Long-term Synaptic Plasticity Research Articles

Artificial synaptic properties of zirconium-doped barium titanate film for neuromorphic computing

The traditional Von Neumann Architecture relies on the separation of memory and CPU, leading to bottlenecks like slow data transfer and high energy consumption. This is especially challenging when addressing the demands of large-scale parallel computing tasks such as artificial intelligence. Devices capable of simulating synaptic properties have gotten significant attention. Neuromorphic computing combines those devices with methods that work with neural networks. They are considered a viable approach to overcoming the Von Neumann Architecture bottleneck. This paper presents a Zr-doped BaTiO3 ferroelectric thin film prepared by a sol-gel process, which mimics the synaptic properties of the nerve: Short-Term Synaptic Plasticity (STP), paired-pulse facilitated (PPD), Long-Term Synaptic Plasticity (LTP) and Spike-Timing-Dependent Plasticity (STDP). An enhanced stochastic adaptive method is used to a built-in Convolutional Neural Network (CNN) to evaluate the device's neuromorphic computing capabilities. According to the results, the device obtains recognition accuracies of 96.5 % and 75.1 % for the MNIST and Fashion-MNIST datasets, respectively. This significantly contributes to the advancement of ferroelectric materials in neuromorphic computing applications.

Adenosine and Cortical Plasticity.

Brain plasticity is the ability of the nervous system to change its structure and functioning in response to experiences. These changes occur mainly at synaptic connections, and this plasticity is named synaptic plasticity. During postnatal development, environmental influences trigger changes in synaptic plasticity that will play a crucial role in the formation and refinement of brain circuits and their functions in adulthood. One of the greatest challenges of present neuroscience is to try to explain how synaptic connections change and cortical maps are formed and modified to generate the most suitable adaptive behavior after different external stimuli. Adenosine is emerging as a key player in these plastic changes at different brain areas. Here, we review the current knowledge of the mechanisms responsible for the induction and duration of synaptic plasticity at different postnatal brain development stages in which adenosine, probably released by astrocytes, directly participates in the induction of long-term synaptic plasticity and in the control of the duration of plasticity windows at different cortical synapses. In addition, we comment on the role of the different adenosine receptors in brain diseases and on the potential therapeutic effects of acting via adenosine receptors.

Cyclic nucleotide-induced bidirectional long-term synaptic plasticity in Drosophila mushroom body.

Activation of the cAMP pathway is one of the common mechanisms underlying long-term potentiation (LTP). In the Drosophila mushroom body, simultaneous activation of odour-coding Kenyon cells (KCs) and reinforcement-coding dopaminergic neurons activates adenylyl cyclase in KC presynaptic terminals, which is believed to trigger synaptic plasticity underlying olfactory associative learning. However, learning induces long-term depression (LTD) at these synapses, contradicting the universal role of cAMP as a facilitator of transmission. Here, we developed a system to electrophysiologically monitor both short-term and long-term synaptic plasticity at KC output synapses and demonstrated that they are indeed an exception in which activation of the cAMP-protein kinase A pathway induces LTD. Contrary to the prevailing model, our cAMP imaging found no evidence for synergistic action of dopamine and KC activity on cAMP synthesis. Furthermore, we found that forskolin-induced cAMP increase alone was insufficient for plasticity induction; it additionally required simultaneous KC activation to replicate the presynaptic LTD induced by pairing with dopamine. On the other hand, activation of the cGMP pathway paired with KC activation induced slowly developing LTP, proving antagonistic actions of the two second-messenger pathways predicted by behavioural study. Finally, KC subtype-specific interrogation of synapses revealed that different KC subtypes exhibit distinct plasticity duration even among synapses on the same postsynaptic neuron. Thus, our work not only revises the role of cAMP in synaptic plasticity by uncovering the unexpected convergence point of the cAMP pathway and neuronal activity, but also establishes the methods to address physiological mechanisms of synaptic plasticity in this important model. KEY POINTS: Although presynaptic cAMP increase generally facilitates synapses, olfactory associative learning in Drosophila, which depends on dopamine and cAMP signalling genes, induces long-term depression (LTD) at the mushroom body output synapses. By combining electrophysiology, pharmacology and optogenetics, we directly demonstrate that these synapses are an exception where activation of the cAMP-protein kinase A pathway leads to presynaptic LTD. Dopamine- or forskolin-induced cAMP increase alone is not sufficient for LTD induction; neuronal activity, which has been believed to trigger cAMP synthesis in synergy with dopamine input, is required in the downstream pathway of cAMP. In contrast to cAMP, activation of the cGMP pathway paired with neuronal activity induces presynaptic long-term potentiation, which explains behaviourally observed opposing actions of transmitters co-released by dopaminergic neurons. Our work not only revises the role of cAMP in synaptic plasticity, but also provides essential methods to address physiological mechanisms of synaptic plasticity in this important model system.

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging.

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

A voltage-based Event-Timing-Dependent Plasticity rule accounts for LTP subthreshold and suprathreshold for dendritic spikes in CA1 pyramidal neurons.

Long-term potentiation (LTP) is a synaptic mechanism involved in learning and memory. Experiments have shown that dendritic sodium spikes (Na-dSpikes) are required for LTP in the distal apical dendrites of CA1 pyramidal cells. On the other hand, LTP in perisomatic dendrites can be induced by synaptic input patterns that can be both subthreshold and suprathreshold for Na-dSpikes. It is unclear whether these results can be explained by one unifying plasticity mechanism. Here, we show in biophysically and morphologically realistic compartmental models of the CA1 pyramidal cell that these forms of LTP can be fully accounted for by a simple plasticity rule. We call it the voltage-based Event-Timing-Dependent Plasticity (ETDP) rule. The presynaptic event is the presynaptic spike or release of glutamate. The postsynaptic event is the local depolarization that exceeds a certain plasticity threshold. Our model reproduced the experimentally observed LTP in a variety of protocols, including local pharmacological inhibition of dendritic spikes by tetrodotoxin (TTX). In summary, we have provided a validation of the voltage-based ETDP, suggesting that this simple plasticity rule can be used to model even complex spatiotemporal patterns of long-term synaptic plasticity in neuronal dendrites.

Repeated Morphine Exposure Alters Temporoamonic-CA1 Synaptic Plasticity in Male Rat Hippocampus

In this study, the electrophysiological and biochemical consequences of repeated exposure to morphine in male rats on glutamatergic synaptic transmission, synaptic plasticity, the expression of GABA receptors and glutamate receptors at the temporoammonic-CA1 synapse along the longitudinal axis of the hippocampus (dorsal, intermediate, ventral, DH, IH, VH, respectively) were investigated. Slice electrophysiological methods, qRT-PCR, and western blotting techniques were used to characterize synaptic plasticity properties. We showed that repeated morphine exposure (RME) reduced excitatory synaptic transmission and ability for long-term potentiation (LTP) in the VH as well as eliminated the dorsoventral difference in paired-pulse responses. A decreased expression of NR2B subunit in the VH and an increased expression GABAA receptor of α1 and α5 subunits in the DH were observed following RME. Furthermore, RME did not affect the expression of NR2A, AMPA receptor subunits, and γ2GABAA and GABAB receptors in either segment of the hippocampus. In sum, the impact of morphine may differ depending on the region of the hippocampus studied. A distinct change in the short- and long-term synaptic plasticity along the hippocampus long axis due to repeated morphine exposure, partially mediated by a change in the expression profile of glutamatergic receptor subunits. These findings can be useful in further understanding the cellular mechanism underlying deficits in information storage and, more generally, cognitive processes resulting from chronic opioid abuse.

Neuroligin1 in excitatory synapses contributes to long-term cognitive impairments after repeated neonatal sevoflurane exposures

BackgroundRepeated sevoflurane exposures in neonatal rats may lead to neuronal apoptosis affecting long-term cognitive function, the mechanism is unknown. Neuroligin1 (NL1) is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals. Herein, we explore the role of NL1 in hippocampal excitatory synapses on long-term cognitive impairments induced by repeated sevoflurane exposures in neonatal rats. MethodsFrom postnatal day six (P6) to P8, neonatal rats were exposed to 30% oxygen or 3% sevoflurane +30% oxygen for 2 h daily. Rats from each litter were randomly assigned to five groups: control group (Con), native control adeno-associated virus (NC-AAV) group (Con + NC-AAV), sevoflurane group (Sev), sevoflurane + recombinant RNAi adeno-associated virus targeting NL1 downregulation (NL1−-AAV) group (Sev + NL1−-AAV) and control + recombinant RNAi adeno-associated virus targeting NL1 upregulation (NL1+-AAV) group (Con + NL1+-AAV). Animals were injected with NC-AAV or NL1-AAV into the bilateral hippocampal CA1 area and caged on P21. From P35 to P40, behavioral tests including open field (OF), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function in adolescent rats. In another experiment, rat brains were harvested for immunofluorescence staining, western blotting, co-immunoprecipitation, and real-time polymerase chain reaction (PCR). ResultsWe found that the mRNA and protein levels of NL1 were substantially higher in the Sev group than in the Con group. Immunofluorescence showed that NL1 and PSD95 were highly colocalized in hippocampal CA1 area and vesicular GABA transporter (vGAT) around neurons decreased after repeated sevoflurane exposures. Co-immunoprecipitation showed that the amount of PSD95 with NL1 antibody was significantly increased in the Sev group compared to the Con group. These rats had a poorer performance in the NOR and FC tests than control rats when they were adolescents. These results were reversed by NL1−-AAV injection into the CA1 area. NL1+-AAV group was similar to the Sev group. ConclusionWe have demonstrated that repeated neonatal sevoflurane exposures decreased inhibitory synaptic inputs (labelled by vGAT) around neurons, which may influence the upregulation of NL1 in hippocampal excitatory synapses and enhanced NL1/PSD95 interaction, ultimately leading to long-term cognitive impairments in adolescent rats. Injecting NL1−-AAV reversed this damage. These results suggested that NL1 in excitatory synapses contributes to long-term cognitive impairments after repeated neonatal sevoflurane exposures.

Bio-Inspired Organic Synaptor with In Situ Ion-Doped Ultrathin Polyelectrolyte Containing Acetylcholine-Like Cation.

An ion-based synaptic transistor (synaptor) is designed to emulate a biological synapse using controlled ion movements. However, developing a solid-state electrolyte that can facilitate ion movement while achieving large-scale integration remains challenging. Here, a bio-inspired organic synaptor (BioSyn) with an in situ ion-doped polyelectrolyte (i-IDOPE) is demonstrated. At the molecular scale, a polyelectrolyte containing the tert-amine cation, inspired by the neurotransmitter acetylcholine is synthesized using initiated chemical vapor deposition (iCVD) with in situ doping, a one-step vapor-phase deposition used to fabricate solid-state electrolytes. This method results in an ultrathin, but highly uniform and conformal solid-state electrolyte layer compatible with large-scale integration, a form that is not previously attainable. At a synapse scale, synapse functionality is replicated, including short-term and long-term synaptic plasticity (STSP and LTSP), along with a transformation from STSP to LTSP regulated by pre-synaptic voltage spikes. On a system scale, a reflex in a peripheral nervous system is mimicked by mounting the BioSyns on various substrates such as rigid glass, flexible polyethylene naphthalate, and stretchable poly(styrene-ethylene-butylene-styrene) for a decentralized processing unit. Finally, a classification accuracy of 90.6% is achieved through semi-empirical simulations of MNIST pattern recognition, incorporating the measured LTSP characteristics from the BioSyns.

Electrophysiological Phenotypes of Hippocampal Synaptic and Network Functions in Cannabinoid Receptor 2 Knockout Mice.

Background: The cannabinoid receptor 2 (CB2R), a cannabinoid receptor primarily expressed in immune cells, has been found in the brain, particularly in the hippocampus, where it plays crucial roles in modulating various neural functions, including synaptic plasticity, neuroprotection, neurogenesis, anxiety and stress responses, and neuroinflammation. Despite this growing understanding, the intricate electrophysiological characteristics of hippocampal neurons in CB2R knockout (CB2R KO) mice remain elusive. Aim and Methods: This study aimed to comprehensively assess the electrophysiological traits of hippocampal synaptic and network functions in CB2R KO mice. The focus was on aspects such as synaptic transmission, short- and long-term synaptic plasticity, and neural network synchrony (theta oscillations). Results: Our findings unveiled multiple functional traits in these CB2R KO mice, notably elevated synaptic transmission in hippocampal CA1 neurons, decreased both synaptic short-term plasticity (paired-pulse facilitation) and long-term potentiation (LTP), and impaired neural network synchronization. Conclusion: In essence, this study yields insightful revelations about the influence of CB2Rs on hippocampal neural functions. By illuminating the electrophysiological modifications in CB2R KO mice, our research enriches the comprehension of CB2R involvement in hippocampal function. Such insights could hold implications for advancing our understanding of the neural mechanisms under the influence of CB2Rs within the brain.

FC2: The effect of Maintenance phase of Transcranial Direct Current Stimulation (tDCS) in Alzheimer’s Dementia

Introduction:Transcranial direct current stimulation (tDCS) has been proposed to affect long-term synaptic plasticity through LTP and LTD, thereby improving cognitive ability. In pathology, the amyloid deposits in AD disrupts the balance between long-term potentiation (LTP) and long-term depression (LTD) of neuronal cells and synaptic plasticity. An increasing number of studies have been concluded a positive therapeutic effect on cognition in AD. In brain stimulation, dorsolateral prefrontal cortex (DLPFC) was associated with improvements in memory enhancement, language, processing speed, global cognitive symptoms, and apathy over a period of treatment. Theoretically, the aftereffect of tDCS would need to be re-stimulated by tDCS to maintain its delayed plastic response benefits. In this pilot study, we investigate the maintenance effects of continuing tDCS at three different times, weekly, every two weeks, and every four weeks, for 12 weeks.Method:Twenty-eight AD participants aged 55-90 years were enrolled (mean age 72.7, 77.3, and 76.2 in the three groups - maintained weekly (7 cases), biweekly (9 cases) and every 4 weeks (12 cases)). The anodal electrode was placed over the left dorsal lateral prefrontal cortex and the cathodal electrode was placed over the right supraorbital area. In each active session, we applied a current intensity of 2 mA and an electrode size of 25 cm2 for 30 min. All subjects received a series of neuropsychological assessments including CDR, MMSE, CASI and WCST at (1) baseline, (2) post-10sessions of tDCS (in 2weeks), and (3) post-maintenance phase (total of 12 weeks). Chi-square tests, Wilcoxon signed rank tests and Mann-Whitney U tests were used to assess differences in participant demographic characteristics and to compare differences in test scores between groups.Results:After 10 sessions of tDCS stimulations, the total CASI scores in the 1-week group improved significantly from baseline to 2 weeks. However, there are no significant difference in MMSE, CASI or WCST between baseline and after maintain phase stimulations in each group.Conclusion:Although tDCS has a positive effect in AD, it is recommended to prolong the number of tDCS stimulations, such as 20 sessions in 4 weeks.

FC1: Effect of Transcranial Direct Current Stimulation (tDCS) on Left Dorsolateral Prefrontal Cortex (DLPFC) in Dementia with Lewy Bodies (DLB)

Introduction:tDCS application to the DLPFC is associated with the improvements of executive function, memory enhancement, language, processing speed, global cognitive symptoms and apathy over time after treatment. DLB is the second most common form of degenerative dementia. There is no FDA-approved medications that can slow, stop or improve the progression of cognitive declines in DLB. Identifying effective treatments is a critical issue for DLB. In neuropathology, extracelluar α-syn oligomers interfere with the expression of long-term potentiation(LTP), and influence memory and learning. tDCS has been proposed to affect long-term synaptic plasticity through LTP and long-term depression, thereby improving cognitive ability. So far, only two studies have evaluated the effect of tDCS in DLB. In this pilot study, we investigate the effect of tDCS on left DLPFC in DLB.Method:Fourteen DLB aged 55-90 years (mean age 76.4, with 4 males and 10 females) were included in a double-blind, randomized, sham-controlled cross over design study. DLB diagnostics is according to DSM-5 criteria. CDR ratings for DLB participants ranged from 0.5 to 2. The active tDCS (or sham) process consists of daily sessions of active tDCS (or sham) for 10 consecutive days. The anodal electrode was placed over the left DLPFC and the cathodal electrode was placed over the right supraorbital area, with a current intensity of 2 mA and an electrode size of 25 cm2 for 30 min in a session. Before and after these treatment sessions, all subjects received a series of neuropsychological tests, including CDR, MMSE, CASI, NPI and WCST. Chi-square test, Wilcoxon signed ranks test and Mann-Whitney U test were used to assess differences in participant demographic characteristics and to compare differences among groups.Results:The active tDCS group showed significant improvements on the three items of CASI, ‘language ability’, ‘concentration and calculation’, ‘categorical verbal fluency’, after active stimulations. There is no improvement in MMSE, CASI, NPI and WCST scores in the sham groups.Conclusion:These results suggest that left DLPFC anodal, and right deltoid cathodal tDCS, may have some cognitive benefits in DLB. Larger-scale trials are needed to confirm the effect of tDCS in DLB.Key words: Transcranial Direct Current Stimulation, Dementia with Lewy Bodies, cognitive function, Wisconsin Card Sorting Test, left DLPFC

MRNA translation in astrocytes controls hippocampal long-term synaptic plasticity and memory.

Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2α (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2α phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2α in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories.

Synapse-specific burst coding sustained by local axonal translation

Neurotransmission in the brain is unreliable, suggesting that high-frequency spike bursts rather than individual spikes carry the neural code. For instance, cortical pyramidal neurons rely on bursts in memory formation. Protein synthesis is another key factor in long-term synaptic plasticity and learning but is widely considered unnecessary for synaptic transmission. Here, however, we show that burst neurotransmission at synapses between neocortical layer 5 pyramidal cells depends on axonal protein synthesis linked to presynaptic NMDA receptors and mTOR. We localized protein synthesis to axons with laser axotomy and puromycylation live imaging. We whole-cell recorded connected neurons to reveal how translation sustained readily releasable vesicle pool size and replenishment rate. We live imaged axons and found sparsely docked RNA granules, suggesting synapse-specific regulation. In agreement, translation boosted neurotransmission onto excitatory but not inhibitory basket or Martinotti cells. Local axonal mRNA translation is thus a hitherto unappreciated principle for sustaining burst coding at specific synapse types.

Targeting memory loss with aspirin, a molecular mechanism perspective for future therapeutic approaches.

Acetylsalicylic acid (ASA), also known as aspirin, was discovered in 1897 as an acetylated form of salicylate. It has been widely used for its anti-inflammatory and antiplatelet effects. It is commonly used for its cardiovascular benefits and is prescribed as secondary prophylaxis after a heart attack. Furthermore, low-dose, long-term ASA is used to reduce the risk of heart attack and stroke in individuals without prior cardiovascular disease. Acetylsalicylic acid acts as a non-selective inhibitor of cyclooxygenase (COX), which inhibits the synthesis of prostaglandins and prevents pro-inflammatory cytokines. Findings suggest that targeting cytokines and growth factors could be a potential therapeutic strategy for reducing neuroinflammation and slowing down the progression of dementia. Additionally, prostaglandins contribute to synaptic plasticity and can act as retrograde messengers in synapses. Research has implicated COX-1, one of the isoforms of the enzyme, in neuroinflammation and neurodegenerative disorders. The inhibition of COX-1 might potentially prevent impairments in working memory and reduce neuroinflammation caused by beta-amyloid proteins in some conditions, such as Alzheimer's disease (AD). Cyclooxygenase-2, an inducible form of the enzyme, is expressed in cortical and hippocampal neurons and is associated with long-term synaptic plasticity. The inhibition or knockout of COX-2 has been shown to decrease long-term potentiation, a process involved in memory formation. Studies have also demonstrated that the administration of COX-2 inhibitors impairs cognitive function and memory acquisition and recall in animal models. There remains a debate regarding the effects of aspirin on dementia and cognitive decline. Although some studies suggest a possible protective effect of non-steroidal anti-inflammatory drugs, including aspirin, against the development of AD, others have shown inconsistent evidence. This review provides an overview of the effects of ASA or its active metabolite salicylate on learning, memory, and synaptic plasticity.

Comparing the synaptic potentiation in schaffer collateral-CA1 synapses in dorsal and intermediate regions of the hippocampus in normal and kindled rats

There is growing evidence that the hippocampus comprises diverse neural circuits that exhibit longitudinal variation in their properties, however, the intermediate region of the hippocampus has received comparatively little attention. Therefore, this study was designed to compared short- and long-term synaptic plasticity between the dorsal and intermediate regions of the hippocampus in normal and PTZ-kindled rats. Short-term plasticity was assessed by measuring the ratio of field excitatory postsynaptic potentials’ (fEPSPs) slope in response to paired-pulse stimulation at three different inter-pulse intervals (20, 80, and 160 ms), while long-term plasticity was assessed using primed burst stimulation (PBS). The results showed that the basal synaptic strength differed between the dorsal and intermediate regions of the hippocampus in both control and kindled rats. In the control group, paired-pulse stimulation of Schaffer collaterals resulted in a significantly lower fEPSP slope in the intermediate part of the hippocampus compared to the dorsal region. Additionally, the magnitude of long-term potentiation (LTP) was significantly lower in the intermediate part of the hippocampus compared to the dorsal region. In PTZ-kindled rats, both short-term facilitation and long-term potentiation were impaired in both regions of the hippocampus. Interestingly, there was no significant difference in synaptic plasticity between the dorsal and intermediate regions in PTZ-kindled rats, despite impairments in both regions. This suggests that seizures eliminate the regional difference between the dorsal and intermediate parts of the hippocampus, resulting in similar electrophysiological activity in both regions in kindled animals. Future studies should consider this when investigating the responses of the dorsal and intermediate regions of the hippocampus following PTZ kindling.

Myeloid cell deficiency of the inflammatory transcription factor Stat4 protects long-term synaptic plasticity from the effects of a high-fat, high-cholesterol diet

Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The cytokine interleukin-12 activates signal transducer and activator of transcription 4 (Stat4), and consumption of a high-fat, high-cholesterol diet (HFD-C) and Stat4 activity are associated with inflammation, atherosclerosis, and a diabetic metabolic phenotype. In studies of in vitro hippocampal slices from control Stat4fl/flLdlr−/− mice fed a HFD-C diabetogenic diet, we show that Schaffer collateral-CA1 synapses exhibited larger reductions in activity-dependent, long-term potentiation (LTP) of synaptic transmission, compared to mice fed a standard diet. Glucose tolerance and insulin sensitivity shifts produced by HFD-C diet were reduced in Stat4ΔLysMLdlr−/− mice compared to Stat4fl/flLdlr−/− controls. Stat4ΔLysMLdlr−/− mice, which lack Stat4 under control of the LysMCre promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4ΔLysMLdlr−/− mice fed the HFD-C diet showed larger LTP than control Stat4fl/flLdlr−/− mice. Expression of a number of neuroinflammatory and synaptic plasticity genes was reduced by HFD-C diet in control mice, and less affected by HFD-C diet in Stat4ΔLysMLdlr−/− mice. These data suggest that suppression of Stat4 activation may protect against effects of Western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer’s disease and other neurodegenerative disorders associated with neuroinflammation.

Reliable Memristor Crossbar Array Based on 2D Layered Nickel Phosphorus Trisulfide for Energy-Efficient Neuromorphic Hardware.

Designing reliable and energy-efficient memristors for artificial synaptic arrays in neuromorphic computing beyond von Neumann architecture remains a challenge. Here, memristors based on emerging layered nickel phosphorus trisulfide (NiPS3 ) are reported that exhibit several favorable characteristics, including uniform bipolar nonvolatile switching with small operating voltage (<1V), fast switching speed (< 20ns), high On/Off ratio (>102 ), and the ability to achieve programmable multilevel resistance states. Through direct experimental evidence using transmission electron microscopy and energy dispersive X-ray spectroscopy, it is revealed that the resistive switching mechanism in the Ti/NiPS3 /Au device is related to the formation and dissolution of Ti conductive filaments. Intriguingly, further investigation into the microstructural and chemical properties of NiPS3 suggests that the penetration of Ti ions is accompanied by the drift of phosphorus-sulfur ions, leading to induced P/S vacancies that facilitate the formation of conductive filaments. Furthermore, it is demonstrated that the memristor, when operating in quasi-reset mode, effectively emulates long-term synaptic weight plasticity. By utilizing a crossbar array, multipattern memorization and multiply-and-accumulate (MAC) operations are successfully implemented. Moreover, owing to the highly linear and symmetric multiple conductance states, a high pattern recognition accuracy of ≈96.4% is demonstrated in artificial neural network simulation for neuromorphic systems.

Pattern detection in the TGFβ cascade controls the induction of long-term synaptic plasticity

Transforming growth factor β (TGFβ) is required for long-term memory (LTM) for sensitization in Aplysia. When LTM is induced using a two-trial training protocol, TGFβ inhibition only blocks LTM when administrated at the second, not the first trial. Here, we show that TGFβ acts as a "repetition detector" during the induction of two-trial LTM. Secretion of the biologically inert TGFβ proligand must coincide with its proteolytic activation by the Bone morphogenetic protein-1 (BMP-1/Tolloid) metalloprotease, which occurs specifically during trial two of our two-trial training paradigm. This paradigm establishes long-term synaptic facilitation (LTF), the cellular correlate of LTM. BMP-1 application paired with a single serotonin (5HT) pulse induced LTF, whereas neither a single 5HT pulse nor BMP-1 alone effectively did so. On the other hand, inhibition of endogenous BMP-1 activity blocked the induction of two-trial LTF. These results suggest a unique role for TGFβ in the interaction of repeated trials: during learning, repeated stimuli engage separate steps of the TGFβ cascade that together are necessary for the induction of long-lasting memories.

Neuromorphic Systems: Devices, Architecture, and Algorithms

The application of the structure and principles of the human brain opens up great opportunities for creating artificial systems based on silicon technology. The energy efficiency and performance of a biosimilar architecture can be significantly higher compared to the traditional von Neumann architecture. This paper presents an overview of the most promising artificial neural network (ANN) and spiking neural network (SNN) architectures for biosimilar systems, called neuromorphic systems. Devices for biosimilar systems, such as memristors and ferroelectric transistors, are considered for use as artificial synapses that determine the possibility of creating various architectures of neuromorphic systems; methods and rules for training structures to work correctly when mimicking biological learning rules, such as long-term synaptic plasticity. Problems hindering the implementation of biosimilar systems and examples of architectures that have been practically implemented are discussed.

Striatonigral direct pathway 2-arachidonoylglycerol contributes to ethanol effects on synaptic transmission and behavior

Endocannabinoids (eCB) and cannabinoid receptor 1 (CB1) play important roles in mediating short- and long-term synaptic plasticity in many brain regions involved in learning and memory, as well as the reinforcing effects of misused substances. Ethanol-induced plasticity and neuroadaptations predominantly occur in striatal direct pathway projecting medium spiny neurons (dMSNs). It is hypothesized that alterations in eCB neuromodulation may be involved. Recent work has implicated a role of eCB 2-arachidonoylglycerol (2-AG) in the rewarding effects of ethanol. However, there is insufficient research to answer which cellular subtype is responsible for mediating the 2-AG eCB signal that might be involved in the rewarding properties of ethanol and the mechanisms by which that occurs. To examine the role of dMSN mediated 2-AG signaling in ethanol related synaptic transmission and behaviors, we used conditional knockout mice in which the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) was deleted in dMSNs, DGLαD1-Cre+. Using acute brain slice photometry and a genetically encoded fluorescent eCB sensor, GRABeCB2.0, to assess real-time eCB mediated activity of sensorimotor inputs from primary motor cortices (M1/M2) to the dorsolateral striatum, we showed that DGLαD1-Cre+ mice had blunted evoked eCB-mediated presynaptic eCB signaling compared to littermate controls. Furthermore, ethanol induced eCB inhibition was significantly reduced in DGLαD1-Cre+ deficient mice. Additionally, there was a reduction in the duration of loss of righting reflex (LORR) to a high dose of ethanol in the DGLαD1-Cre+ mice compared to controls. These mice also showed a male-specific decrease in ethanol preference accompanied by an increase in ethanol-induced water consumption in a voluntary drinking paradigm. There were no significant differences observed in sucrose and quinine consumption between the genotypes. These findings reveal a novel role for dMSN mediated 2-AG signaling in modulating ethanol effects on presynaptic function and behavior.