Complex Spike Research Articles

Protein kinase Cγ in cerebellar Purkinje cells regulates Ca2+-activated large-conductance K+ channels and motor coordination

The cerebellum, the site where protein kinase C (PKC) was first discovered, contains the highest amount of PKC in the central nervous system, with PKCγ being the major isoform. Systemic PKCγ-knockout (KO) mice showed impaired motor coordination and deficient pruning of surplus climbing fibers (CFs) from developing cerebellar Purkinje cells (PCs). However, the physiological significance of PKCγ in the mature cerebellum and the cause of motor incoordination remain unknown. Using adeno-associated virus vectors targeting PCs, we showed that impaired motor coordination was restored by re-expression of PKCγ in mature PKCγ-KO mouse PCs in a kinase activity-dependent manner, while normal motor coordination in mature Prkcgfl/fl mice was impaired by the Cre-dependent removal of PKCγ from PCs. Notably, the rescue or removal of PKCγ from mature PKCγ-KO or Prkcgfl/fl mice, respectively, did not affect the CF innervation profile of PCs, suggesting the presence of a mechanism distinct from multiple CF innervation of PCs for the motor defects in PKCγ-deficient mice. We found marked potentiation of Ca2+-activated large-conductance K+ (BK) channel currents in PKCγ-deficient mice, as compared to wild-type mice, which decreased the membrane resistance, resulting in attenuation of the electrical signal during the propagation and significant alterations of the complex spike waveform. These changes in PKCγ-deficient mice were restored by the rescue of PKCγ or pharmacological suppression of BK channels. Our results suggest that PKCγ is a critical regulator that negatively modulates BK currents in PCs, which significantly influences PC output from the cerebellar cortex and, eventually, motor coordination.

Behavioral Timescale Cooperativity and Competitive Synaptic Interactions Regulate the Induction of Complex Spike Burst-Dependent Long-Term Potentiation.

Although Hebbian LTP has an important role in memory formation, the properties of Hebbian LTP cannot fully account for, and in some cases seem incompatible with, fundamental properties of associative learning. Importantly, findings from computational and neurophysiological studies suggest that burst-dependent forms of plasticity, where dendritic spikes and bursts of action potentials provide the postsynaptic depolarization needed for LTP induction, may overcome some of the limitations of conventional Hebbian LTP. Thus, I investigated how excitatory synapses onto CA1 pyramidal cells interact during the induction of complex spike (CS) burst-dependent LTP in hippocampal slices from male mice. Consistent with previous findings, theta-frequency trains of synaptic stimulation induce a Hebbian form of plasticity where postsynaptic CS bursts provide the depolarization needed for NMDAR activation and LTP induction. However, in contrast to conventional Hebbian plasticity, where cooperative LTP induction requires coactivation of synapses on a timescale of tens of milliseconds, cooperative interactions between synapses activated several seconds apart can induce CS burst-dependent LTP. A novel, retroactive form of heterosynaptic plasticity, where activation of one group of synapses triggers LTP induction at other synapses that were active seconds earlier, also contributes to cooperativity in CS burst-dependent LTP. Moreover, competitive synaptic interactions that emerge during prolonged bouts of postsynaptic CS bursting potently regulate CS burst-dependent LTP. Together, the unusual properties of synaptic cooperativity and competition in CS burst-dependent LTP enable Hebbian synapses to operate and interact on behavioral timescales.SIGNIFICANCE STATEMENT While EPSP-evoked complex spike (CS) bursting induces LTP at excitatory synapses onto hippocampal CA1 pyramidal cells, the properties of synaptic interactions during the induction of CS burst-dependent LTP have not been investigated. Here I report that interactions between independent synaptic inputs during the induction of CS burst-dependent LTP exhibit a number of novel, computationally relevant properties. Unlike conventional Hebbian LTP, the induction of CS burst-dependent LTP is regulated by proactive and retroactive cooperative interactions between synapses activated several seconds apart. Moreover, activity-dependent, competitive interactions between synapses allow strongly activated synapses to suppress LTP induction at more weakly activated synapses. Thus, CS burst-dependent LTP exhibits a number of the unique properties that overcome significant limitations of standard Hebbian plasticity rules.

Arrays of Nanocomposite Crossbar Memristors for the Implementation of Formal and Spiking Neuromorphic Systems

Memristors are promising devices for use as synapses in hardware-based artificial formal and spiking neural networks. Their use can increase the energy efficiency of such networks when solving various cognitive tasks. At the same time, for the implementation of hardware-based neural networks, a large number of rather densely packed structures are required, which can be achieved by creating memristive matrices in a crossbar architecture. Crossbar arrays of nanocomposite memristors on silicon substrates with protection against edge effects are developed and manufactured, their resistive switching is investigated, a formal neural network is created on their basis, which is capable of recognizing simple patterns after loading a pretrained weight map, and the possibility of precise adjustment of the conductivity of the crossbar memristors by various means applicable in the creation of more complex spiking and formal neural networks is demonstrated.

Olivocerebellar control of movement symmetry

Coordination of bilateral movements is essential for a large variety of animal behaviors. The olivocerebellar system is critical for the control of movement, but its role in bilateral coordination has yet to be elucidated. Here, we examined whether Purkinje cells encode and influence synchronicity of left-right whisker movements. We found that complex spike activity is correlated with a prominent left-right symmetry of spontaneous whisker movements within parts, but not all, of Crus1 and Crus2. Optogenetic stimulation of climbing fibers in the areas with high and low correlations resulted in symmetric and asymmetric whisker movements, respectively. Moreover, when simple spike frequency prior to the complex spike was higher, the complex spike-related symmetric whisker protractions were larger. This finding alludes to a role for rebound activity in the cerebellar nuclei, which indeed turned out to be enhanced during symmetric protractions. Tracer injections suggest that regions associated with symmetric whisker movements are anatomically connected to the contralateral cerebellar hemisphere. Together, these data point toward the existence of modules on both sides of the cerebellar cortex that can differentially promote or reduce the symmetry of left and right movements in a context-dependent fashion.

Is the inferior olive central to essential tremor? Yes.

We consider the question whether the inferior olive (IO) is required for essential tremor (ET). Much evidence shows that the olivocerebellar system is the main system capable of generating the widespread synchronous oscillatory Purkinje cell (PC) complex spike (CS) activity across the cerebellar cortex that would be capable of generating the type of bursting cerebellar output from the deep cerebellar nuclei (DCN) that could underlie tremor. Normally, synchronous CS activity primarily reflects the effective electrical coupling of IO neurons by gap junctions, and traditionally, ET research has focused on the hypothesis of increased coupling of IO neurons as the cause of hypersynchronous CS activity underlying tremor. However, recent pathology studies of brains from humans with ET and evidence from mutant mice, particularly the hotfoot17 mouse, that largely replicate the pathology of ET, suggest that the abnormal innervation of multiple Purkinje cells (PCs) by climbing fibers (Cfs) is related to tremor. In addition, ET brains show partial PC loss and axon terminal sprouting by surviving PCs. This may provide another mechanism for tremor. It is proposed that in ET, these three mechanisms may promote tremor. They all involve hypersynchronous DCN activity and an intact IO, but the level at which excessive synchronization occurs may be at the IO level (from abnormal afferent activity to this nucleus), the PC level (via aberrant Cfs), or the DCN level (via terminal PC collateral innervation).

Multi-level scoring approach to discover multi-targeting potency of medicinal plant phytochemicals against protein targets in SARS-CoV-2 and human ACE-2 receptor

SARS-CoV-2 pandemic has become a major threat to human healthcare and world economy. Due to the rapid spreading and deadly nature of infection, we are in a situation to develop quick therapeutics to combat SARS-CoV-2. In this study, we have adopted a multi-level scoring approach to identify multi-targeting potency of bioactive compounds in selected medicinal plants and compared its efficacy with two reference drugs, Nafamostat and Acalabrutinib which are under clinical trials to treat SARS-CoV-2. In particular, we employ molecular docking and implicit solvent free energy calculations (as implemented in the Molecular Mechanics -Generalized Born Surface Area approach) and QM fragmentation approach for validating the potency of bioactive compounds from the selected medicinal plants against four different viral targets and one human receptor (Angiotensin-converting enzyme 2 -ACE-2) which facilitates the SARS-CoV-2entry into the cell. The protein targets considered for the study are viral 3CL main protease (3CLpro), papain-like protease (PLpro), RNA dependent RNA polymerase (RdRp), and viral spike protein-human hACE-2 complex (Spike:hACE2)including human protein target (hACE-2). Herein, thereliable multi-level scoring approach was used to validate the mechanism behind the multi-targeting potency of selected phytochemicals from medicinal plants. The present study evidenced that the phytochemicals Chebulagic acid, Stigmosterol, Repandusinic acid and Geranin exhibited efficient inhibitory activity against PLpro while Chebulagic acid was highly active against 3CLpro. Chebulagic acid andGeranin also showed excellent target specific activity against RdRp.Luteolin, Quercetin, Chrysoeriol and Repandusinic acid inhibited the interaction of viral spike protein with human ACE-2 receptor. Moreover Piperlonguminine and Piperine displayed significant inhibitory activity against human ACE-2 receptor. Therefore, the identified compounds namely Chebulagic acid, Geranin and Repandusinic acid can serve as potent multi-targeting phytomedicine for treating COVID-19

Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses.

Transcranial direct current stimulation (tDCS) of the cerebellum has rapidly raised interest but the effects of tDCS on cerebellar neurons remain unclear. Assessing the cellular response to tDCS is challenging because of the uneven, highly stratified cytoarchitecture of the cerebellum, within which cellular morphologies, physiological properties, and function vary largely across several types of neurons. In this study, we combine MRI-based segmentation of the cerebellum and a finite element model of the tDCS-induced electric field (EF) inside the cerebellum to determine the field imposed on the cerebellar neurons throughout the region. We then pair the EF with multicompartment models of the Purkinje cell (PC), deep cerebellar neuron (DCN), and granule cell (GrC) and quantify the acute response of these neurons under various orientations, physiological conditions, and sequences of presynaptic stimuli. We show that cerebellar tDCS significantly modulates the postsynaptic spiking precision of the PC, which is expressed as a change in the spike count and timing in response to presynaptic stimuli. tDCS has modest effects, instead, on the PC tonic firing at rest and on the postsynaptic activity of DCN and GrC. In Purkinje cells, anodal tDCS shortens the repolarization phase following complex spikes (-14.7 ± 6.5% of baseline value, mean ± S.D.; max: -22.7%) and promotes burstiness with longer bursts compared to resting conditions. Cathodal tDCS, instead, promotes irregular spiking by enhancing somatic excitability and significantly prolongs the repolarization after complex spikes compared to baseline (+37.0 ± 28.9%, mean ± S.D.; max: +84.3%). tDCS-induced changes to the repolarization phase and firing pattern exceed 10% of the baseline values in Purkinje cells covering up to 20% of the cerebellar cortex, with the effects being distributed along the EF direction and concentrated in the area under the electrode over the cerebellum. Altogether, the acute effects of tDCS on cerebellum mainly focus on Purkinje cells and modulate the precision of the response to synaptic stimuli, thus having the largest impact when the cerebellar cortex is active. Since the spatiotemporal precision of the PC spiking is critical to learning and coordination, our results suggest cerebellar tDCS as a viable therapeutic option for disorders involving cerebellar hyperactivity such as ataxia.

Purkinje cells translate subjective salience into readiness to act and choice performance

The brain selectively allocates attention from a continuous stream of sensory input. This process is typically attributed to computations in distinct regions of the forebrain and midbrain. Here, we explore whether cerebellar Purkinje cells encode information about the selection of sensory inputs and could thereby contribute to non-motor forms of learning. We show that complex spikes of individual Purkinje cells change the sensory modality they encode to reflect changes in the perceived salience of sensory input. Comparisons with mouse models deficient in cerebellar plasticity suggest that changes in complex spike activity instruct potentiation of Purkinje cells simple spike firing, which is required for efficient learning. Our findings suggest that during learning, climbing fibers do not directly guide motor output, but rather contribute to a general readiness to act via changes in simple spike activity, thereby bridging the sequence from non-motor to motor functions.

Mid-lateral cerebellar complex spikes encode multiple independent reward-related signals during reinforcement learning

Although the cerebellum has been implicated in simple reward-based learning recently, the role of complex spikes (CS) and simple spikes (SS), their interaction and their relationship to complex reinforcement learning and decision making is still unclear. Here we show that in a context where a non-human primate learned to make novel visuomotor associations, classifying CS responses based on their SS properties revealed distinct cell-type specific encoding of the probability of failure after the stimulus onset and the non-human primate’s decision. In a different context, CS from the same cerebellar area also responded in a cell-type and learning independent manner to the stimulus that signaled the beginning of the trial. Both types of CS signals were independent of changes in any motor kinematics and were unlikely to instruct the concurrent SS activity through an error based mechanism, suggesting the presence of context dependent, flexible, multiple independent channels of neural encoding by CS and SS. This diversity in neural information encoding in the mid-lateral cerebellum, depending on the context and learning state, is well suited to promote exploration and acquisition of wide range of cognitive behaviors that entail flexible stimulus-action-reward relationships but not necessarily motor learning.

Distributed sensory coding by cerebellar complex spikes in units of cortical segments.

Sensory processing is essential for motor control. Climbing fibers from the inferior olive transmit sensory signals to Purkinje cells, but how the signals are represented in the cerebellar cortex remains elusive. To examine the olivocerebellar organization of the mouse brain, we perform quantitative Ca2+ imaging to measure complex spikes (CSs) evoked by climbing fiber inputs over the entire dorsal surface of the cerebellum simultaneously. The surface is divided into approximately 200 segments, each composed of ∼100 Purkinje cells that fire CSs synchronously. Our invivo imaging reveals that, although stimulation of four limb muscles individually elicits similar global CS responses across nearly all segments, the timing and location of a stimulus are derived by Bayesian inference from coordinated activation and inactivation of multiple segments on a single trial basis. We propose that the cerebellum performs segment-based, distributed-population coding that represents the conditional probability of sensory events.

Exploiting the electrothermal timescale in PrMnO3 RRAM for a compact, clock-less neuron exhibiting biological spiking patterns

Spiking neural networks (SNNs) are gaining widespread momentum in the field of neuromorphic computing. These network systems integrated with neurons and synapses provide computational efficiency by mimicking the human brain. It is desired to incorporate the biological neuronal dynamics, including complex spiking patterns which represent diverse brain activities within the neural networks. Earlier hardware realization of neurons was (a) area intensive because of large capacitors in the circuit design, (b) neuronal spiking patterns were demonstrated with clocked neurons at the device level. To achieve more realistic biological neuron spiking behavior, emerging memristive devices are considered promising alternatives. In this paper, we propose, PrMnO3 (PMO)-resistive random-access memory (RRAM) device-based neuron. The voltage-controlled electrothermal timescales of the compact PMO RRAM device replace the electrical timescales of charging a large capacitor. The electrothermal timescale is used to implement an integration block with multiple voltage-controlled timescales coupled with a refractory block to generate biological neuronal dynamics. Here, first, a Verilog-A implementation of the thermal device model is demonstrated, which captures the current-temperature dynamics of the PMO device. Second, a driving circuitry is designed to mimic different spiking patterns of cortical neurons, including intrinsic bursting and chattering. Third, a neuron circuit model is simulated, which includes the PMO RRAM device model and the driving circuitry to demonstrate the asynchronous neuron behavior. Finally, a hardware-software hybrid analysis is done in which the PMO RRAM device is experimentally characterized to mimic neuron spiking dynamics. The work presents a realizable and more biologically comparable hardware-efficient solution for large-scale SNNs.

Activity of Cerebellar Nuclei Neurons Correlates with ZebrinII Identity of Their Purkinje Cell Afferents.

Purkinje cells (PCs) in the cerebellar cortex can be divided into at least two main subpopulations: one subpopulation that prominently expresses ZebrinII (Z+), and shows a relatively low simple spike firing rate, and another that hardly expresses ZebrinII (Z–) and shows higher baseline firing rates. Likewise, the complex spike responses of PCs, which are evoked by climbing fiber inputs and thus reflect the activity of the inferior olive (IO), show the same dichotomy. However, it is not known whether the target neurons of PCs in the cerebellar nuclei (CN) maintain this bimodal distribution. Electrophysiological recordings in awake adult mice show that the rate of action potential firing of CN neurons that receive input from Z+ PCs was consistently lower than that of CN neurons innervated by Z– PCs. Similar in vivo recordings in juvenile and adolescent mice indicated that the firing frequency of CN neurons correlates to the ZebrinII identity of the PC afferents in adult, but not postnatal stages. Finally, the spontaneous action potential firing pattern of adult CN neurons recorded in vitro revealed no significant differences in intrinsic pacemaking activity between ZebrinII identities. Our findings indicate that all three main components of the olivocerebellar loop, i.e., PCs, IO neurons and CN neurons, operate at a higher rate in the Z– modules.

P-sort: an open-source software for cerebellar neurophysiology.

Analysis of electrophysiological data from Purkinje cells (P-cells) of the cerebellum presents unique challenges to spike sorting. Complex spikes have waveforms that vary significantly from one event to the next, raising the problem of misidentification. Even when complex spikes are detected correctly, the simple spikes may belong to a different P-cell, raising the danger of misattribution. To address these identification and attribution problems, we wrote an open-source, semiautomated software called P-sort, and then tested it by analyzing data from P-cells recorded in three species: marmosets, macaques, and mice. Like other sorting software, P-sort relies on nonlinear dimensionality reduction to cluster spikes. However, it also uses the statistical relationship between simple and complex spikes to merge disparate clusters and split a single cluster. In comparison with expert manual curation, occasionally P-sort identified significantly more complex spikes, as well as prevented misattribution of clusters. Three existing automatic sorters performed less well, particularly for identification of complex spikes. To improve the development of analysis tools for the cerebellum, we provide labeled data for 313 recording sessions, as well as statistical characteristics of waveforms and firing patterns of P-cells in three species.NEW & NOTEWORTHY Algorithms that perform spike sorting depend on waveforms to cluster spikes. However, a cerebellar Purkinje-cell produces two types of spikes; simple and complex spikes. A complex spike coincides with the suppression of generating simple spikes. Here, we recorded neurophysiological data from three species and developed a spike analysis software named P-sort that relies on this statistical property to improve both the detection and the attribution of simple and complex spikes in the cerebellum.

Cerebellar complex spikes multiplex complementary behavioral information.

Purkinje cell (PC) discharge, the only output of cerebellar cortex, involves 2 types of action potentials, high-frequency simple spikes (SSs) and low-frequency complex spikes (CSs). While there is consensus that SSs convey information needed to optimize movement kinematics, the function of CSs, determined by the PC’s climbing fiber input, remains controversial. While initially thought to be specialized in reporting information on motor error for the subsequent amendment of behavior, CSs seem to contribute to other aspects of motor behavior as well. When faced with the bewildering diversity of findings and views unraveled by highly specific tasks, one may wonder if there is just one true function with all the other attributions wrong? Or is the diversity of findings a reflection of distinct pools of PCs, each processing specific streams of information conveyed by climbing fibers? With these questions in mind, we recorded CSs from the monkey oculomotor vermis deploying a repetitive saccade task that entailed sizable motor errors as well as small amplitude saccades, correcting them. We demonstrate that, in addition to carrying error-related information, CSs carry information on the metrics of both primary and small corrective saccades in a time-specific manner, with changes in CS firing probability coupled with changes in CS duration. Furthermore, we also found CS activity that seemed to predict the upcoming events. Hence PCs receive a multiplexed climbing fiber input that merges complementary streams of information on the behavior, separable by the recipient PC because they are staggered in time.

A Structural Update of Neutralizing Epitopes on the HIV Envelope, a Moving Target.

Antibodies that can neutralize diverse HIV-1 strains develop in ~10–20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of broadly reactive antibodies in complex with the HIV-1 spike indicate that there are a limited number of sites of vulnerability on the spike. Analysis of their structures can help reveal commonalities that would be useful in vaccine design and provide insights on combinations of antibodies that can be used to minimize the incidence of viral resistance mutations. In this review, we give an update on recent structures determined of the spike in complex with broadly neutralizing antibodies in the context of all epitopes on the HIV-1 spike identified to date.

Place fields of single spikes in hippocampus involve Kcnq3 channel-dependent entrainment of complex spike bursts

Hippocampal pyramidal cells encode an animal’s location by single action potentials and complex spike bursts. These elementary signals are believed to play distinct roles in memory consolidation. The timing of single spikes and bursts is determined by intrinsic excitability and theta oscillations (5–10 Hz). Yet contributions of these dynamics to place fields remain elusive due to the lack of methods for specific modification of burst discharge. In mice lacking Kcnq3-containing M-type K+ channels, we find that pyramidal cell bursts are less coordinated by the theta rhythm than in controls during spatial navigation, but not alert immobility. Less modulated bursts are followed by an intact post-burst pause of single spike firing, resulting in a temporal discoordination of network oscillatory and intrinsic excitability. Place fields of single spikes in one- and two-dimensional environments are smaller in the mutant. Optogenetic manipulations of upstream signals reveal that neither medial septal GABA-ergic nor cholinergic inputs alone, but rather their joint activity, is required for entrainment of bursts. Our results suggest that altered representations by bursts and single spikes may contribute to deficits underlying cognitive disabilities associated with KCNQ3-mutations in humans.

Anti-injury function of complex spiking neural networks under targeted attack

Brain-like intelligence is to simulate the structure and function of the biological brain as much as possible based on the latest findings in brain science. The biological brain has strong robustness under external attacks. In this study, two complex spiking neural networks (CSNNs) are constructed: a spiking neural network (SNN) with small-world topology and a SNN with scale-free topology, in which the nodes are Izhikevich neuron model, and the edges are the synaptic plasticity model including excitatory and inhibitory synapses. For the targeted attack, the anti-injury function of two CSNNs is comparatively analyzed. On this basis, the anti-injury mechanism of CSNN is explored. The experimental results show that: (1) Small-world SNN (SWSNN) has better performance than scale-free SNN (SFSNN) in the anti-injury ability under targeted attack on high-degree nodes, and they are similar in the anti-injury ability under targeted attack on intermediate and low-degree nodes; the results of the robustness of topology are consistent with the results of anti-injury function of CSNNs, which indicates that the anti-injury ability of two kinds of CSNNs is affected by topology. (2) The dynamic evolutions of neuron firing, synaptic weight, and topological characteristic in the information processing of CSNN have a linkage effect under targeted attack; the dynamic evolution of synaptic weight is significantly related to the anti-injury ability of CSNNs, which clues synaptic plasticity is the intrinsic factor of the anti-injury function of CSNNs.

Population calcium responses of Purkinje cells in the oculomotor cerebellum driven by nonvisual input.

The climbing fiber input to the cerebellum conveys instructive signals that can induce synaptic plasticity and learning by triggering complex spikes accompanied by large calcium transients in Purkinje cells. In the cerebellar flocculus, which supports oculomotor learning, complex spikes are driven by image motion on the retina, which could indicate an oculomotor error. In the same neurons, complex spikes also can be driven by nonvisual signals. It has been shown that the calcium transients accompanying each complex spike can vary in amplitude, even within a given cell, therefore, we compared the calcium responses associated with the visual and nonvisual inputs to floccular Purkinje cells. The calcium indicator GCaMP6f was selectively expressed in Purkinje cells, and fiber photometry was used to record the calcium responses from a population of Purkinje cells in the flocculus of awake behaving mice. During visual (optokinetic) stimuli and pairing of vestibular and visual stimuli, the calcium level increased during contraversive retinal image motion. During performance of the vestibulo-ocular reflex in the dark, calcium increased during contraversive head rotation and the associated ipsiverse eye movements. The amplitude of this nonvisual calcium response was comparable to that during conditions with retinal image motion present that induce oculomotor learning. Thus, population calcium responses of Purkinje cells in the cerebellar flocculus to visual and nonvisual input are similar to what has been reported previously for complex spikes, suggesting that multimodal instructive signals control the synaptic plasticity supporting oculomotor learning.NEW & NOTEWORTHY It was long known that the climbing fiber input to Purkinje cells in the cerebellar flocculus conveys visual feedback about the accuracy of image-stabilizing oculomotor reflexes. More recently, the same climbing fibers were reported to carry nonvisual signals. Here, we report that both visual and nonvisual inputs can elicit robust calcium responses in the Purkinje cells, suggesting that the instructive signals guiding oculomotor plasticity are multimodal.

Simple and complex spike responses of mouse cerebellar Purkinje neurons to regular trains and omissions of somatosensory stimuli.

Cerebellar Purkinje neurons help compute absolute subsecond timing, but how their firing is affected during repetitive sensory stimulation with consistent subsecond intervals remains unaddressed. Here, we investigated how simple and complex spikes of Purkinje cells change during regular application of air puffs (3.3 Hz for ∼4 min) to the whisker pad of awake, head-fixed female mice. Complex spike responses fell into two categories: those in which firing rates increased (at ∼50 ms) and then fell [complex spike elevated (CxSE) cells] and those in which firing rates decreased (at ∼70 ms) and then rose [complex spike reduced (CxSR) cells]. Both groups had indistinguishable rates of basal complex (∼1.7 Hz) and simple (∼75 Hz) spikes and initially responded to puffs with a well-timed sensory response, consisting of a short-latency (∼15 ms), transient (4 ms) suppression of simple spikes. CxSE more than CxSR cells, however, also showed a longer-latency increase in simple spike rate, previously shown to reflect motor command signals. With repeated puffs, basal simple spike rates dropped greatly in CxSR but not CxSE cells; complex spike rates remained constant, but their temporal precision rose in CxSR cells and fell in CxSE cells. Also over time, transient simple spike suppression gradually disappeared in CxSE cells, suggesting habituation, but remained stable in CxSR cells, suggesting reliable transmission of sensory stimuli. During stimulus omissions, both categories of cells showed complex spike suppression with different latencies. The data indicate two modes by which Purkinje cells transmit regular repetitive stimuli, distinguishable by their climbing fiber signals.NEW & NOTEWORTHY Responses of cerebellar Purkinje cells in awake mice form two categories defined by complex spiking during regular trains of brief, somatosensory stimuli. Cells in which complex spike probability first increases or decreases show simple spike suppressions that habituate or persist, respectively. Stimulus omissions alter complex spiking. The results provide evidence for differential suppression of olivary cells during sensory stimulation and omissions and illustrate that climbing fiber innervation defines Purkinje cell responses to repetitive stimuli.

Emulation of multiple-functional synapses using V2C memristors with coexistence of resistive and threshold switching

Mxenes, an emerging class of two-dimensional materials, have attracted extensive attention due to their unique electronic properties. One of the MXenes that has been successfully synthesized recently is vanadium carbide MXene. In this work, this new member of MXenes, V2C, was applied as the active layers of memristors involving Ag and W electrodes. The transition from threshold switching to resistive switching was found in the V2C-based memristors which could be achieved via tuning compliance current. The essence of the switching mechanisms was assumed to be the diffusion process of Ag ions. This process can functionally resemble Ca2+ dynamics in synaptic transmission. Together with a positive analog behavior observed, the coexistence of the threshold and resistive switching mechanisms eventually allowed the V2C-based memristors to emulate various synaptic functions. Furthermore, the study of intrinsic frequency dependence of the V2C memristor also indicated that both spike-timing-dependent plasticity (STDP) and spike-rate-dependent plasticity (SRDP) could be achieved on a single V2C memristor without complex pulse engineering or spike overlapping, which may dramatically reduce the complexity of both circuit and algorithm design. The V2C-based memristors thus show great potential to promote the efficiency and scalability of brain-inspired computing systems in the future by simplifying the artificial synapses design.