Solution-Processed Polymer Memcapacitors with Stimulus-Controlled and Evolvable Synaptic Functionalities: From Short-Term Plasticity to Long-Term Plasticity to Metaplasticity.

In the vanguard of neuromorphic engineering, we develop a paradigm of biocompatible polymer memcapacitors using a seamless solution process, unleashing comprehensive synaptic capabilities depending on both the stimulation form and history. Like the human brain to learn and adapt, the memcapacitors exhibit analogue-type and evolvable capacitance shifts that mirror the complex flexibility of synaptic strengthening and weakening. With increasing frequency and intensity of the stimulation, the memcapacitors demonstrate an evolution from short-term plasticity (STP) to long-term plasticity (LTP), and even to metaplasticity (MP) at a higher level. A physical picture, featuring the stimulus-controlled spatiotemporal ion redistribution in the polymer, elaborates the origin of the memcapacitive prowess and resultant versatile synaptic plasticity. The distinctive MP behavior endows the memcapacitors with a dynamic learning rate (LR), which is utilized in an artificial neural network. The superiority of implementing a dynamic LR compared with conventional practices of using constant LR shines light on the potential of the memcapacitors to exploit organic neuromorphic computing hardware.

Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors.

Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.

Flexible Organic Electrochemical Transistors for Energy-Efficient Neuromorphic Computing.

Brain-inspired flexible neuromorphic devices are of great significance for next-generation high-efficiency wearable sensing and computing systems. In this paper, we propose a flexible organic electrochemical transistor using poly[(bithiophene)-alternate-(2,5-di(2-octyldodecyl)- 3,6-di(thienyl)-pyrrolyl pyrrolidone)] (DPPT-TT) as the organic semiconductor and poly(methyl methacrylate) (PMMA)/LiClO4 solid-state electrolyte as the gate dielectric layer. Under gate voltage modulation, an electric double layer (EDL) forms between the dielectric layer and the channel, allowing the device to operate at low voltages. Furthermore, by leveraging the double layer effect and electrochemical doping within the device, we successfully mimic various synaptic behaviors, including excitatory post-synaptic currents (EPSC), paired-pulse facilitation (PPF), high-pass filtering characteristics, transitions from short-term plasticity (STP) to long-term plasticity (LTP), and demonstrate its image recognition and storage capabilities in a 3 × 3 array. Importantly, the device's electrical performance remains stable even after bending, achieving ultra-low-power consumption of 2.08 fJ per synaptic event at -0.001 V. This research may contribute to the development of ultra-low-power neuromorphic computing, biomimetic robotics, and artificial intelligence.

Labile glutamate synaptic transmission in the adult CA1 stratum-lacunosum-moleculare region.

The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum radiatum (SR) receives input from the hippocampal CA3 region while the distal part in the stratum-lacunosum-moleculare (SLM) receives input mainly from the entorhinal cortex. The AMPA receptor-mediated (AMPA) signalling of SLM synapses in slices from neonatal rats was previously found to considerably differ from that of the SR synapses. In the present study, AMPA signalling of SLM synapses in 1-month-old rats has been examined, that is, when the hippocampus is essentially functionally mature. For the SR synapses, this time is characterized by a facilitatory shift in short-term plasticity, in the disappearance of labile postsynaptic AMPA signalling, a property thought to be important for early activity-dependent organization of neural circuits, and the expression of an adult form of long-term potentiation. We found that the SLM synapses alter their short-term plasticity similarly to that of the SR synapses. However, the labile postsynaptic AMPA signalling was not only maintained but substantially enhanced in the SLM synapses. The long-term potentiation observed was not of the adult form but like that of the neonatal SR synapses based on unsilencing of AMPA labile synapses. We propose that these features of the SLM synapses in the mature hippocampus will help to produce a flexible map of the multimodal sensory input reaching the SLM required for its conjunctive operation with the SR input to generate a proper functional output from the CA1 region.

Critically Assessing the Unanswered Questions of How, Where, and When to Induce Plasticity in the Posttraumatic Stress Disorder Network With Transcranial Magnetic Stimulation.

Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in posttraumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (TMS) is thought to work through long-term potentiation-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. In a recent failed randomized controlled trial we emphasized the necessity of correctly identifying cortical targets, the directionality of TMS protocols, and the role of memory activation. Here, we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature by searching for repetitive TMS clinical trials involving patients with PTSD and outcomes. We searched MEDLINE through October 25, 2023, for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k = 17 randomized controlled trials, k = 14 open label). Randomized controlled trial protocols were varied in terms of TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority of low-frequency (k = 5) versus high-frequency (k = 6) protocols or by stimulation location. Memory provocation or exposure protocols (k = 7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.

Plasticity mechanisms of genetically distinct Purkinje cells.

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.

A coupled neural field model for the standard consolidation theory.

The standard consolidation theory states that short-term memories located in the hippocampus enable the consolidation of long-term memories in the neocortex. In other words, the neocortex slowly learns long-term memories with a transient support of the hippocampus that quickly learns unstable memories. However, it is not clear yet what could be the neurobiological mechanisms underlying these differences in learning rates and memory time-scales. Here, we propose a novel modeling approach of the standard consolidation theory, that focuses on its potential neurobiological mechanisms. In addition to synaptic plasticity and spike frequency adaptation, our model incorporates adult neurogenesis in the dentate gyrus as well as the difference in size between the neocortex and the hippocampus, that we associate with distance-dependent synaptic plasticity. We also take into account the interconnected spatial structure of the involved brain areas, by incorporating the above neurobiological mechanisms in a coupled neural field framework, where each area is represented by a separate neural field with intra- and inter-area connections. To our knowledge, this is the first attempt to apply neural fields to this process. Using numerical simulations and mathematical analysis, we explore the short-term and long-term dynamics of the model upon alternance of phases of hippocampal replay and retrieval cue of an external input. This external input is encodable as a memory pattern in the form of a multiple bump attractor pattern in the individual neural fields. In the model, hippocampal memory patterns become encoded first, before neocortical ones, because of the smaller distances between the bumps of the hippocampal memory patterns. As a result, retrieval of the input pattern in the neocortex at short time-scales necessitates the additional input delivered by the memory pattern of the hippocampus. Neocortical memory patterns progressively consolidate at longer times, up to a point where their retrieval does not need the support of the hippocampus anymore. At longer times, perturbation of the hippocampal neural fields by neurogenesis erases the hippocampus pattern, leading to a final state where the memory pattern is exclusively evoked in the neocortex. Therefore, the dynamics of our model successfully reproduces the main features of the standard consolidation theory. This suggests that neurogenesis in the hippocampus and distance-dependent synaptic plasticity coupled to synaptic depression and spike frequency adaptation, are indeed critical neurobiological processes in memory consolidation.

Unveiling the Role of Side Chain for Improving Nonvolatile Characteristics of Conjugated Polymers-Based Artificial Synapse.

Interest has grown in services that consume a significant amount of energy, such as large language models (LLMs), and research is being conducted worldwide on synaptic devices for neuromorphic hardware. However, various complex processes are problematic for the implementation of synaptic properties. Here, synaptic characteristics are implemented through a novel method, namely side chain control of conjugated polymers. The developed devices exhibit the characteristics of the biological brain, especially spike-timing-dependent plasticity (STDP), high-pass filtering, and long-term potentiation/depression (LTP/D). Moreover, the fabricated synaptic devices show enhanced nonvolatile characteristics, such as long retention time (≈102 s), high ratio of Gmax/Gmin, high linearity, and reliable cyclic endurance (≈103 pulses). This study presents a new pathway for next-generation neuromorphic computing by modulating conjugated polymers with side chain control, thereby achieving high-performance synaptic properties.

Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons.

Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.

Silences, spikes and bursts: Three-part knot of the neural code.

When a neuron breaks silence, it can emit action potentials in a number of patterns. Some responses are so sudden and intense that electrophysiologists felt the need to single them out, labelling action potentials emitted at a particularly high frequency with a metonym - bursts. Is there more to bursts than a figure of speech? After all, sudden bouts of high-frequency firing are expected to occur whenever inputs surge. The burst coding hypothesis advances that the neural code has three syllables: silences, spikes and bursts. We review evidence supporting this ternary code in terms of devoted mechanisms for burst generation, synaptic transmission and synaptic plasticity. We also review the learning and attention theories for which such a triad is beneficial.

Mechanistic Insights into Synaptic Plasticity Behaviors of Electrolyte-Gated Flexible Transistor Devices.

Biological synaptic function simulation using flexible electronic devices based on low-dimensional semiconductor materials is an emerging and rapidly evolving research field with promising applications in brain-like computers and artificial intelligence systems. In this work, we present the fabrication of solution compatible MoS2 thin-film transistors on the ultrathin polymethyl methacrylate substrates via layer-by-layer assembly followed by a one-step transfer printing method. The MoS2 transport channel is controlled by ionic liquid gating with 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, resulting in excellent synaptic performances for emulating memory and perception synapse functions. To investigate the synaptic behaviors, we conduct a series of synaptic spike-dependent experiments and propose an advanced model that delineates the long-term plasticity and short-term plasticity with separate characteristic factors. These findings provide insights into the fundamental mechanisms of synaptic plasticity in electric double-layer devices and contribute to a better understanding of their synaptic performances. In addition, we examine the effects of bending conditions on synaptic plasticity and synaptic weights, unveiling the synergistic interplay between mechanical deformation and synaptic behaviors. Our experimental results, combined with the developed model, are in good agreement and shed light on the influence of mechanical flexibility on the synaptic properties of the devices. In summary, this study establishes a solid foundation for further development of flexible synaptic devices from both practical and theoretical perspectives.

New biophysical rate-based modeling of long-term plasticity in mean-field neuronal population models.

The formation of customized neural networks as the basis of brain functions such as receptive field selectivity, learning or memory depends heavily on the long-term plasticity of synaptic connections. However, the current mean-field population models commonly used to simulate large-scale neural network dynamics lack explicit links to the underlying cellular mechanisms of long-term plasticity. In this study, we developed a new mean-field population model, the plastic density-based neural mass model (pdNMM), by incorporating a newly developed rate-based plasticity model based on the calcium control hypothesis into an existing density-based neural mass model. Derivation of the plasticity model was carried out using population density methods. Our results showed that the synaptic plasticity represented by the resulting rate-based plasticity model exhibited Bienenstock-Cooper-Munro-like learning rules. Furthermore, we demonstrated that the pdNMM accurately reproduced previous experimental observations of long-term plasticity, including characteristics of Hebbian plasticity such as longevity, associativity and input specificity, on hippocampal slices, and the formation of receptive field selectivity in the visual cortex. In conclusion, the pdNMM is a novel approach that can confer long-term plasticity to conventional mean-field neuronal population models.

Electrophysiology of Endocannabinoid Signaling.

Electrophysiological technique is an efficient tool for investigating the synaptic regulatory effects mediated by the endocannabinoid system. Stimulation of presynaptic type 1 cannabinoid receptor (CB1) is the principal mode by which endocannabinoids suppress transmitter release in the central nervous system, but a non-retrograde manner of functioning and other receptors have also been described. Endocannabinoids are key modulators of both short- and long-term plasticity. Here, we discuss ex vivo electrophysiological approaches to examine synaptic signaling induced by cannabinoid and endocannabinoid molecules in the mammalian brain.

Long-term cortical plasticity following sensory deprivation is reduced in male Rett model mice.

PURPOSE/AIM: Rett (RTT) syndrome, a neurodevelopmental disorder, results from loss-of-function mutations in methyl-CpG-binding protein 2. We studied activity-dependent plasticity induced by sensory deprivation via whisker trimming in early symptomatic male mutant mice to assess neural rewiring capability. METHODS: One whisker was trimmed for 0-14 days and intrinsic optical imaging of the transient reduction of brain blood oxygenation resulting from neural activation by 1 second of wiggling of the whisker stump was compared to that of an untrimmed control whisker. RESULTS: Cortical evoked responses to wiggling a non-trimmed whisker were constant for 14 days, reduced for a trimmed whisker by 49.0 ± 4.3% in wild type (n = 14) but by only 22.7 ± 4.6% in mutant (n = 18, p = 0.001). CONCLUSION: As the reduction in neural activation following sensory deprivation in whisker barrel cortex is known to be dependent upon evoked and basal neural activity, impairment of cortical re-wiring following whisker trimming provides a paradigm suitable to explore mechanisms underlying deficiencies in the establishment and maintenance of synapses in RTT, which can be potentially targeted by therapeutics.

Long-Term Synaptic Plasticity Tunes the Gain of Information Channels through the Cerebellum Granular Layer.

A central hypothesis on brain functioning is that long-term potentiation (LTP) and depression (LTD) regulate the signals transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, granule cells have been shown to control the gain of signals transmitted through the mossy fiber pathway by exploiting synaptic inhibition in the glomeruli. However, the way LTP and LTD control signal transformation at the single-cell level in the space, time and frequency domains remains unclear. Here, the impact of LTP and LTD on incoming activity patterns was analyzed by combining patch-clamp recordings in acute cerebellar slices and mathematical modeling. LTP reduced the delay, increased the gain and broadened the frequency bandwidth of mossy fiber burst transmission, while LTD caused opposite changes. These properties, by exploiting NMDA subthreshold integration, emerged from microscopic changes in spike generation in individual granule cells such that LTP anticipated the emission of spikes and increased their number and precision, while LTD sorted the opposite effects. Thus, akin with the expansion recoding process theoretically attributed to the cerebellum granular layer, LTP and LTD could implement selective filtering lines channeling information toward the molecular and Purkinje cell layers for further processing.

Developmental and activity-dependent modulation of coupling distance between release site and Ca2+ channel.

Synapses are junctions between a presynaptic neuron and a postsynaptic cell specialized for fast and precise information transfer. The presynaptic terminal secretes neurotransmitters via exocytosis of synaptic vesicles. Exocytosis is a tightly regulated reaction that occurs within a millisecond of the arrival of an action potential. One crucial parameter in determining the characteristics of the transmitter release kinetics is the coupling distance between the release site and the Ca2+ channel. Still, the technical limitations have hindered detailed analysis from addressing how the coupling distance is regulated depending on the development or activity of the synapse. However, recent technical advances in electrophysiology and imaging are unveiling their different configurations in different conditions. Here, I will summarize developmental- and activity-dependent changes in the coupling distances revealed by recent studies.

Opposing actions of CRF-R1 and CB1 receptor on facial stimulation-induced MLI-PC plasticity in mouse cerebellar cortex.

BACKGROUND: Corticotropin-releasing factor (CRF) is the major neuromodulator orchestrating the stress response, and is secreted by neurons in various regions of the brain. Cerebellar CRF is released by afferents from inferior olivary neurons and other brainstem nuclei in response to stressful challenges, and contributes to modulation of synaptic plasticity and motor learning behavior via its receptors. We recently found that CRF modulates facial stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission via CRF type 1 receptor (CRF-R1) in vivo in mice, suggesting that CRF modulates sensory stimulation-evoked MLI-PC synaptic plasticity. However, the mechanism of how CRF modulates MLI-PC synaptic plasticity is unclear. We investigated the effect of CRF on facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological methods. RESULTS: Facial stimulation at 1 Hz induced LTD of MLI-PC synaptic transmission under control conditions, but not in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by application of a selective CRF-R1 antagonist, BMS-763,534 (200 nM), but it was not restored by application of a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-triggered MLI-PC long-term potentiation (LTP) via CRF-R1. Notably, either inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca2+ with cyclopiazonic acid (100 µM), completely prevented CRF-triggered MLI-PC LTP in mouse cerebellar cortex in vivo. CONCLUSIONS: The present results indicated that CRF blocked sensory stimulation-induced opioid-dependent MLI-PC LTD by triggering MLI-PC LTP through CRF-R1/PKC and intracellular Ca2+ signaling pathway in mouse cerebellar cortex. These results suggest that activation of CRF-R1 opposes opioid-mediated cerebellar MLI-PC plasticity in vivo in mice.

ALSA: Associative Learning Based Supervised Learning Algorithm for SNN.

Spiking neural network (SNN) is considered to be the brain-like model that best conforms to the biological mechanism of the brain. Due to the non-differentiability of the spike, the training method of SNNs is still incomplete. This paper proposes a supervised learning method for SNNs based on associative learning: ALSA. The method is based on the associative learning mechanism, and its realization is similar to the animal conditioned reflex process, with strong physiological plausibility and rationality. This method uses improved spike-timing-dependent plasticity (STDP) rules, combined with a teacher layer to induct spikes of neurons, to strengthen synaptic connections between input spike patterns and specified output neurons, and weaken synaptic connections between unrelated patterns and unrelated output neurons. Based on ALSA, this paper also completed the supervised learning classification tasks of the IRIS dataset and the MNIST dataset, and achieved 95.7 and 91.58% recognition accuracy, respectively, which fully proves that ALSA is a feasible SNNs supervised learning method. The innovation of this paper is to establish a biological plausible supervised learning method for SNNs, which is based on the STDP learning rules and the associative learning mechanism that exists widely in animal training.

Transcranial focused ultrasound induces sustained synaptic plasticity in rat hippocampus.

Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30+ minutes after tFUS administration. In N = 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 °C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.