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Background: Western and Mediterranean diets differentially affect cerebral cortical gene expression, brain structure, and socioemotional behavior in middle‐aged female nonhuman primates (NHP) (Macaca fascicularis). In this study, we investigate the effect of diet on brain molecular composition. Method: Using a machine learning approach, we quantified the impact of these diets on the presynaptic proteome in the lateral temporal cortex determined by synaptometry by time of flight (SynTOF) mass spectrometry and examined associations between the proteome, transcriptome, and an array of multisystem phenotypes. For this, we consider NHP fed with Mediterranean (n = 17) or Western (n = 19) diet for 31 months before brain retrieval (see study overview in Figure 1). Result: Diet has a significant effect on presynaptic proteins (AUC = 0.86, Pvalue = 0.0002) (Figure 2A). We identified six presynaptic proteins (DAT, Aβ42, calreticulin, LC3B, K48‐Ubiquitin, SLC6A8) elevated in the presynaptic proteome bythe Mediterranean compared to the Western diet (p<0.05) (Figure 2B). Interestingly, we demonstrated that transcriptomic data from adjacent cortex predict all the SynTOF markers (pvalue <0.05) (Figure 2C). We found that the SPATA22 transcript was positively correlated with five SynTOF markers (LRRK2, TMEM230, GAMT and 3NT, Aβ40) (all p<0.05). Transcription Factor AP‐2 Gamma transcript (TFAP2C) was positively correlated with SynTOF markers pTau, CD47, and GAD65. Together, the multi‐system phenotypes significantly predicted 26 SynTOF markers, the strongest relationships were between GFAP and brain volumetrics (Figure 2D). Numerous SynTOF markers correlated with hepatosteatosis, suggesting the relationships between liver health and presynapses composition. SynTOF markers were also associated with behavioral and physiological measures of social‐environmental stress. Conclusion: Together these observations demonstrate that diet composition drives temporal presynaptic protein composition, that transcription profiles strongly predict the presynaptic proteomic profile, and that presynaptic proteins are closely associated with peripheral metabolism, stress responsivity, and socioemotional behavior. These data demonstrate the impact of diet composition on brain molecular composition. [ABSTRACT FROM AUTHOR]

Synapses in the brain are highly noisy, which leads to a large trial-by-trial variability. Given how costly synapses are in terms of energy consumption these high levels of noise are surprising. Here we propose that synapses use noise to represent uncertainties about the somatic activity of the postsynaptic neuron. To show this, we developed a mathematical framework, in which the synapse as a whole interacts with the soma of the postsynaptic neuron in a similar way to an agent that is situated and behaves in an uncertain, dynamic environment. This framework suggests that synapses use an implicit internal model of the somatic membrane dynamics that is being updated by a synaptic learning rule, which resembles experimentally well-established LTP/LTD mechanisms. In addition, this approach entails that a synapse utilizes its inherently noisy synaptic release to also encode its uncertainty about the state of the somatic potential. Although each synapse strives for predicting the somatic dynamics of its postsynaptic neuron, we show that the emergent dynamics of many synapses in a neuronal network resolve different learning problems such as pattern classification or closed-loop control in a dynamic environment. Hereby, synapses coordinate themselves to represent and utilize uncertainties on the network level in behaviorally ambiguous situations.

The heterogeneity in venom composition and potency in disparate Eastern Russell’s viper (Daboia siamensis) populations has repercussions for the efficacy of antivenoms. This is particularly pronounced in geographical areas in which the venom of the local species has not been well studied and locally produced antivenoms are unavailable. In such cases, alternative therapies following envenoming, which are not limited by species specificity, may be employed to complement antivenoms. We studied the neuromuscular activity of D. siamensis venom from Thailand and Java (Indonesia) and the ability of Thai antivenoms and/or Varespladib to prevent or reverse these effects. Both Thai and Javanese D. siamensis venoms displayed potent pre-synaptic neurotoxicity but weak myotoxicity in the chick biventer cervicis nerve–muscle preparation. Whilst the neurotoxicity induced by both venoms was abolished by the prior administration of Thai D. siamensis monovalent antivenom or pre-incubation with Varespladib, Thai neuro-polyvalent antivenom only produced partial protection when added prior to venom. Pre-synaptic neurotoxicity was not reversed by the post-venom addition of either antivenom 30 or 60 min after either venom. Varespladib, when added 60 min after venom, prevented further inhibition of indirect twitches. However, the subsequent addition of additional concentrations of Varespladib did not result in further recovery from neurotoxicity. The combination of Thai monovalent antivenom and Varespladib, added 60 min after venom, resulted in additional recovery of twitches caused by either Thai or Javanese venoms compared with antivenom alone. In conclusion, we have shown that Varespladib can prevent and partially reverse the pre-synaptic neurotoxicity induced by either Thai or Javanese D. siamensis venoms. The efficacy of Thai D. siamensis monovalent antivenom in reversing pre-synaptic neurotoxicity was significantly enhanced by its co-administration with Varespladib. Further work is required to establish the efficacy of Varespladib as a primary or adjunct therapy in human envenoming.

The widespread geographical distribution of Russell’s vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, potentially, the presence or absence of some toxins in venoms across the geographical spectrum. In this study, we aimed to isolate and pharmacologically characterise the major neurotoxic components of D. siamensis venoms from Thailand and Java (Indonesia) and explore the efficacy of antivenom and a PLA2 inhibitor, Varespladib, against the neuromuscular activity. These data will provide insights into the link between venom components and likely clinical outcomes, as well as potential treatment strategies. Venoms were fractionated using RP-HPLC and the in vitro activity of isolated toxins assessed using the chick biventer cervicis nerve-muscle preparation. Two major PLA2 fractions (i.e., fractions 8 and 10) were isolated from each venom. Fraction 8 from both venoms produced pre-synaptic neurotoxicity and myotoxicity, whereas fraction 10 from both venoms was weakly neurotoxic. The removal of the two fractions from each venom abolished the in vitro neurotoxicity, and partially abolished myotoxicity, of the whole venom. A combination of the two fractions from each venom produced neurotoxic activity that was equivalent to the respective whole venom (10 µg/mL), but the myotoxic effects were not additive. The in vitro neurotoxicity of fraction 8 (100 nM) from each venom was prevented by the pre-administration of Thai Russell’s viper monovalent antivenom (2× recommended concentration) or preincubation with Varespladib (100 nM). Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100–300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA2 toxins in each venom.

Cholecystokinin (CCK) has been confirmed to be essential in NMDA‐dependent long‐term potentiation (LTP) at mouse cortical synapses. This paper has proven that CCK is necessary for LTP induced by high‐frequency stimulation of mouse hippocampal synapses projected from the entorhinal cortex. We show that the subunit of the axonal NMDA receptor dominant modulates the activity‐induced LTP by triggering pre‐synaptic CCK release. A functional pre‐synaptic NMDA receptor is required to induce LTP mediated by the axonal Ca2+ elevation and CCK exocytosis at CCK‐specific neurons. Genetic depletion of the GluN1 subunit of NMDA receptors on CCK neurons, which projected from the entorhinal cortex largely abolished the axonal Ca2+ elevation and disturbed the secretion of CCK in hippocampus. These results demonstrate that activity‐induced LTP at the hippocampal synapse is CCK‐dependent, and CCK secretion from the axonal terminal is modulated by pre‐synaptic NMDA receptors. [ABSTRACT FROM AUTHOR]

N-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic NMDAR (pre-NMDAR) function is largely unexplored. Different pre-NMDAR subunit populations are documented at synapses, suggesting that subunit composition influences neuronal transmission. Here, we used electrophysiological recordings at Schaffer collateral-CA1 synapses partnered with Ca2+ imaging and glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of pre-NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential-evoked Ca2+ influx via modulation of small-conductance Ca2+-activated K+ channels, while activation of the GluN2A population does the opposite. Critically, the level of functional expression of the subunits is subject to homeostatic regulation, bidirectionally affecting short-term facilitation, thus providing a capacity for a fine adjustment of information transfer. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as “synaptopathy.” Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.

Spontaneous subthreshold activity in the central nervous system is fundamental to information processing and transmission, as it amplifies and optimizes sub-threshold signals, thereby improving action potential initiation and maintaining reliable firing. This form of spontaneous activity, which is frequently considered noise, is particularly important at auditory synapses where acoustic information is encoded by rapid and temporally precise firing rates. In contrast, when present in excess, this form of noise becomes detrimental to acoustic information as it contributes to the generation and maintenance of auditory disorders such as tinnitus. The most prominent contribution to subthreshold noise is spontaneous synaptic transmission (synaptic noise). Although numerous studies have examined the role of synaptic noise on single cell excitability, little is known about its pre-synaptic modulation owing in part to the difficulties of combining noise modulation with monitoring synaptic release. Here we study synaptic noise in the auditory brainstem dorsal cochlear nucleus (DCN) of mice and show that pharmacological potentiation of Kv3 K+ currents reduces the level of synaptic bombardment onto DCN principal fusiform cells. Using a transgenic mouse line (SyG37) expressing SyGCaMP2-mCherry, a calcium sensor that targets pre-synaptic terminals, we show that positive Kv3 K+ current modulation decreases calcium influx in a fifth of pre-synaptic boutons. Furthermore, while maintaining rapid and precise spike timing, positive Kv3 K+ current modulation increases the synchronization of local circuit neurons by reducing spontaneous activity. In conclusion, our study identifies a unique pre-synaptic mechanism which reduces synaptic noise at auditory synapses and contributes to the coherent activation of neurons in a local auditory brainstem circuit. This form of modulation highlights a new therapeutic target, namely the pre-synaptic bouton, for ameliorating the effects of hearing disorders which are dependent on aberrant spontaneous activity within the central auditory system.

BACKGROUND AND PURPOSE:Nerve injury induces concurrent up-regulation of the voltage-gated calcium channel subunit Cav α2 δ1 and the extracellular matrix protein thrombospondin-4 (TSP4) in dorsal root ganglia and dorsal spinal cord, leading to the development of a neuropathic pain state. Interactions of these proteins promote aberrant excitatory synaptogenesis that contributes to neuropathic pain state development through unknown mechanisms. We investigated the contributions of Cav α2 δ1 subunits and TSP4 to synaptogenesis, and the pathways involved in vitro, and whether treatment with gabapentin could block this process and pain development in vivo. EXPERIMENTAL APPROACH:A co-culture system of sensory and spinal cord neurons was used to study the contribution from each protein to synaptogenesis and the pathway(s) involved. Anti-synaptogenic actions of gabapentin were studied in TSP4-injected mice. KEY RESULTS:Only presynaptic, but not postsynaptic, Cav α2 δ1 subunits interacted with TSP4 to initiate excitatory synaptogenesis through a pathway modulated by T-type calcium channels. Cav α2 δ1 /TSP4 interactions were not required for maintenance of already formed synapses. In vivo, early, but not delayed, treatment with low-dose gabapentin blocked this pathway and the development of the pain state. CONCLUSIONS AND IMPLICATIONS:Cav α2 δ1 /TSP4 interactions were critical for the initiation, but not for the maintenance, of abnormal synapse formation between sensory and spinal cord neurons. This process was blocked by early, but was not reversed by delayed, treatment with gabapentin. Early intervention with gabapentin may prevent the development of injury-induced chronic pain, resulting from Cav α2 δ1 /TSP4-initiated abnormal synapse formation. LINKED ARTICLES:This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, the reasons why synapses are particularly vulnerable to such a broad range of neurodegeneration inducing stimuli remains unknown. To identify molecular modulators of synaptic stability and degeneration, we have used the Cln3 -/- mouse model of a juvenile form of NCL. We profiled and compared the molecular composition of anatomically-distinct, differentially-affected pre-synaptic populations from the Cln3 -/- mouse brain using proteomics followed by bioinformatic analyses. Identified protein candidates were then tested using a Drosophila CLN3 model to study their ability to modify the CLN3-neurodegenerative phenotype in vivo. We identified differential perturbations in a range of molecular cascades correlating with synaptic vulnerability, including valine catabolism and rho signalling pathways. Genetic and pharmacological targeting of key 'hub' proteins in such pathways was sufficient to modulate phenotypic presentation in a Drosophila CLN3 model. We propose that such a workflow provides a target rich method for the identification of novel disease regulators which could be applicable to the study of other conditions where appropriate models exist.

The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from pre-synaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the pre-synaptic compartment in AD.

The role of pre-synaptic DC bias is investigated in three-terminal organic neuromorphic architectures based on electrolyte-gated organic transistors—EGOTs. By means of pre-synaptic offset it is possible to finely control the number of discrete conductance states in short-term plasticity experiments, to obtain, at will, both depressive and facilitating response in the same neuromorphic device and to set the ratio between two subsequent pulses in paired-pulse experiments. The charge dynamics leading to these important features are discussed in relationship with macroscopic device figures of merit such as conductivity and transconductance, establishing a novel key enabling parameter in devising the operation of neuromorphic organic electronics.

The widespread geographical distribution of Russell's vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, potentially, the presence or absence of some toxins in venoms across the geographical spectrum. In this study, we aimed to isolate and pharmacologically characterise the major neurotoxic components of D. siamensis venoms from Thailand and Java (Indonesia) and explore the efficacy of antivenom and a PLA2 inhibitor, Varespladib, against the neuromuscular activity. These data will provide insights into the link between venom components and likely clinical outcomes, as well as potential treatment strategies. Venoms were fractionated using RP-HPLC and the in vitro activity of isolated toxins assessed using the chick biventer cervicis nerve-muscle preparation. Two major PLA2 fractions (i.e., fractions 8 and 10) were isolated from each venom. Fraction 8 from both venoms produced pre-synaptic neurotoxicity and myotoxicity, whereas fraction 10 from both venoms was weakly neurotoxic. The removal of the two fractions from each venom abolished the in vitro neurotoxicity, and partially abolished myotoxicity, of the whole venom. A combination of the two fractions from each venom produced neurotoxic activity that was equivalent to the respective whole venom (10 µg/mL), but the myotoxic effects were not additive. The in vitro neurotoxicity of fraction 8 (100 nM) from each venom was prevented by the pre-administration of Thai Russell's viper monovalent antivenom (2× recommended concentration) or preincubation with Varespladib (100 nM). Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100–300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA2 toxins in each venom. [ABSTRACT FROM AUTHOR]

BackgroundUp-regulation of voltage-gated calcium channel α2 δ1 subunit post spinal nerve ligation (SNL) injury or in α2 δ1 -overexpressing transgenic (Tg) mice correlates with tactile allodynia, a pain state mediated mainly by Aβ sensory fibres forming synaptic connections with deep dorsal horn (DDH) neurons. It is not clear, however, whether dysregulated α2 δ1 alters DDH synaptic neurotransmission that underlies tactile allodynia development post nerve injury.MethodsTactile allodynia was tested in the SNL and α2 δ1 Tg models. Miniature excitatory/inhibitory post-synaptic currents were recorded in DDH neurons from these animal models using whole-cell patch clamp slice recording techniques.ResultsThere was a significant increase in the frequency, but not amplitude, of miniature excitatory post-synaptic currents (mEPSC) in DDH neurons that correlated with tactile allodynia in SNL and α2 δ1 Tg mice. Gabapentin, an α2 δ1 ligand that is known to block tactile allodynia in these models, also normalized mEPSC frequency dose-dependently in DDH neurons from SNL and α2 δ1 Tg mice. In contrast, neither frequency nor amplitude of miniature inhibitory post-synaptic currents was altered in DDH neurons from SNL and α2 δ1 Tg mice.ConclusionOur data suggest that α2 δ1 dysregulation is highly likely contributing to tactile allodynia through a pre-synaptic mechanism involving facilitation of excitatory synaptic neurotransmission in DDH of spinal cord.

Repair of DNA double strand breaks by homologous recombination (HR) is initiated by Rad51 filament nucleation on single-stranded DNA (ssDNA), which catalyzes strand exchange with homologous duplex DNA. BRCA2 and the Rad51 paralogs are tumor suppressors and critical mediators of Rad51. To gain insight into Rad51 paralog function, we investigated a heterodimeric Rad51 paralog complex, RFS-1/RIP-1, and uncovered the molecular basis by which Rad51 paralogs promote HR. Unlike BRCA2, which nucleates RAD-51-ssDNA filaments, RFS-1/RIP-1 binds and remodels pre-synaptic filaments to a stabilized, "open," and flexible conformation, in which the ssDNA is more accessible to nuclease digestion and RAD-51 dissociation rate is reduced. Walker box mutations in RFS-1, which abolish filament remodeling, fail to stimulate RAD-51 strand exchange activity, demonstrating that remodeling is essential for RFS-1/RIP-1 function. We propose that Rad51 paralogs stimulate HR by remodeling the Rad51 filament, priming it for strand exchange with the template duplex.

Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABAA in NaV1.8-positive sensory neurons (Scn10aCre;Gabrb3fl/fl) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABAA. Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABAA and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8+ afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABAA in NaV1.8+ nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.

A major hurdle preventing effective interventions for patients with mild traumatic brain injury (mTBI) is the lack of known mechanisms for the long-term cognitive impairment that follows mTBI. The closed head impact model of repeated engineered rotational acceleration (rCHIMERA), a non-surgical animal model of repeated mTBI (rmTBI), mimics key features of rmTBI in humans. Using the rCHIMERA in rats, this study was designed to characterize rmTBI-induced behavioral disruption, underlying electrophysiological changes in the medial prefrontal cortex (mPFC), and associated mitochondrial dysfunction. Rats received 6 closed-head impacts over 2 days at 2 Joules of energy. Behavioral testing included automated analysis of behavior in open field and home-cage environments, rotarod test for motor skills, novel object recognition, and fear conditioning. Following rmTBI, rats spent less time grooming and less time in the center of the open field arena. Rats in their home cage had reduced inactivity time 1 week after mTBI and increased exploration time 1 month after injury. Impaired associative fear learning and memory in fear conditioning test, and reduced short-term memory in novel object recognition test were found 4 weeks after rmTBI. Single-unit in vivo recordings showed increased neuronal activity in the mPFC after rmTBI, partially attributable to neuronal disinhibition from reduced inhibitory synaptic transmission, possibly secondary to impaired mitochondrial function. These findings help validate this rat rmTBI model as replicating clinical features, and point to impaired mitochondrial functions after injury as causing imbalanced synaptic transmission and consequent impaired long-term cognitive dysfunction.

Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavalpha2delta1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavalpha2delta1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavalpha2delta1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavalpha2delta1 transgenic mice. Our data indicated that overexpression of Cavalpha2delta1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavalpha2delta1-mediated spinal sensitization in which elevated Cavalpha2delta1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous stimuli. This spinal sensitization mechanism may mediate at least partially the neuropathic pain states derived from increased pre-synaptic Cavalpha2delta1 expression.

Spinal interneurons are partially phase-locked to physiological tremor around 10Hz. The phase of spinal interneuron activity is approximately opposite to descending drive to motoneurons, leading to partial phase cancellation and tremor reduction. Pre-synaptic inhibition of afferent feedback modulates during voluntary movements, but it is not known whether it tracks more rapid fluctuations in motor output such as during tremor. In this study, dorsal root potentials (DRPs) were recorded from the C8 and T1 roots in two macaque monkeys following intra-spinal micro-stimulation (random inter-stimulus interval 1.5-2.5 s, 30-100µA), whilst the animals performed an index finger flexion task which elicited peripheral oscillations around 10Hz. Forty one responses were identified with latency

Learning synaptic weights of spiking neural network (SNN) models that can reproduce target spike trains from provided neural firing data is a central problem in computational neuroscience and spike-based computing. The discovery of the optimal weight values can be posed as a supervised learning task wherein the weights of the model network are chosen to maximize the similarity between the target spike trains and the model outputs. It is still largely unknown whether optimizing spike train similarity of highly recurrent SNNs produces weight matrices similar to those of the ground truth model. To this end, we propose flexible heuristic supervised learning rules, termed Pre-Synaptic Pool Modification (PSPM), that rely on stochastic weight updates in order to produce spikes within a short window of the desired times and eliminate spikes outside of this window. PSPM improves spike train similarity for all-to-all SNNs and makes no assumption about the post-synaptic potential of the neurons or the structure of the network since no gradients are required. We test whether optimizing for spike train similarity entails the discovery of accurate weights and explore the relative contributions of local and homeostatic weight updates. Although PSPM improves similarity between spike trains, the learned weights often differ from the weights of the ground truth model, implying that connectome inference from spike data may require additional constraints on connectivity statistics. We also find that spike train similarity is sensitive to local updates, but other measures of network activity such as avalanche distributions, can be learned through synaptic homeostasis.

In olfaction, all volatile odor information is tunneled through the main olfactory bulb (OB). Odor information is then processed before it is transferred to higher brain centers. Odor processing in the OB is carried out by numerous local inhibitory circuits and modulated by top-down input. Top-down modulation of OB function has been shown to act via interneurons but evidence also exists for its direct impact onto the principle mitral and tufted cells (M/Ts). Here, we used monosynaptic rabies trans-synaptic tracing from the OB to map and quantify the local and top-down pre-synaptic landscape of M/Ts and local inhibitory interneurons. We found that M/Ts receive a significant amount of top-down inputs from various brain regions that match qualitatively but not quantitatively those that synapse onto local inhibitory inter-neurons. These results show that M/Ts are direct targets of top-down inputs.