to study the detailed molecular dynamics of dopamine secretion at single vesicle resolution. 

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4. The potassium channel subunit K _v β1 serves as a major control point for synaptic facilitation

   https://doi.org/10.1073/pnas.2000790117  

   Cho, In Ha; Panzera, Lauren C.; Chin, Morven; Alpizar, Scott A.; Olveda, Genaro E.; Hill, Robert A.; Hoppa, Michael B. (November 2020, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Analysis of the presynaptic action potential’s (AP syn ) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca 2+ in cultured hippocampal neurons. These recordings revealed a critical and selective role for K v 1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic K v 1 channel inactivation was mediated by the K v β1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of K v β1 blocked all broadening of the AP syn during high-frequency stimulation and eliminated synaptic facilitation without altering the initial probability of vesicle release. Thus, using all quantitative optical measurements of presynaptic physiology, we reveal a critical role for presynaptic K v channels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery. 

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5. Synaptic vesicle fusion is modulated through feedback inhibition by dopamine auto‐receptors

   https://doi.org/10.1002/syn.22131  

   Formisano, Rosaria; Mersha, Mahlet D.; Caplan, Jeff; Singh, Abhyudai; Rankin, Catharine H.; Tavernarakis, Nektarios; Dhillon, Harbinder S. (September 2019, Synapse)

   Abstract Mechanisms of synaptic vesicular fusion and neurotransmitter clearance are highly controlled processes whose finely‐tuned regulation is critical for neural function. This modulation has been suggested to involve pre‐synaptic auto‐receptors; however, their underlying mechanisms of action remain unclear. Previous studies with the well‐definedC. elegansnervous system have used functional imaging to implicate acid sensing ion channels (ASIC‐1) to describe synaptic vesicle fusion dynamics within its eight dopaminergic neurons. Implementing a similar imaging approach with a pH‐sensitive fluorescent reporter and fluorescence resonance after photobleaching (FRAP), we analyzed dynamic imaging data collected from individual synaptic termini in live animals. We present evidence that constitutive fusion of neurotransmitter vesicles on dopaminergic synaptic termini is modulated through DOP‐2 auto‐receptors via a negative feedback loop. Integrating our previous results showing the role of ASIC‐1 in a positive feedback loop, we also put forth an updated model for synaptic vesicle fusion in which, along with DAT‐1 and ASIC‐1, the dopamine auto‐receptor DOP‐2 lies at a modulatory hub at dopaminergic synapses. Our findings are of potential broader significance as similar mechanisms are likely to be used by auto‐receptors for other small molecule neurotransmitters across species. 

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