On-Site Formation of Functional Dopaminergic Presynaptic Terminals on Neuroligin-2-Modified Gold-Coated Microspheres.

Advancements in neural interface technologies have enabled the direct connection of neurons and electronics, facilitating chemical communication between neural systems and external devices. One promising approach is a synaptogenesis-involving method, which offers an opportunity for synaptic signaling between these systems. Janus synapses, one type of synaptic interface utilizing synaptic cell adhesion molecules for interface construction, possess unique features that enable the determination of location, direction of signal flow, and types of neurotransmitters involved, promoting directional and multifaceted communication. This study presents the first successful establishment of a Janus synapse between dopaminergic (DA) neurons and abiotic substrates by using a neuroligin-2 (NLG2)-mediated synapse-inducing method. NLG2 immobilized on gold-coated microspheres can induce synaptogenesis upon contact with spatially isolated DA axons. The induced DA Janus synapses exhibit stable synaptic activities comparable to that of native synapses over time, suggesting their suitability for application in neural interfaces. By calling for DA presynaptic organizations, the NLG2-immobilized abiotic substrate is a promising tool for the on-site detection of synaptic dopamine release.

Iontronic analog of synaptic plasticity: Hydrogel-based ionic diode with chemical precipitation and dissolution.

In this study, an aqueous nonlinear synaptic element showing plasticity behavior is developed, which is based on the chemical processes in an ionic diode. The device is simple, fully ionic, and easily configurable, requiring only two terminals-for input and output-similar to biological synapses. The key processes realizing the plasticity features are chemical precipitation and dissolution, which occur at forward- or reverse-biased ionic diode junctions in appropriate reservoir electrolytes. Given that the precipitate acts as a physical barrier in the circuit, the above processes change the diode conductivity, which can be interpreted as adjusting "synaptic weight" of the system. By varying the operating conditions, we first demonstrate the four types of plasticity that can be found in biological system: long-term potentiation/depression and short-term potentiation/depression. The plasticity of the proposed iontronic device has characteristics similar to those of neural synapses. To demonstrate its potential use in comparatively complex information processing, we develop a precipitation-based iontronic synapse (PIS) capable of both potentiation and depression. Finally, we show that the postsynaptic signals from the multiple excitatory or inhibitory PISs can be integrated into the total "dendritic" current, which is a function of time and input history, as in actual hippocampal neural circuits.

Inverted Ion Current Rectification-Based Chemical Delivery Probes for Stimulation of Neurons.

Ion current rectification (ICR), diodelike behavior in surface-charged nanopores, shows promise in the design of delivery probes for manipulation of neural networks as it can solve diffusive leakages that might be critical in clinical and research applications. However, it has not been achieved because ICR has restrictions in nanosized dimension and low electrolyte concentration, and rectification direction is inappropriate for delivery. Herein, we present a polyelectrolyte gel-filled (PGF) micropipette harnessing inverted ICR as a delivery probe, which quantitatively transports glutamate to stimulate primary cultured neurons with high efficiency while minimizing leakages. Since the gel works as an ensemble of numerous surface-charged nanopores, the current is rectified in the micro-opening and physiological environment. By extending the charge-selective region using the gel, inverted ICR is generated, which drives outward deliveries of major charge carriers. This study will help in exploring new aspects of ICR and broaden its applications for advanced chemical delivery.

Neuroligin-1-Modified Electrodes for Specific Coupling with a Presynaptic Neuronal Membrane.

Coordination of synapses onto electrodes with high specificity and maintaining a stable and long-lasting interface have importance in the field of neural interfaces. One potential approach is to present ligands on the surface of electrodes that would be bound through a protein-protein interaction to specific areas of neuronal cells. Here, we functionalize electrode surfaces with genetically engineered neuroligin-1 protein and demonstrate the formation of a nascent presynaptic bouton upon binding to neurexin-1 ß on the presynaptic membrane of neurons. The resulting synaptically connected electrode shows an assembly of presynaptic proteins and comparable exocytosis kinetics to that of native synapses. Importantly, a neuroligin-1-induced synapse-electrode interface exhibits type specificity and structural robustness. We envision that the use of synaptic adhesion proteins in modified neural electrodes may lead to new approaches in the interfacing of neural circuity and electronics.

Hydrogel-Based Iontronics on a Polydimethylsiloxane Microchip.

In response to the extensive utilization of ionic circuits, including in iontronics and wearable devices, a new method for fabricating a hydrogel-based ionic circuit on a polydimethylsiloxane (PDMS) microchip is reported. Prolonged UV/ozone oxidation combined with proper surface functionalizations and a novel microchip bonding method using thiol-epoxy click reaction enable the robust attachment of the photopolymerized hydrogel to the microchannel surface for eventual operation in electrolytes as an ionic circuit. The stretchable ionic diode constructed on the PDMS microchip shows a superior rectification ratio even under tensile stress and long-term storage stability. Furthermore, the combination of the ionic circuit and unique material properties of PDMS allows us to maximize the versatility and diversify the functionalities of the iontronic device, as demonstrated in a pressure-driven ionic switch and chip-integrated ionic regulator. Its iontronic signal transmission mimicking the excitatory and inhibitory synapses also evinces the potential of the hydrogel-based iontronics on the PDMS microchip as developed toward an aqueous neuromimetic information processor while opening up new opportunities for various bioinspired applications.

Ion-to-ion amplification through an open-junction ionic diode.

As biological signals are mainly based on ion transport, the differences in signal carriers have become a major issue for the intimate communication between electrical devices and biological areas. In this respect, an ionic device which can directly interpret ionic signals from biological systems needs to be designed. Particularly, it is also required to amplify the ionic signals for effective signal processing, since the amount of ions acquired from biological systems is very small. Here, we report the signal amplification in ionic systems as well as sensing through the modified design of polyelectrolyte hydrogel-based ionic diodes. By designing an open-junction structure, ionic signals from the external environment can be directly transmitted to an ionic diode. Moreover, the minute ionic signals injected into the devices can also be amplified to a large amount of ions. The signal transduction mechanism of the ion-to-ion amplification is suggested and clearly verified by revealing the generation of breakdown ionic currents during an ion injection. Subsequently, various methods for enhancing the amplification are suggested.

Robust Induced Presynapse on Artificial Substrates as a Neural Interfacing Method.

Over the recent years, the development of neural interface systems has stuck to using electrical cues to stimulate neurons and read out neural signals, although neurons relay signals via chemical release and recognition at synapses. In addition, conventional neural interfaces are vulnerable to cell migration and glial encapsulation due to the absence of connection anchoring the neuron into the device unlike synapses, which are firmly sustained by protein bonding. To close this discrepancy, we conducted an intensive investigation into the induced synapse interface by employing engineered synaptic proteins from a neural interface perspective. The strong potential of induced synaptic differentiation as an emerging neural interfacing technique is demonstrated by exploring its structural features, chemical release kinetics, robustness, and scalability to the brain tissue. We show that the exocytosis kinetics of induced synapses is similar to that of endogenous synapses. Moreover, induced synapses show remarkable stability, despite cell migration and growth. The synapse-inducing technique has broad applications to cultured hippocampal and cortex tissues and suggests a promising method to integrate neural circuits with digital elements.