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The central nervous system is organized into different neural circuits, each with particular functions and properties. Studying neural circuits is essential to understanding brain function and neuronal diseases. Microfluidic systems are widely used for reconstructing and studying neural circuits but still need improvement to allow modulation and monitoring of the physiological properties of circuits. In this study, we constructed an improved microfluidic device that supports the electrical modulation of neural circuits and proper reassembly. We demonstrated that our microfluidic device provides a platform for electrically modulating and monitoring the physiological function of neural circuits with genetic indicators for synaptic functionality in corticostriatal (CStr) circuits. In particular, our microfluidic device measures activity-driven Ca2+ dynamics using Ca2+ indicators (synaptophysin-GCaMP6f and Fluo5F-AM), as well as activity-driven synaptic transmission and retrieval using vGlut-pHluorin. Overall, our findings indicate that the improved microfluidic platform described here is an invaluable tool for studying the physiological properties of specific neural circuits. [ABSTRACT FROM AUTHOR]

Cell‐type‐specific, activity‐dependent electrophysiology can allow in‐depth analysis of functional connectivity inside complex neural circuits composed of various cell types. To date, optics‐based fluorescence recording devices enable monitoring cell‐type‐specific activities. However, the monitoring is typically limited to a single brain region, and the temporal resolution is significantly low. Herein, a multimodal multi‐shank fluorescence neural probe that allows cell‐type‐specific electrophysiology from multiple deep‐brain regions at a high spatiotemporal resolution is presented. A photodiode and an electrode‐array pair are monolithically integrated on each tip of a minimal‐form‐factor silicon device. Both fluorescence and electrical signals are successfully measured simultaneously in GCaMP6f expressing mice, and the cell type from sorted neural spikes is identified. The probe's capability of combined electro‐optical recordings for cell‐type‐specific electrophysiology at multiple brain regions within a neural circuit is demonstrated. The new experimental paradigm to enable the precise investigation of functional connectivity inside and across complex neural circuits composed of various cell types is expected. [ABSTRACT FROM AUTHOR]

The neural circuits of the central nervous system are the regulatory pathways for feeling, motion control, learning, and memory, and their dysfunction is closely related to various neurodegenerative diseases. Despite the growing demand for the unraveling of the physiology and functional connectivity of the neural circuits, their fundamental investigation is hampered because of the inability to access the components of neural circuits and the complex microenvironment. As an alternative approach, in vitro human neural circuits show principles of in vivo human neuronal circuit function. They allow access to the cellular compartment and permit real-time monitoring of neural circuits. In this review, we summarize recent advances in reconstituted in vitro neural circuits using engineering techniques. To this end, we provide an overview of the fabrication techniques and methods for stimulation and measurement of in vitro neural circuits. Subsequently, representative examples of in vitro neural circuits are reviewed with a particular focus on the recapitulation of structures and functions observed in vivo , and we summarize their application in the study of various brain diseases. We believe that the in vitro neural circuits can help neuroscience and the neuropharmacology. Despite the growing demand to unravel the physiology and functional connectivity of the neural circuits, the studies on the in vivo neural circuits are frequently limited due to the poor accessibility. Furthermore, single neuron-based analysis has an inherent limitation in that it does not reflect the full spectrum of the neural circuit physiology. As an alternative approach, in vitro engineered neural circuit models have arisen because they can recapitulate the structural and functional characteristics of in vivo neural circuits. These in vitro neural circuits allow the mimicking of dysregulation of the neural circuits, including neurodegenerative diseases and traumatic brain injury. Emerging in vitro engineered neural circuits will provide a better understanding of the (patho-)physiology of neural circuits. [Display omitted] [ABSTRACT FROM AUTHOR]

Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models. Currently technologies for monitoring and controlling neural activities in 3D models are lacking. Here the authors report a 3D high-density multielectrode array, with optical stimulation and drug delivery, to investigate neural circuit dynamics in engineered 3D neural tissues. [ABSTRACT FROM AUTHOR]

Investigation and modulation of neural circuits in vivo at the cellular level are very important for studying functional connectivity in a brain. Recently, neural probes with stimulation capabilities have been introduced, and they provided an opportunity for studying neural activities at a specific region in the brain using various stimuli. However, previous methods have a limitation in dissecting long-range neural circuits due to inherent limitations on their designs. Moreover, the large size of the previously reported probes induces more significant tissue damage. Herein, we present a multifunctional multi-shank MEMS neural probe that is monolithically integrated with an optical waveguide for optical stimulation, microfluidic channels for drug delivery, and microelectrode arrays for recording neural signals from different regions at the cellular level. In this work, we successfully demonstrated the functionality of our probe by confirming and modulating the functional connectivity between the hippocampal CA3 and CA1 regions in vivo. Microelectromechanical neural probes can cause tissue damage and often cannot record from distant brain areas. Here the authors combine electrical recording, optical stimulation and microfluidic drug delivery in one multi-shank probe with thinner shanks to reduce damage and a flexible design to target long-range neural circuits. [ABSTRACT FROM AUTHOR]

Investigation of the chemical and electrical signals of cells in vivo is critical for studying functional connectivity and brain diseases. Most previous studies have observed either the electrical signals or the chemical signals of cells because recording electrical signals and neurochemicals are done by fundamentally different methods. Herein, we present a bimodal MEMS neural probe that is monolithically integrated with an array of microelectrodes for recording electrical activity, microfluidic channels for sampling extracellular fluid, and a microfluidic interface chip for multiple drug delivery and sample isolation from the localized region at the cellular level. In this work, we successfully demonstrated the functionality of our probe by monitoring and modulating bimodal (electrical and chemical) neural activities through the delivery of chemicals in a co-localized brain region in vivo. We expect our bimodal probe to provide opportunities for a variety of in-depth studies of brain functions as well as for the investigation of neural circuits related to brain diseases. • The bimodal neural probe enables the observation of co-localized electrical and chemical signals from the cells in vivo in a live animal. • The bimodal neural probe has the capabilities to deliver multiple drugs for neuromodulation and to isolate collected samples without interrupting in vivo experiments. • This paper provides the experimental and simulation results for the characteristics of the bimodal neural probe to verify the feasibility of in vivo experiments. • This paper provides results that simultaneously observe co-localized multimodal signals of cells in vivo in the intact mouse brain. [ABSTRACT FROM AUTHOR]