Electrical Synapses Research Articles

Synchronization in Hindmarsh–Rose neurons subject to higher-order interactions

Higher-order interactions might play a significant role in the collective dynamics of the brain. With this motivation, we here consider a simplicial complex of neurons, in particular, studying the effects of pairwise and three-body interactions on the emergence of synchronization. We assume pairwise interactions to be mediated through electrical synapses, while for second-order interactions, we separately study diffusive coupling and nonlinear chemical coupling. For all the considered cases, we derive the necessary conditions for synchronization by means of linear stability analysis, and we compute the synchronization errors numerically. Our research shows that the second-order interactions, even if of weak strength, can lead to synchronization under significantly lower first-order coupling strengths. Moreover, the overall synchronization cost is reduced due to the introduction of three-body interactions if compared to pairwise interactions.

Trichloroacetic Acid Fixation and Antibody Staining of Zebrafish Larvae.

Larval zebrafish have been established as an excellent model for examining vertebrate biology, with many researchers using the system for neuroscience. Controlling a fast escape response of the fish, the Mauthner cells and their associated network are an attractive model, given their experimental accessibility and fast development, driving ethologically relevant behavior in the first five days of development. Here, we describe methods for immunostaining electrical and chemical synapse proteins at 3-7 days post fertilization (dpf) in zebrafish using tricholoracetic acid fixation. The methods presented are ideally suited to easily visualize neural circuits and synapses within the fish.

The disconnect2 mutation disrupts the tjp1b gene that is required for electrical synapse formation.

To investigate electrical synapse formation in vivo we used forward genetics to disrupt genes affecting Mauthner cell electrical synapses in larval zebrafish. We identify the disconnect2 ( dis2 ) mutation for its failure to localize neural gap junction channels at electrical synapses. We mapped this mutation to chromosome 25 and identified a splice-altering mutation in the tjp1b gene. We demonstrated that the dis2 mutation disrupts tjp1b function using complementation analysis with CRISPR generated mutants. We conclude that the dis2 mutation disrupts the tjp1b gene that is required for electrical synapse formation.

Hamiltonian energy and coexistence of hidden firing patterns from bidirectional coupling between two different neurons

In this paper, bidirectional-coupled neurons through an asymmetric electrical synapse are investigated. These coupled neurons involve 2D Hindmarsh–Rose (HR) and 2D FitzHugh–Nagumo (FN) neurons. The equilibria of the coupled neurons model are investigated, and their stabilities have revealed that, for some values of the electrical synaptic weight, the model under consideration can display either self-excited or hidden firing patterns. In addition, the hidden coexistence of chaotic bursting with periodic spiking, chaotic spiking with period spiking, chaotic bursting with a resting pattern, and the coexistence of chaotic spiking with a resting pattern are also found for some sets of electrical synaptic coupling. For all the investigated phenomena, the Hamiltonian energy of the model is computed. It enables the estimation of the amount of energy released during the transition between the various electrical activities. Pspice simulations are carried out based on the analog circuit of the coupled neurons to support our numerical results. Finally, an STM32F407ZE microcontroller development board is exploited for the digital implementation of the proposed coupled neurons model.

CAMP controls a trafficking mechanism that maintains the neuron specificity and subcellular placement of electrical synapses.

Electrical synapses are established between specific neurons and within distinct subcellular compartments, but the mechanisms that direct gap junction assembly in the nervous system are largely unknown. Here, we show that a developmental program tunes cAMP signaling to direct the neuron-specific assembly and placement of electrical synapses in the C.elegans motor circuit. We use live-cell imaging to visualize electrical synapses invivo and an optogenetic assay to confirm that they are functional. In ventral A class (VA) motor neurons, the UNC-4 transcription factor blocks expression of cAMP antagonists that promote gap junction miswiring. In unc-4 mutants, VA electrical synapses are established with an alternative synaptic partner and are repositioned from the VA axon to soma. cAMP counters these effects by driving gap junction trafficking into the VA axon for electrical synapse assembly. Thus, our experiments establish that cAMP regulates gap junction trafficking for the biogenesis of functional electrical synapses.

Chimera states in a multi-weighted neuronal network

There are multiple types of interactions among neurons, each of which has a remarkable effect on the neurons' behavior. Due to the significance of chimeras in neural processes, in this paper, we study the impact of different electrical, chemical, and ephaptic couplings on the emergence of chimera. Consequently, a multi-weighted small-world network of neurons is considered. The simultaneous effects of two and three couplings are explored on the chimera and complete synchronization. The results represent that the synchronization is achieved in very small coupling strengths in the absence of chemical synapses. In contrast, without electrical synapses, the neurons only exhibit chimera behavior. In the three-weighted network, the synchronization is enhanced for special chemical coupling strengths. The network with directed links is also examined. The general behaviors of the directed and undirected networks are the same; however, the directed links lead to lower synchronization error.

Synaptic changes modulate spontaneous transitions between tonic and bursting neural activities in coupled Hindmarsh-Rose neurons.

Experimentally, certain cells in the brain exhibit a spike-burst activity with burst synchronization at transition to and during sleep (or drowsiness), while they demonstrate a desynchronized tonic activity in the waking state. We herein investigated the neural activities and their transitions by using a model of coupled Hindmarsh-Rose neurons in an Erdős-Rényi random network. By tuning synaptic strength, spontaneous transitions between tonic and bursting neural activities can be realized. With excitatory chemical synapses or electrical synapses, slow-wave activity (SWA) similar to that observed during sleep can appear, as a result of synchronized bursting activities. SWA cannot appear in a network that is dominated by inhibitory chemical synapses, because neurons exhibit desynchronized bursting activities. Moreover, we found that the critical synaptic strength related to the transitions of neural activities depends only on the network average degree (i.e., the average number of signals that all the neurons receive). We demonstrated, both numerically and analytically, that the critical synaptic strength and the network average degree obey a power-law relation with an exponent of -1. Our study provides a possible dynamical network mechanism of the transitions between tonic and bursting neural activities for the wakefulness-sleep cycle, and of the SWA during sleep. Further interesting and challenging investigations are briefly discussed as well.

GABABR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus.

Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABAB receptor activity, here we examined the impact of GABAB receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABAB receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABAB activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABAB receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects.

Respiratory disturbances and high risk of sudden death in the neonatal connexin-36 knockout mouse.

Neural circuits at the brainstem involved in the central generation of the motor patterns of respiration and cardiorespiratory chemoreflexes organize as cell assemblies connected by chemical and electrical synapses. However, the role played by the electrical connectivity mainly mediated by connexin36 (Cx36), which expression reaches peak value during the postnatal period, is still unknown. To address this issue, we analyzed here the respiratory phenotype of a mouse strain devoid constitutively of Cx36 at P14. Male Cx36‐knockout mice at rest showed respiratory instability of variable degree, including a periodic Cheyne–Stokes breathing. Moreover, mice lacking Cx36 exhibited exacerbated chemoreflexes to normoxic and hypoxic hypercapnia characterized by a stronger inspiratory/expiratory coupling due to an increased sensitivity to CO2. Deletion of Cx36 also impaired the generation of the recurrent episodes of transient bradycardia (ETBs) evoked during hypercapnic chemoreflexes; these EBTs constituted a powerful mechanism of cardiorespiratory coupling capable of improving alveolar gaseous exchange under hypoxic hypercapnia conditions. Approximately half of the homo‐ and heterozygous Cx36KO, but none WT, mice succumbed by respiratory arrest when submitted to hypoxia‐hypercapnia, the principal exogenous stressor causing sudden infant death syndrome (SIDS). The early suppression of EBTs, which worsened arterial O2 saturation, and the generation of a paroxysmal generalized clonic‐tonic activity, which provoked the transition from eupneic to gasping respiration, were the critical events causing sudden death in the Cx36KO mice. These results indicate that Cx36 expression plays a pivotal role in respiratory control, cardiorespiratory coordination, and protection against SIDS at the postnatal period.

Extensive GJD2 Expression in the Song Motor Pathway Reveals the Extent of Electrical Synapses in the Songbird Brain.

Simple SummaryElectrical synapses are ubiquitous in nervous systems, where they coordinate the activity of neural networks in time. However, their role in the execution and learning of complex behaviors remains unknown. Electrical synapses have remained unexplored in the songbird brain, which provides a model to link the production and learning of a complex behavior to the synaptic structure of defined neural circuits. Here, we show that GJD2 mRNA, coding for the major channel-forming electrical synapse protein connexin 36 (Cx36), is extensively expressed in the two nuclei that control song production, HVC and RA and their embedding regions. Our in situ hybridizations, together with the analysis of published transcriptomics data, demonstrate that electrical synapses are a general and widespread feature of song premotor nuclei in songbirds, where they show brain region-specific, cell type-specific expression patterns, dynamic during neuronal differentiation. We propose songbirds as a suitable model to investigate the contribution of the major vertebrate electrical synapse protein, Cx36, to the production and learning of motor skills in vertebrates.Birdsong is a precisely timed animal behavior. The connectivity of song premotor neural networks has been proposed to underlie the temporal patterns of neuronal activity that control vocal muscle movements during singing. Although the connectivity of premotor nuclei via chemical synapses has been characterized, electrical synapses and their molecular identity remain unexplored. We show with in situ hybridizations that GJD2 mRNA, coding for the major channel-forming electrical synapse protein in mammals, connexin 36, is expressed in the two nuclei that control song production, HVC and RA from canaries and zebra finches. In canaries’ HVC, GJD2 mRNA is extensively expressed in GABAergic and only a fraction of glutamatergic cells. By contrast, in RA, GJD2 mRNA expression is widespread in glutamatergic and GABAergic neurons. Remarkably, GJD2 expression is similar in song nuclei and their respective embedding brain regions, revealing the widespread expression of GJD2 in the avian brain. Inspection of a single-cell sequencing database from zebra and Bengalese finches generalizes the distributions of electrical synapses across cell types and song nuclei that we found in HVC and RA from canaries, reveals a differential GJD2 mRNA expression in HVC glutamatergic subtypes and its transient increase along the neurogenic lineage. We propose that songbirds are a suitable model to investigate the contribution of electrical synapses to motor skill learning and production.

Cell Systems Bioelectricity: How Different Intercellular Gap Junctions Could Regionalize a Multicellular Aggregate.

Simple SummaryElectric potential patterns across tissues are instructive for development, regeneration, and tumorigenesis because they can influence transcription, migration, and differentiation through biochemical and biomechanical downstream processes. Determining the origins of the spatial domains of distinct potential, which in turn decide anatomical features such as limbs, eyes, brain, and heart, is critical to a mature understanding of how bioelectric signaling drives morphogenesis. We studied theoretically how connexin proteins with different voltage-gated gap junction conductances can maintain multicellular regions at distinct membrane potentials. We analyzed a minimal model that incorporates effective conductances ultimately related to specific ion channel and junction proteins that are amenable to external regulation. We also consider a bioelectrical relationship between the connexin composition of the intercellular gap junction and different stages of cancer.Electric potential distributions can act as instructive pre-patterns for development, regeneration, and tumorigenesis in cell systems. The biophysical states influence transcription, proliferation, cell shape, migration, and differentiation through biochemical and biomechanical downstream transduction processes. A major knowledge gap is the origin of spatial patterns in vivo, and their relationship to the ion channels and the electrical synapses known as gap junctions. Understanding this is critical for basic evolutionary developmental biology as well as for regenerative medicine. We computationally show that cells may express connexin proteins with different voltage-gated gap junction conductances as a way to maintain multicellular regions at distinct membrane potentials. We show that increasing the multicellular connectivity via enhanced junction function does not always contribute to the bioelectrical normalization of abnormally depolarized multicellular patches. From a purely electrical junction view, this result suggests that the reduction rather than the increase of specific connexin levels can also be a suitable bioelectrical approach in some cases and time stages. We offer a minimum model that incorporates effective conductances ultimately related to specific ion channel and junction proteins that are amenable to external regulation. We suggest that the bioelectrical patterns and their encoded instructive information can be externally modulated by acting on the mean fields of cell systems, a complementary approach to that of acting on the molecular characteristics of individual cells. We believe that despite the limitations of a biophysically focused model, our approach can offer useful qualitative insights into the collective dynamics of cell system bioelectricity.

Effects of autapse on the chimera state in a Hindmarsh-Rose neuronal network

Autapse is introduced as a self-feedback connection that connects the dendrites and axons of the same neuron. Previous studies have revealed that the existence of the autapse can influence the synchronized behaviours of the coupled neurons. In this paper, the chimera state is studied in the presence of autaptic connections. To this aim, a regular network of Hindmarsh-Rose neurons with electrical synapses and autapses is considered. The neurons' collective behaviour and firing patterns are investigated by varying the coupling and the autapse parameters. The results show that for short autaptic time delays, the chimera's occurrence domain is shifted towards lower autapse gains by increasing the coupling strength. On the other hand, the coupling strength has less effect for more extended time delays, and the chimera's domain is only dependent on the autapse gain. However, when the coupling strength grows too large, the time delay loses its effect. Consequently, a desirable dynamical state can be attained by regulating the coupling strength, coupling range, autapse time delay and autapse gain.

Control the collective behaviors in a functional neural network

Specific biophysical neurons are presented to detect different stimuli, and these external exciting signals are encoded to trigger appropriate firing modes and action potentials for signal propagation between neurons in the network. A thermosensitive neuron can estimate the effect of temperature changes on the excitability and firing modes in nervous system, a photocurrent-dependent neuron can be sensitive to the changes of external illumination or light, and an auditory neuron can perceive acoustic wave when the vibration energy is absorbed and converted into field energy in the loop of neural circuits. From biophysical viewpoint, some specific electric components such as thermistor, phototube, and piezoelectric ceramics can be incorporated into neural circuits for activating specific functions, and thus the external stimuli such as heat, light and vibration can be detected because these energy injections can be converted to intrinsic field energy in the neural circuits. In this paper, three kinds of different neural circuits are coupled in a close loop, energy pumping and the stability of phase synchronization are investigated by regulating the properties of coupling channels, furthermore, the noise effect is also estimated. When induction coil is used to couple the neural circuits, phase stability is controlled under magnetic field coupling, and the activation of noise can change the stability of phase synchronization. The intrinsic field energy in the light-dependent neuron is increased with the increase of coupling intensity when voltage coupling via resistor and magnetic field coupling via induction coil are switched on. In case of electric field coupling via capacitor, the energy in the light-dependent neural circuit keeps oscillatory with small amplitude. These results indicate that magnetic field can be the most suitable way for realizing synchronous information encoding between different functional neurons than the electric synapse coupling because continuous pumping of ions can induce magnetic field in the cell, and all the neurons are controlled completely by effective pumping in field energy.

Neuron dynamics and synchronous transition of symmetrical electrically coupled Sherman

Based on the study of the synchronization of two electric synapse-coupled Sherman neuron systems, this paper analyzes the rich discharge behavior of Sherman neurons through the peak-to-peak interval bifurcation diagram, which determines the parameter values for the study of the electrical synapse coupling Sherman neuron system synchronization. By using the synchronization difference and the correlation coefficient value, this paper analyzes the synchronous transition process of the two electrical synapse-coupled Sherman neuron systems with the change of coupling intensity and studies the bifurcation behavior of neurons in the two electrical synapse-coupled Sherman neuron systems. The experimental results show the transition process of two electrical synapse-coupled Sherman neurons from nonsynchronized, peak-independent cluster synchronization to fully synchronized. In addition, we study the synchronization process of the ring-connected electrical synapse-coupled Sherman neuron system. The experimental results show that the two electrical synapse-coupled Sherman neuron systems show a similar synchronous transition process.

UV light modulated synaptic behavior of MoTe2/BN heterostructure

Electrical synaptic devices are the basic components for the hardware based neuromorphic computational systems, which are expected to break the bottleneck of current von Neumann architecture. So far, synaptic devices based on three-terminal transistors are considered to provide the most stable performance, which usually use gate pulses to modulate the channel conductance through a floating gate and/or charge trapping layer. Herein, we report a three-terminal synaptic device based on a two-dimensional molybdenum ditelluride (MoTe2)/hexagonal boron nitride (hBN) heterostructure. This structure enables stable and prominent conductance modulation of the MoTe2 channel by the photo-induced doping method through electron migration between the MoTe2 channel and ultraviolet (UV) light excited mid-gap defect states in hBN. Therefore, it is free of the floating gate and charge trapping layer to reduce the thickness and simplify the fabrication/design of the device. Moreover, since UV illumination is indispensable for stable doping in MoTe2 channel, the device can realize both short- (without UV illumination) and long- (with UV illumination) term plasticity. Meanwhile, the introduction of UV light allows additional tunability on the MoTe2 channel conductance through the wavelength and power intensity of incident UV, which may be important to mimic advanced synaptic functions. In addition, the photo-induced doping method can bidirectionally dope MoTe2 channel, which not only leads to large high/low resistance ratio for potential multi-level storage, but also implement both potentiation (n-doping) and depression (p-doping) of synaptic weight. This work explores alternative three-terminal synaptic configuration without floating gate and charge trapping layer, which may inspire researches on novel electrical synapse mechanisms.

Enhance sensitivity to illumination and synchronization in light-dependent neurons* *Project supported by the National Natural Science Foundation of China (Grant No. 12062009).

When a phototube is activated to connect a neural circuit, the output voltage becomes sensitive to external illumination because the photocurrent across the phototube can be controlled by external electromagnetic wave. The channel currents from different branch circuits have different impacts on the outputs voltage of the neural circuit. In this paper, a phototube is incorporated into different branch circuits in a simple neural circuit, and then a light-controlled neuron is obtained for further nonlinear analysis. Indeed, the phototube is considered as exciting source when it is activated by external illumination, and two kinds of light-sensitive neurons are obtained when the phototube is connected to capacitor or induction coil, respectively. Electric synapse coupling is applied to detect possible synchronization between two functional neurons, and the energy consumption along the coupling channel via resistor is estimated. The analog circuits for the two kinds of light-sensitive neurons are supplied for further confirmation by using Multisim. It is found that two light-sensitive neurons and neural circuits can be synchronized by taming the coupling intensity carefully. It provides possible clues to understand the synchronization mechanism for eyes and artificial sensors which are sensitive to illumination. Finally, a section for open problems is supplied for further investigation about its collective behaviors in the network with/without synapse coupling.

Gjd2b-mediated gap junctions promote glutamatergic synapse formation and dendritic elaboration in Purkinje neurons.

Gap junctions between neurons serve as electrical synapses, in addition to conducting metabolites and signaling molecules. During development, early-appearing gap junctions are thought to prefigure chemical synapses, which appear much later. We present evidence for this idea at a central, glutamatergic synapse and provide some mechanistic insights. Loss or reduction in the levels of the gap junction protein Gjd2b decreased the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in cerebellar Purkinje neurons (PNs) in larval zebrafish. Ultrastructural analysis in the molecular layer showed decreased synapse density. Further, mEPSCs had faster kinetics and larger amplitudes in mutant PNs, consistent with their stunted dendritic arbors. Time-lapse microscopy in wild-type and mutant PNs reveals that Gjd2b puncta promote the elongation of branches and that CaMKII may be a critical mediator of this process. These results demonstrate that Gjd2b-mediated gap junctions regulate glutamatergic synapse formation and dendritic elaboration in PNs.

Polarity Reversal Effect of a Memristor From the Circuit Point of View and Insights Into the Memristor Fuse

As the memristor device is asymmetrical in nature, it is not a bilateral element like the resistor in terms of circuit functionality. Thus, it causes hindrance in some memristor-based applications such as in cellular nonlinear network neighborhood connections and in some application areas where its orientation is essentially expected to act as a bilateral circuit element reliable for bidirectional communication, for example, in signal and image processing or in electrical synapse devices. We introduce a memristor-based network for each purpose where we replace the conventional series resistances by memristors. The memristor asymmetry is described from the circuit point of view allowing us to observe its interaction within the network. Moreover, a memristor fuse is proposed in order to achieve the memristive effect with symmetry, which is formed basically by connecting two memristors antiserially. We, therefore, analyze the memristor fuse from its basic principle along with the theoretical analysis and then observe the response from the circuit point of view.

Assortativity-induced explosive synchronization in a complex neuronal network.

In this study, we consider a scale-free network of nonidentical Chialvo neurons, coupled through electrical synapses. For sufficiently strong coupling, the system undergoes a transition from completely out of phase synchronized to phase synchronized state. The principal focus of this study is to investigate the effect of the degree of assortativity over the synchronization transition process. It is observed that, depending on assortativity, bistability between two asymptotically stable states allows one to develop a hysteresis loop which transforms the phase transition from second order to first order. An expansion in the area of hysteresis loop is noticeable with increasing degree-degree correlation in the network. Our study also reveals that effective frequencies of nodes simultaneously go through a continuous or sudden transition to the synchronized state with the corresponding phases. Further, we examine the robustness of the results under the effect of network size and average degree, as well as diverse frequency setup. Finally, we investigate the dynamical mechanism in the process of generating explosive synchronization. We observe a significant impact of lower degree nodes behind such phenomena: in a positive assortative network the low degree nodes delay the synchronization transition.

PTEN Expression Regulates Gap Junction Connectivity in the Retina.

Manipulation of the phosphatase and tensin homolog (PTEN) pathway has been suggested as a therapeutic approach to treat or prevent vision loss due to retinal disease. In this study, we investigated the effects of deleting one copy of Pten in a well-characterized class of retinal ganglion cells called α-ganglion cells in the mouse retina. In Pten+/– retinas, α-ganglion cells did not exhibit major changes in their dendritic structure, although most cells developed a few, unusual loop-forming dendrites. By contrast, α-ganglion cells exhibited a significant decrease in heterologous and homologous gap junction mediated cell coupling with other retinal ganglion and amacrine cells. Additionally, the majority of OFF α-ganglion cells (12/18 cells) formed novel coupling to displaced amacrine cells. The number of connexin36 puncta, the predominant connexin that mediates gap junction communication at electrical synapses, was decreased by at least 50% on OFF α-ganglion cells. Reduced and incorrect gap junction connectivity of α-ganglion cells will affect their functional properties and alter visual image processing in the retina. The anomalous connectivity of retinal ganglion cells would potentially limit future therapeutic approaches involving manipulation of the Pten pathway for treating ganglion cell degeneration in diseases like glaucoma, traumatic brain injury, Parkinson’s, and Alzheimer’s diseases.