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.
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.
Abstract
NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains ...unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition.
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mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical
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Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing.
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Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in
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mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.
Abstract
Assessing the neurological and behavioral effects of drugs is important in developing pharmacological treatments, as well as understanding the mechanisms associated with neurological ...disorders. Herein, we present a miniaturized, wireless neural probe system with the capability of delivering drugs for the real-time investigation of the effects of the drugs on both behavioral and neural activities in socially interacting mice. We demonstrate wireless drug delivery and simultaneous monitoring of the resulting neural, behavioral changes, as well as the dose-dependent and repeatable responses to drugs. Furthermore, in pairs of mice, we use a food competition assay in which social interaction was modulated by the delivery of the drug, and the resulting changes in their neural activities are analyzed. During modulated food competition by drug injection, we observe changes in neural activity in mPFC region of a participating mouse over time. Our system may provide new opportunities for the development of studying the effects of drugs on behaviour and neural activity.
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
Brain‐machine interfaces (BMIs) that link the brain to a machine are promising for the treatment of neurological disorders through the bi‐directional translation of neural information over extended ...periods. However, the longevity of such implanted devices remains limited by the deterioration of their signal sensitivity over time due to acute inflammation from insertion trauma and chronic inflammation caused by the foreign body reaction. To address this challenge, a lubricated surface is fabricated to minimize friction during insertion and avoid immunogenicity during neural signal recording. Reduced friction force leads to 86% less impulse on the brain tissue, and thus immediately increases the number of measured signal electrodes by 102% upon insertion. Furthermore, the signal measurable period increases from 8 to 16 weeks due to the prevention of gliosis. By significantly reducing insertion damage and the foreign body reaction, the lubricated immune‐stealthy probe surface (LIPS) can maximize the longevity of implantable BMIs.
Signal sensitivity of neural probes deteriorates over time due to acute and chronic inflammations. To overcome these problems, lubricated immune‐stealth probe surface (LIPS) is fabricated with nonimmunogenic properties. Near‐frictionless properties of LIPS minimizing insertion trauma increases signal‐to‐noise ratio and the number of neurons from short‐term neural recording. Furthermore, anti‐biofouling properties of LIPS improve its longevity, doubling the signal recording time‐length.
Integration of stimulation modalities (e.g. electrical, optical, and chemical) on a large array of neural probes can enable an investigation of important underlying mechanisms of brain disorders that ...is not possible through neural recordings alone. Furthermore, it is important to achieve this integration of multiple functionalities in a compact structure to utilize a large number of the mouse models. Here we present a successful optical modulation of in vivo neural signals of a transgenic mouse through our compact 2D MEMS neural array (optrodes). Using a novel fabrication method that embeds a lower cladding layer in a silicon substrate, we achieved a thin silicon 2D optrode array that is capable of delivering light to multiple sites using SU-8 as a waveguide core. Without additional modification to the microelectrodes, the measured impedance of the multiple microelectrodes was below 1 MΩ at 1 kHz. In addition, with a low background noise level (± 25 μV), neural spikes from different individual neurons were recorded on each microelectrode. Lastly, we successfully used our optrodes to modulate the neural activity of a transgenic mouse through optical stimulation. These results demonstrate the functionality of the 2D optrode array and its potential as a next-generation tool for optogenetic applications.
Human spinal-cord-like tissues induced from human pluripotent stem cells are typically insufficiently mature and do not mimic the morphological features of neurulation. Here, we report a ...three-dimensional culture system and protocol for the production of human spinal-cord-like organoids (hSCOs) recapitulating the neurulation-like tube-forming morphogenesis of the early spinal cord. The hSCOs exhibited neurulation-like tube-forming morphogenesis, cellular differentiation into the major types of spinal-cord neurons as well as glial cells, and mature synaptic functional activities, among other features of the development of the spinal cord. We used the hSCOs to screen for antiepileptic drugs that can cause neural-tube defects. hSCOs may also facilitate the study of the development of the human spinal cord and the modelling of diseases associated with neural-tube defects.
The cerebral organoid (CO) model has been used in the study of various neurodegenerative diseases owing to its physiological implications. However, the CO model may only be representative of certain ...clinical findings in affected patients, while some features are not recapitulated. In this study, we found that neurons in the CO model from patients with Alzheimer's disease were less responsive to depolarization, in contrast to previous reports. This difference may be partly attributed to the variations in brain spatial identity depending on the genetic background of the induced pluripotent stem cells. Our current observation raises concerns that the phenotypes observed in the CO model need to be carefully evaluated for their clinical implications.
Abstract
Miniaturized fluorescence imaging systems are promising platforms that overcome the limited use of conventional microscopes in the biomedical field. However, there are physical limitations ...for multicolor fluorescence imaging in existing miniaturized imaging systems because multiple filters have to be integrated into a small structure. Here, we present a miniaturized multicolor fluorescence imaging system integrated with single polydimethylsiloxane (PDMS) light-guide plate (LGP) for multicolor fluorescence imaging. The PDMS LGP allows guiding the transmitted light from the light source only to the fluorescent samples regardless of the wavelength of the light source. Thus, our system is capable of multicolor fluorescence imaging without multiple filters that block the excitation light. We demonstrated the usability of our system in the biomedical field by observing green- and red-labeled cells in the incubator. Our proposed system can be used in a wide range of applications for studies that require multicolor fluorescence imaging in the biomedical field.
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