Synaptic Patterns Research Articles

Contactin-1 autoimmunity: Serologic, neurologic, and pathologic correlates.

ObjectiveTo determine serologic characteristics, frequency, phenotype, paraneoplastic associations, and electrodiagnostic and histopathologic features accompanying contactin-1 autoimmunity.MethodsArchived sera known to produce synaptic tissue-based immunofluorescence patterns were reevaluated, and contactin-1 specificity was confirmed by recombinant protein assays. Screening of 233 chronic/relapsing demyelinating neuropathies for additional cases was performed.ResultsWe identified 10 contactin-1 IgG seropositive cases. Frequency of contactin-1 immunoglobulin (Ig) G among tested Mayo Clinic chronic/relapsing demyelinating neuropathies was 2%. Sensory predominant presentations (n = 9, 90%), neuropathic pain (n = 6, 60%), and subacute progression (n = 5, 50%) were commonly encountered among contactin-1 neuropathies. Two patients had chronic immune sensory polyradiculopathy-like phenotype at presentation. Electrodiagnostic studies were consistent with demyelination (slowed conduction velocities and/or prolonged distal latencies) without conduction block. Markedly elevated CSF protein (median 222 mg/dL, range 69–960 mg/dL), thickening/gadolinium enhancement of nerve roots (4/5), and subperineural edema on nerve biopsy (4/4) were other characteristic features. Three cases were diagnosed with paraneoplastic demyelinating neuropathies (thymoma, n = 1; breast cancer, n = 1; plasmacytoma, n = 1). Four of the 9 patients treated with IV immunoglobulin demonstrated initial clinical improvement, but the favorable response was sustained in only 1 case (median follow-up, 60 months). Sustained clinical stabilization or improvement was observed among 3 of the 6 cases in whom second-line therapies (rituximab, cyclophosphamide, and azathioprine) were used.ConclusionContactin-1 IgG has a distinct sensory predominant presentation commonly associated with neuropathic pain, with demyelinating changes on electrophysiologic studies. A paraneoplastic cause should be considered. Testing of contactin-1 IgG among cases with similar presentations may guide immunotherapy selection, especially second-line immunotherapy consideration.

A muscle-epidermis-glia signaling axis sustains synaptic specificity during allometric growth in Caenorhabditis elegans.

Synaptic positions underlie precise circuit connectivity. Synaptic positions can be established during embryogenesis and sustained during growth. The mechanisms that sustain synaptic specificity during allometric growth are largely unknown. We performed forward genetic screens in C. elegans for regulators of this process and identified mig-17, a conserved ADAMTS metalloprotease. Proteomic mass spectrometry, cell biological and genetic studies demonstrate that MIG-17 is secreted from cells like muscles to regulate basement membrane proteins. In the nematode brain, the basement membrane does not directly contact synapses. Instead, muscle-derived basement membrane coats one side of the glia, while glia contact synapses on their other side. MIG-17 modifies the muscle-derived basement membrane to modulate epidermal-glial crosstalk and sustain glia location and morphology during growth. Glia position in turn sustains the synaptic pattern established during embryogenesis. Our findings uncover a muscle-epidermis-glia signaling axis that sustains synaptic specificity during the organism's allometric growth.

Distinct Developmental Mechanisms Act Independently to Shape Biased Synaptic Divergence from an Inhibitory Neuron.

Neurons often contact more than one postsynaptic partner type and display stereotypic patterns of synaptic divergence. Such synaptic patterns usually involve some partners receiving more synapses than others. The developmental strategies generating "biased" synaptic distributions remain largely unknown. To gain insight, we took advantage of a compact circuit in the vertebrate retina, whereby the AII amacrine cell (AII AC) provides inhibition onto cone bipolar cell (BC) axons and retinal ganglion cell (RGC) dendrites, but makes the majority of its synapses with the BCs. Using light and electron microscopy, we reconstructed the morphology and connectivity of mouse retinal AII ACs across postnatal development. We found that AII ACs do not elaborate their presynaptic structures, the lobular appendages, until BCs differentiate about a week after RGCs are present. Lobular appendages are present in mutant mice lacking BCs, implying that although synchronized with BC axonal differentiation, presynaptic differentiation of the AII ACs is not dependent on cues from BCs. With maturation, AII ACs maintain a constant number of synapses with RGCs, preferentially increase synaptogenesis with BCs, and eliminate synapses with wide-field amacrine cells. Thus, AII ACs undergo partner type-specific changes in connectivity to attain their mature pattern of synaptic divergence. Moreover, AII ACs contact non-BCs to the same extent in bipolarless retinas, indicating that AII ACs establish partner-type-specific connectivity using diverse mechanisms that operate in parallel but independently.

Synaptic Plasticity Depends on the Fine-Scale Input Pattern in Thin Dendrites of CA1 Pyramidal Neurons

Coordinated long-term plasticity of nearby excitatory synaptic inputs has been proposed to shape experience-related neuronal information processing. To elucidate the induction rules leading to spatially structured forms of synaptic potentiation in dendrites, we explored plasticity of glutamate uncaging-evoked excitatory input patterns with various spatial distributions in perisomatic dendrites of CA1 pyramidal neurons in slices from adult male rats. We show that (1) the cooperativity rules governing the induction of synaptic LTP depend on dendritic location; (2) LTP of input patterns that are subthreshold or suprathreshold to evoke local dendritic spikes (d-spikes) requires different spatial organization; and (3) input patterns evoking d-spikes can strengthen nearby, nonsynchronous synapses by local heterosynaptic plasticity crosstalk mediated by NMDAR-dependent MEK/ERK signaling. These results suggest that multiple mechanisms can trigger spatially organized synaptic plasticity on various spatial and temporal scales, enriching the ability of neurons to use synaptic clustering for information processing.SIGNIFICANCE STATEMENT A fundamental question in neuroscience is how neuronal feature selectivity is established via the combination of dendritic processing of synaptic input patterns with long-term synaptic plasticity. As these processes have been mostly studied separately, the relationship between the rules of integration and rules of plasticity remained elusive. Here we explore how the fine-grained spatial pattern and the form of voltage integration determine plasticity of different excitatory synaptic input patterns in perisomatic dendrites of CA1 pyramidal cells. We demonstrate that the plasticity rules depend highly on three factors: (1) the location of the input within the dendritic branch (proximal vs distal), (2) the strength of the input pattern (subthreshold or suprathreshold for dendritic spikes), and (3) the stimulation of neighboring synapses.

Disruption of synaptic expression pattern and age-related DNA oxidation in a neuronal model of lead-induced toxicity

Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.

Underglycosylated prion protein modulates plaque formation in the brain.

The prion agent is unique in biology and is comprised of prion protein scrapie (PrPSc), a self-templating conformational variant of the host encoded prion protein cellular (PrPC). The deposition patterns of PrPSc in the CNS can vary considerably from a diffuse synaptic pattern to large plaque-like aggregates. Alterations of PrPC posttranslational processing can change PrPSc deposition patterns; however, the mechanism underlying these observations is unclear. In this issue of the JCI, Sevillano and authors determined that parenchymal PrPSc plaques of the mouse brain preferentially incorporated underglycosylated PrPC that had been liberated from the cell surface by the metalloproteinase, ADAM-10, in combination with heparan sulfate. These results provide mechanistic insight into the formation of PrPSc plaques and suggest that PrP posttranslational modifications direct pathogenicity as well as the rate of disease progression.

Auditory Brainstem Responses in Children with Auditory Processing Disorder

The ASHA recommends including electrophysiological measures in an auditory processing disorder (APD) assessment battery, but few audiologists do so, potentially because of limited published evidence for its utility. This study compared the auditory brainstem responses (ABRs) of children with APD with age-matched children and adults. This study retrospectively examined the records of 108 children suspected of APD (sAPD) who had click-evoked ABRs recorded as part of their clinical assessment. Twenty adults and 22 typically developing (TD) children were recruited as controls. Click-evoked ABRs were recorded at slow (13.3 clicks/sec) and faster (57.7 clicks/sec) stimulation rates. ABRs were analyzed using typical clinical measures (latencies and interpeak intervals for waves I, III, and V) and using a model proposed by Ponton et al that offered a more detailed analysis of axonal conduction time and synaptic transmission delay. Both clinical measures and the Ponton model analysis showed no significant differences between TD children and adults. Children sAPD showed absolute latencies that were significantly prolonged when compared with adults but not when compared with TD children. But individual children sAPD showed clinically significant delays (>2 standard deviations of TD children's data). Examination of responses delineating axonal versus synaptic transmission showed significant delays in synaptic transmission in the group of children sAPD in comparison to TD children and adults. These results suggest that a significant portion of children with listening difficulties showed evidence of reduced or atypical brainstem functioning. Examining the responses for axonal and synaptic delays revealed evidence of a synaptic pattern of abnormalities in a significant portion (37.03%) of children sAPD. Such observations could provide objective evidence of factors potentially contributing to listening difficulties that are frequently reported in children identified with APD. Children sAPD often showed abnormalities in the ABR, suggesting a neurophysiologic origin of their reported difficulties, frequently originating at or before the first synapse. This study provides supportive evidence for the value of click-evoked ABRs in comprehensive auditory processing assessment batteries.

FGF receptors are required for proper axonal branch targeting in Drosophila

Proper axonal branch growth and targeting are essential for establishing a hard-wired neural circuit. Here, we examined the role of Fibroblast Growth Factor Receptors (FGFRs) in axonal arbor development using loss of function and overexpression genetic analyses within single neurons. We used the invariant synaptic connectivity patterns of Drosophila mechanosensory neurons with their innate cleaning reflex responses as readouts for errors in synaptic targeting and circuit function. FGFR loss of function resulted in a decrease in axonal branch number and lengths, and overexpression of FGFRs resulted in ectopic branches and increased lengths. FGFR mutants produced stereotyped axonal targeting errors. Both loss of function and overexpression of FGFRs within the mechanosensory neuron decreased the animal’s frequency of response to mechanosensory stimulation. Our results indicate that FGFRs promote axonal branch growth and proper branch targeting. Disrupting FGFRs results in miswiring and impaired neural circuit function.

The mouse olfactory peduncle 4: Development of synapses, perineuronal nets, and capillaries.

Olfaction is critical for survival in neonatal mammals. However, little is known about the neural substrate for this ability as few studies of synaptic development in several olfactory processing regions have been reported. Odor information detected in the nasal cavity is first processed by the olfactory bulb and then sent via the lateral olfactory tract to a series of olfactory cortical areas. The first of these, the anterior olfactory nucleus pars principalis (AONpP), is a simple, two layered cortex with an outer plexiform and inner cell zone (Layers 1 and 2, respectively). Five sets of studies examined age-related changes in the AONpP. First, immunocytochemistry for glutamatergic (VGlut1 and VGlut2) and GABAergic (VGAT) synapses demonstrated that overall synaptic patterns remained uniform with age. The second set quantified synaptic development with electron microscopy and found different developmental patterns between Layers 1 and 2. As many of the interhemispheric connections in the olfactory system arise from AONpP, the third set examined the development of crossed projections using anterograde tracers and electron microscopy to explore the maturation of this pathway. A fourth study examined ontogenetic changes in immunostaining for the proteoglycans aggrecan and brevican, markers of mesh-like extracellular structures known as perineuronal nets whose maturation is associated with the end of early critical periods of synaptogenesis. A final study found no age-related changes in the density of vasculature in the peduncle from P5 to P30. This work is among the first to examine early postnatal changes in this initial cortical region of the olfactory system.

Neurochondrin neurological autoimmunity.

ObjectivesTo describe the neurologic spectrum and treatment outcomes for neurochondrin-IgG positive cases identified serologically in the Mayo Clinic Neuroimmunology Laboratory.MethodsArchived serum and CSF specimens previously scored positive for IgGs that stained mouse hippocampal tissue in a nonuniform synaptic pattern by immunofluorescence assay (89 among 616,025 screened, 1993–2019) were reevaluated. Antibody characterization experiments revealed specificity for neurochondrin, confirmed by recombinant protein assays.ResultsIgG in serum (9) or CSF (4) from 8 patients yielded identical neuron-restricted CNS patterns, most pronounced in hippocampus (stratum lucidum in particular), cerebellum (Purkinje cells and molecular layer), and amygdala. All were neurochondrin-IgG positive. Five were women; median symptom onset age was 43 years (range, 30–69). Of 7 with clinical data, 6 presented with rapidly progressive cerebellar ataxia, brainstem signs, or both; 1 had isolated unexplained psychosis 1 year prior. Five of 6 had cerebellar signs, 4 with additional brainstem symptoms or signs (eye movement abnormalities, 3; dysphagia, 2; nausea and vomiting, 1). One patient with brainstem signs (vocal cord paralysis and VII nerve palsy) had accompanying myelopathy (longitudinally extensive abnormality on MRI; aquaporin-4-IgG and myelin oligodendrocyte glycoprotein-IgG negative). The 7th patient had small fiber neuropathy only. Just 1 of 7 had contemporaneous cancer (uterine). Six patients with ataxia or brainstem signs received immunotherapy, but just 1 remained ambulatory. At last follow-up, 5 had MRI evidence of severe cerebellar atrophy.ConclusionIn our series, neurochondrin autoimmunity was usually accompanied by a nonparaneoplastic rapidly progressive rhombencephalitis with poor neurologic outcomes. Other phenotypes and occasional paraneoplastic causes may occur.

Characterizing the morphology of somatostatin-expressing interneurons and their synaptic innervation pattern in the barrel cortex of the GFP-expressing inhibitory neurons mouse.

Somatostatin-expressing (SST+) cells form the second largest subpopulation of neocortical GABAergic neurons that contain diverse subtypes, which participate in layer-specific cortical circuits. Martinotti cells, as the most abundant subtype of SST+ interneurons, are mainly located in layers II/III and V/VI, and are characterized by dense axonal arborizations in layer I. GFP-expressing inhibitory neurons (GIN), representing a fraction of mainly upper layer SST+ interneurons in various cortical areas, were recently claimed to include both Martinotti cells and non-Martinotti cells. This makes it necessary to examine in detail the morphology and synaptic innervation pattern of the GIN cells, in order to better predict their functional implications. In our study, we characterized the neurochemical specificity, somatodendritic morphology, synaptic ultrastructure as well as synaptic innervation pattern of GIN cells in the barrel cortex in a layer-specific manner. We showed that GIN cells account for 44% of the SST+ interneurons in layer II/III and around 35% in layers IV and Va. There are 29% of GIN cells coexpressing calretinin with 54% in layer II/III, 8% in layer IV, and 13% in layer V. They have diverse somatodendritic configurations and form relatively small synapses across all examined layers. They almost exclusively innervate dendrites of excitatory cells, preferentially targeting distal apical dendrites and apical dendritic tufts of pyramidal neurons in layer I, and rarely target other inhibitory neurons. In summary, our study reveals unique features in terms of the morphology and output of GIN cells, which can help to better understand their diversity and structure-function relationships.

Mechanisms of Persistent Neurobiological Changes Following Adolescent Alcohol Exposure: NADIA Consortium Findings.

The Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms. Using adolescent intermittent ethanol (AIE) exposure models, NADIA investigators identified long‐lasting AIE‐induced changes in adult behavior that are consistent with observations in humans, such as increased alcohol drinking, increased anxiety (particularly social anxiety), increased impulsivity, reduced behavioral flexibility, impaired memory, disrupted sleep, and altered responses to alcohol. These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the molecular level, AIE results in long‐lasting changes in neuroimmune/trophic factor balance and epigenetic–microRNA (miRNA) signaling across glia and neurons. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology. This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. Many of these AIE‐induced brain changes replicate findings seen in postmortem brains of humans with alcohol use disorder (AUD). NADIA researchers are now elucidating mechanisms of these adaptations. Emerging data demonstrate that exercise, antiinflammatory drugs, anticholinesterases, histone deacetylase inhibitors, and other pharmacological compounds are able to prevent (administered during AIE) and/or reverse (given after AIE) AIE‐induced pathology in adulthood. These studies support hypotheses that adolescent binge drinking increases risk of adult hazardous drinking and influences brain development, and may provide insight into novel therapeutic targets for AIE‐induced neuropathology and AUDs.

Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve discrimination of input synchrony.

How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration are shaped by the frequency-dependent neuronal membrane impedance. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper Schistocerca americana. This neuron, the lobula giant movement detector (LGMD), exhibits consistent impedance properties across frequencies and membrane potentials. Two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and by muscarine-sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD's natural range of membrane potentials and synaptic input frequencies. Additionally, we found that a model based on the LGMD's branching morphology increased the gain and decreased the delay associated with the mapping of synaptic input currents to membrane potential. More generally, this was true for a wide range of model neuron morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings show the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration.NEW & NOTEWORTHY Neuronal filtering and integration of synaptic input patterns depend on the electrochemical properties of dendrites. We used an identified collision detection neuron in grasshoppers to examine how its morphology and two conductances affect its membrane impedance in relation to the computations it performs. The neuronal properties examined are ubiquitous and therefore promote a general understanding of neuronal computations, including those in the human brain.

Synaptic Strengths Dominate Phasing of Motor Circuit: Intrinsic Conductances of Neuron Types Need Not Vary across Animals.

Identified neurons and the networks they compose produce stereotypical, albeit individually unique, activity across members of a species. We propose, for a motor circuit driven by a central pattern generator (CPG), that the uniqueness derives mainly from differences in synaptic strength rather than from differences in intrinsic membrane conductances. We studied a dataset of recordings from six leech (Hirudo sp.) heartbeat control networks, containing complete spiking activity patterns from inhibitory premotor interneurons, motor output spike patterns, and synaptic strength patterns to investigate the source of uniqueness. We used a conductance-based multicompartmental motor neuron model to construct a bilateral motor circuit model, and controlled it by playing recorded input spike trains from premotor interneurons to generate output inhibitory synaptic patterns similar to experimental measurements. By generating different synaptic conductance parameter sets of this circuit model, we found that relative premotor synaptic strengths impinging onto motor neurons must be different across individuals to produce animal-specific output burst phasing. Obtaining unique outputs from each individual's circuit model did not require different intrinsic ionic conductance parameters. Furthermore, changing intrinsic conductances failed to compensate for modified synaptic strength patterns. Thus, the pattern of synaptic strengths of motor neuron inputs is critical for the phasing of this motor circuit and can explain individual differences. When intrinsic conductances were allowed to vary, they exhibited the same conductance correlations across individuals, suggesting a motor neuron "type" required for proper network function. Our results are general and may translate to other systems and neuronal networks that control output phasing.

Structure of auditory nerve synapses in normal and in hearing impaired

The neurons of the cochlear nuclei in the brainstem are the first central processors of auditory information, and they provide inputs to all the major brainstem and midbrain auditory nuclei. The synaptic connectivity pattern of neural networks in each part of the cochlear nuclear complex is an essential determinant of their role in information processing. The synapse of the auditory nerve on principal neurons in the cochlear nucleus is biophysically and anatomically specialized for the fast conduction of excitatory currents into the auditory pathway. A growing interest in the field is to determine how auditory nerve synapses adapt to fluctuations in the sound environment. In this paper, we will discuss novel findings related to the structural and molecular responses of auditory nerve synapses and enwrapping astrocytes in the normal hearing and in the hearing impaired.Support or Funding InformationNIDCD/NIH: R01DC013048; R56DC013048This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dendritic, Cellular and Circuit Mechanisms of Spatial Representations

How are neuronal representations of the spatial environment generated at the level of synapses, neurons, and neuronal circuits? Neurons in the hippocampal formation produce striking spatial firing patterns that may provide the brain with a cognitive map of the environment. We have combined computational modelling, in vivo and in vitro recordings to understand how spatially modulated firing is generated at the synaptic, cellular and network level. We address this question in several key circuits that are critical for spatial cognition and memory, such as the medial entorhinal cortex and the dentate gyrus. We find that in both regions, nonlinear properties of individual neurons can specifically contribute to the computations performed by these circuits: In the medial entorhinal cortex, nonlinear integration can sharpen the precision of the temporal code and enhance the robustness of the rate code of grid cell firing, whereas in the dentate gyrus, nonlinear properties of individual neurons can help to distinguish between similar synaptic inputs patterns.

An Excitatory/Inhibitory Switch From Asymmetric Sensory Neurons Defines Postsynaptic Tuning for a Rapid Response to NaCl in Caenorhabditis elegans.

The neural networks that regulate animal behaviors are encoded in terms of neuronal excitation and inhibition at the synapse. However, how the temporal activity of neural circuits is dynamically and precisely characterized by each signaling interaction via excitatory or inhibitory synapses, and how both synaptic patterns are organized to achieve fine regulation of circuit activities is unclear. Here, we show that in Caenorhabditis elegans, the excitatory/inhibitory switch from asymmetric sensory neurons (ASEL/R) following changes in NaCl concentration is required for a rapid and fine response in postsynaptic interneurons (AIBs). We found that glutamate released by the ASEL neuron inhibits AIBs via a glutamate-gated chloride channel localized at the distal region of AIB neurites. Conversely, glutamate released by the ASER neuron activates AIBs via an AMPA-type ionotropic receptor and a G-protein-coupled metabotropic glutamate receptor. Interestingly, these excitatory receptors are mainly distributed at the proximal regions of the neurite. Our results suggest that these convergent synaptic patterns can tune and regulate the proper behavioral response to environmental changes in NaCl.

Dendritic and Axonal Propagation Delays May Shape Neuronal Networks With Plastic Synapses.

Biological neuronal networks are highly adaptive and plastic. For instance, spike-timing-dependent plasticity (STDP) is a core mechanism which adapts the synaptic strengths based on the relative timing of pre- and postsynaptic spikes. In various fields of physiology, time delays cause a plethora of biologically relevant dynamical phenomena. However, time delays increase the complexity of model systems together with the computational and theoretical analysis burden. Accordingly, in computational neuronal network studies propagation delays were often neglected. As a downside, a classic STDP rule in oscillatory neurons without propagation delays is unable to give rise to bidirectional synaptic couplings, i.e., loops or uncoupled states. This is at variance with basic experimental results. In this mini review, we focus on recent theoretical studies focusing on how things change in the presence of propagation delays. Realistic propagation delays may lead to the emergence of neuronal activity and synaptic connectivity patterns, which cannot be captured by classic STDP models. In fact, propagation delays determine the inventory of attractor states and shape their basins of attractions. The results reviewed here enable to overcome fundamental discrepancies between theory and experiments. Furthermore, these findings are relevant for the development of therapeutic brain stimulation techniques aiming at shifting the diseased brain to more favorable attractor states.

Active Tuning of Synaptic Patterns Enhances Immune Discrimination.

Immune cells learn about their antigenic targets using tactile sense: a self-organized motif named immunological synapse forms between an immune cell and an antigen-presenting cell (APC) during recognition. Via synapses, immune cells apply mechanical pulling forces to selectively extract antigen (Ag) from APCs. Curiously, depending on its stage of development, a B lymphocyte exhibits distinct synaptic patterns and uses force at different strength and timing, which appears to strongly impact its ability to distinguish Ag affinities. We use a statistical-mechanical model to study how the experimentally observed synaptic architectures can originate from normal cytoskeletal forces coupled to the lateral organization of mobile receptors, and show how this active regulation scheme, collective in nature, may enhance the efficiency and capacity of discrimination.

Multinode implementation of an extended Hodgkin–Huxley simulator

Mathematical models with varying degrees of complexity have been proposed and simulated in an attempt to represent the intricate mechanisms of the human neuron. One of the most biochemically realistic and analytical models, based on the Hodgkin–Huxley (HH) model, has been selected for study in this paper. In order to satisfy the model’s computational demands, we present a simulator implemented on Intel Xeon Phi Knights Landing manycore processors. This high-performance platform features an x86-based architecture, allowing our implementation to be portable to other common manycore processing machines. This is reinforced by the fact that Phi adopts the popular OpenMP and MPI programming models. The simulator performance is evaluated when calculating neuronal networks of varying sizes, density and network connectivity maps. The evaluation leads to an analysis of the neuronal synaptic patterns and their impact on performance when tackling this type of workload on a multinode system. It will be shown that the simulator can calculate 100 ms of simulated brain activity for up to 2 millions of biophysically-accurate neurons and 2 billion neuronal synapses within one minute of execution time. This level of performance renders the application an efficient solution for large-scale detailed model simulation.