The ultrastructure of macaque mesencephalic trigeminal nucleus neurons.

Primary afferents originating from the mesencephalic trigeminal nucleus provide the main source of proprioceptive information guiding mastication, and thus represent an important component of this critical function. Unlike those of other primary afferents, their cell bodies lie within the central nervous system. It is believed that this unusual central location allows them to be regulated by synaptic input. In this study, we explored the ultrastructure of macaque mesencephalic trigeminal nucleus neurons to determine the presence and nature of this synaptic input in a primate. We first confirmed the location of macaque mesencephalic trigeminal neurons by retrograde labeling from the masticatory muscles. Since the labeled neurons were by far the largest cells located at the edge of the periaqueductal gray, we could undertake sampling for electron microscopy based on soma size. Ultrastructurally, mesencephalic trigeminal neurons had very large somata with euchromatic nuclei that sometimes displayed deeply indented nuclear membranes. Terminal profiles with varied vesicle characteristics and synaptic density thicknesses were found in contact with either their somatic plasma membranes or somatic spines. However, in contradistinction to other, much smaller, somata in the region, the plasma membranes of the mesencephalic trigeminal somata had only a few synaptic contacts. They did extend numerous somatic spines of various lengths into the neuropil, but most of these also lacked synaptic contact. The observed ultrastructural organization indicates that macaque trigeminal mesencephalic neurons do receive synaptic contacts, but despite their central location, they only avail themselves of very limited input.

Comparison of the predictive power of two models of cortico-cortical connections in primates: the distance rule model and the structural model.

Synaptic tract-tracing studies in macaques have provided a wealth of data about cortico-cortical connections that have been used to identify regularities and propose models and theories to explain cortical connectivity. The two most relevant of these models are the distance rule model (DRM) and the structural model (SM). They relate the strength and laminar pattern of cortico-cortical connections to two different factors: Euclidean distance (according to the DRM) and cortical type distance (according to the SM). If both predictive factors were correlated, the DRM and the SM would be compatible, but quite often, two cortical areas of similar cortical type are far apart from each other. In the present article, we have performed a conceptual analysis of the DRM and the SM to obtain predictions from each of the two models about strength and laminar pattern of cortico-cortical connections. We then tested the predictive power of each model with analyses of several cortico-cortical connectivity databases to check which of them provide the most accurate predictions. We conclude that the DRM and the SM capture the decrease in connection strength with increasing Euclidean and cortical type distances, respectively; but, for laminar pattern, type distance is a better predictor than Euclidean distance.

Neural Stem Cells Transplanted into Rhesus Monkey Cortical Traumatic Brain Injury Can Survive and Differentiate into Neurons.

Cortical traumatic brain injury (TBI) is a major cause of cognitive impairment accompanied by motor and behavioral deficits, and there is no effective treatment strategy in the clinic. Cell transplantation is a promising therapeutic strategy, and it is necessary to verify the survival and differentiation of cells after transplantation in large animal models like rhesus monkeys. In this study, we transplanted neural stem cells (NSCs) and simultaneously injected basic fibroblast growth factor/epidermal growth factor (bFGF/EGF) into the cortex (visual and sensory cortices) of rhesus monkeys with superficial TBI. The results showed that the transplanted NSCs did not enter the cerebrospinal fluid (CSF) and were confined to the transplantation site for at least one year. The transplanted NSCs differentiated into mature neurons that formed synaptic connections with host neurons, but glial scar formation between the graft and the host tissue did not occur. This study is the first to explore the repairing effect of transplanting NSCs into the superficial cerebral cortex of rhesus monkeys after TBI, and the results show the ability of NSCs to survive long-term and differentiate into neurons, demonstrating the potential of NSC transplantation for cortical TBI.

Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex.

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.

Dynamics of Hopfield-Type Neural Networks with Modulo Periodic Unpredictable Synaptic Connections, Rates and Inputs.

In this paper, we rigorously prove that unpredictable oscillations take place in the dynamics of Hopfield-type neural networks (HNNs) when synaptic connections, rates and external inputs are modulo periodic unpredictable. The synaptic connections, rates and inputs are synchronized to obtain the convergence of outputs on the compact subsets of the real axis. The existence, uniqueness, and exponential stability of such motions are discussed. The method of included intervals and the contraction mapping principle are applied to attain the theoretical results. In addition to the analysis, we have provided strong simulation arguments, considering that all the assumed conditions are satisfied. It is shown how a new parameter, degree of periodicity, affects the dynamics of the neural network.

Spatial Memory in a Spiking Neural Network with Robot Embodiment.

Cognitive maps and spatial memory are fundamental paradigms of brain functioning. Here, we present a spiking neural network (SNN) capable of generating an internal representation of the external environment and implementing spatial memory. The SNN initially has a non-specific architecture, which is then shaped by Hebbian-type synaptic plasticity. The network receives stimuli at specific loci, while the memory retrieval operates as a functional SNN response in the form of population bursts. The SNN function is explored through its embodiment in a robot moving in an arena with safe and dangerous zones. We propose a measure of the global network memory using the synaptic vector field approach to validate results and calculate information characteristics, including learning curves. We show that after training, the SNN can effectively control the robot's cognitive behavior, allowing it to avoid dangerous regions in the arena. However, the learning is not perfect. The robot eventually visits dangerous areas. Such behavior, also observed in animals, enables relearning in time-evolving environments. If a dangerous zone moves into another place, the SNN remaps positive and negative areas, allowing escaping the catastrophic interference phenomenon known for some AI architectures. Thus, the robot adapts to changing world.

HSP27 immunization reinforces AII amacrine cell and synapse damage induced by S100 in an autoimmune glaucoma model.

Previous studies have revealed a loss of retinal ganglion cells (RGCs) and optic nerve fibers after immunization with the S100B protein. Addition of heat shock protein 27 (HSP27) also leads to a decrease of RGCs. Our present aim has been to analyze various retinal cell types after immunization with S100B or S100B + HSP27 (S100 + HSP). After 28 days, retinas were processed for immunohistology and Western blot. RGCs, immunostained for NeuN, were significantly decreased in the S100 and the S100 + HSP groups. Significantly fewer ChAT+ cells were noted in both groups, whereas parvalbumin+ cells were only affected in the S100 + HSP group. Western blot results also revealed fewer ChAT signals in both immunized groups. No changes were noted with regard to PKCα+ rod bipolar cells, whereas a significant loss of recoverin+ cone bipolar cells was observed in both groups via immunohistology and Western blot. The presynaptic marker Bassoon and the postsynaptic marker PSD95 were significantly reduced in the S100 + HSP group. Opsin+ and rhodopsin+ photoreceptors revealed no changes in either group. Thus, the inner retinal layers are affected by immunization. However, the combination of S100 and HSP27 has a stronger additive effect on the retinal synapses and AII amacrine cells.

High-resolution and cell-type-specific photostimulation mapping shows weak excitatory vs. strong inhibitory inputs in the bed nucleus of the stria terminalis.

The bed nucleus of the stria terminalis (BNST) is a key component of the extended amygdala and has been implicated in anxiety and addiction. As individual neurons function within neural circuits, it is important to understand local microcircuits and larger network connections of identified neuronal types and understand how maladaptive changes in the BNST neural networks are induced by stress and drug abuse. However, due to limitations of classic anatomical and physiological methods, the local circuit organization of synaptic inputs to specific BNST neuron types is not well understood. In this study, we report on the application of high-resolution and cell-type-specific photostimulation methodology developed in our laboratory to local circuit mapping in the BNST. Under calibrated experimental conditions, laser photostimulation via glutamate uncaging or channelrhodopsin-2 photoactivation evokes spiking of BNST neurons perisomatically, without activating spikes from axons of passage or distal dendrites. Whole cell recordings, combined with spatially restricted photostimulation of presynaptic neurons at many different locations over a large region, allow high-resolution mapping of presynaptic input sources to single recorded neurons in the BNST. We constructed maps of synaptic inputs impinging onto corticotrophin-releasing hormone-expressing (CRH+) BNST neurons in the dorsolateral BNST and found that the CRH+ neurons receive predominant local inhibitory synaptic connections with very weak excitatory connections. Through cell-type-specific optogenetic stimulation mapping, we generated maps of somatostatin-expressing neuron-specific inhibitory inputs to BNST neurons. Taken together, the photostimulation-based techniques offer us powerful tools for determining the functional organization of local circuits of specific BNST neuron types.

Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission.

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how trans-synaptic bridges change to reflect the functional states of the synapse. Here, we develop optical tools to visualize in firing synapses the molecular behavior of two trans-synaptic proteins, LGI1 and ADAM23, and find that neuronal activity acutely rearranges their abundance at the synaptic cleft. Surprisingly, synaptic LGI1 is primarily not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitates the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Accordingly, we find that patient-derived autoantibodies against LGI1 reduce its surface fraction and cause increased glutamate release. Our findings suggest that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical control point for synaptic function.

Comparing mouse and human brains.

Inhibitory circuit motifs in the mouse brain and the human brain are strikingly similar.

BDNF guides neural stem cell-derived axons to ventral interneurons and motor neurons after spinal cord injury.

Neural stem cells (NSCs) implanted into sites of spinal cord injury (SCI) extend very large numbers of new axons over very long distances caudal to the lesion site, and support partial functional recovery. Newly extending graft axons distribute throughout host gray and white matter caudal to the injury. We hypothesized that provision of trophic gradients caudal to the injury would provide neurotrophic guidance to newly extending graft-derived axons to specific intermediate and ventral host gray matter regions, thereby potentially further improving neural relay formation. Immunodeficient rats underwent C5 lateral hemisection lesions, following by implants of human NSC grafts two weeks later. After an additional two weeks, animals received injections of AAV2-BDNF expressing vectors three spinal segments (9 mm) caudal to the lesion in host ventral and intermediate gray matter. After 2 months additional survival, we found a striking, 5.5-fold increase in the density of human axons innervating host ventral gray matter (P < 0.05) and 2.7-fold increase in intermediate gray matter (P < 0.01). Moreover, stem cell-derived axons formed a substantially greater number of putative synaptic connections with host motor neurons (P < 0.01). Thus, trophic guidance is an effective means of enhancing and guiding neural stem cell axon growth after SCI and will be used in future experiments to determine whether neural relay formation and functional outcomes can be improved.

Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits.

Cortical processing depends on finely tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here we test the effect of reduced somatostatin interneuron-mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrate human cellular, circuit, and gene expression data to generate detailed models of human cortical microcircuits in health and depression. We simulate microcircuit baseline and response activity and find a reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. We thus apply models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

Detecting synaptic connections in neural systems using compressive sensing.

Revealing synaptic connections between neurons is of great significance and practical value to biomedicine and bio-neurology. We present a general approach to reconstruct neuronal synapses, which is based on compressive sensing and special data processing. And this approach is more suitable for nervous system with peak time series. Numerical simulations illustrate the feasibility and effectiveness of the proposed approach. Moreover, this approach not only adapts to the asymmetry of neural connections and the diversity of coupling strength, but also adapts to the excitability and inhibition of neural node classification. In addition, the effects of the factors on the synaptic connection identification performance and their optimal states for the synaptic connection recovery are discussed. Besides, it is of great practical significance to control the order of Taylor expansion to improve the performance of synaptic connection recognition.

Synaptic environment and extrasynaptic glutamate signals: The quest continues.

Behaviour of a mammal relies on the brain's excitatory circuits equipped with glutamatergic synapses. In most cases, glutamate escaping from the synaptic cleft is rapidly buffered and taken up by high-affinity transporters expressed by nearby perisynaptic astroglial processes (PAPs). The spatial relationship between glutamatergic synapses and PAPs thus plays a crucial role in understanding glutamate signalling actions, yet its intricate features can only be fully appreciated using methods that operate beyond the diffraction limit of light. Here, we examine principal aspects pertaining to the receptor actions of glutamate, inside and outside the synaptic cleft in the brain, where the organisation of synaptic micro-physiology and micro-environment play a critical part. In what conditions and how far glutamate can escape the synaptic cleft activating its target receptors outside the immediate synapse has long been the subject of debate. Evidence is also emerging that neuronal activity- and astroglia-dependent glutamate spillover actions could be important across the spectrum of cognitive functions This article is part of the special issue on 'Glutamate Receptors - The Glutamatergic Synapse'.

A Novel Method to Assess Motor Cortex Connectivity and Event Related Desynchronization Based on Mass Models.

Knowledge of motor cortex connectivity is of great value in cognitive neuroscience, in order to provide a better understanding of motor organization and its alterations in pathological conditions. Traditional methods provide connectivity estimations which may vary depending on the task. This work aims to propose a new method for motor connectivity assessment based on the hypothesis of a task-independent connectivity network, assuming nonlinear behavior. The model considers six cortical regions of interest (ROIs) involved in hand movement. The dynamics of each region is simulated using a neural mass model, which reproduces the oscillatory activity through the interaction among four neural populations. Parameters of the model have been assigned to simulate both power spectral densities and coherences of a patient with left-hemisphere stroke during resting condition, movement of the affected, and movement of the unaffected hand. The presented model can simulate the three conditions using a single set of connectivity parameters, assuming that only inputs to the ROIs change from one condition to the other. The proposed procedure represents an innovative method to assess a brain circuit, which does not rely on a task-dependent connectivity network and allows brain rhythms and desynchronization to be assessed on a quantitative basis.

Prediction of the Molecular Mechanisms Underlying Erlong Zuoci Treatment of Age-Related Hearing Loss via Network Pharmacology-Based Analyses Combined with Experimental Validation.

Background: The traditional Chinese medicine formula ErLong ZuoCi (ELZC) has been extensively used to treat age-related hearing loss (ARHL) in clinical practice in China for centuries. However, the underlying molecular mechanisms are still poorly understood. Objective: Combine network pharmacology with experimental validation to explore the potential molecular mechanisms underlying ELZC with a systematic viewpoint. Methods: The chemical components of ELZC were collected from the Traditional Chinese Medicine System Pharmacology database, and their possible target proteins were predicted using the SwissTargetPrediction database. The putative ARHL-related target proteins were identified from the database: GeneCards and OMIM. We constructed the drug-target network as well as drug-disease specific protein-protein interaction networks and performed clustering and topological property analyses. Functional annotation and signaling pathways were performed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Finally, in vitro experiments were also performed to validate ELZC's key target proteins and treatment effects on ARHL. Results: In total, 63 chemical compounds from ELZC and 365 putative ARHL-related targets were identified, and 1860 ARHL-related targets were collected from the OMIM and GeneCards. A total of 145 shared targets of ELZC and ARHL were acquired by Venn diagram analysis. Functional enrichment analysis suggested that ELZC might exert its pharmacological effects in multiple biological processes, such as cell proliferation, apoptosis, inflammatory response, and synaptic connections, and the potential targets might be associated with AKT, ERK, and STAT3, as well as other proteins. In vitro experiments revealed that ELZC pretreatment could decrease senescence-associated ß-galactosidase activity in hydrogen peroxide-induced auditory hair cells, eliminate DNA damage, and reduce cellular senescence protein p21 and p53. Finally, Western blot analysis confirmed that ELZC could upregulate the predicted target ERK phosphorylation. Conclusion: We provide an integrative network pharmacology approach, in combination with in vitro experiments to explore the underlying molecular mechanisms governing ELZC treatment of ARHL. The protective effects of ELZC against ARHL were predicted to be associated with cellular senescence, inflammatory response, and synaptic connections which might be linked to various pathways such as JNK/STAT3 and ERK cascade signaling pathways. As a prosperous possibility, our experimental data suggest phosphorylation ERK is essential for ELZC to prevent degeneration of cochlear.

Diversity in striatal synaptic circuits arises from distinct embryonic progenitor pools in the ventral telencephalon.

Synaptic circuits in the brain are precisely organized, but the processes that govern this precision are poorly understood. Here, we explore how distinct embryonic neural progenitor pools in the lateral ganglionic eminence contribute to neuronal diversity and synaptic circuit connectivity in the mouse striatum. In utero labeling of Tα1-expressing apical intermediate progenitors (aIP), as well as other progenitors (OP), reveals that both progenitors generate direct and indirect pathway spiny projection neurons (SPNs) with similar electrophysiological and anatomical properties and are intermingled in medial striatum. Subsequent optogenetic circuit-mapping experiments demonstrate that progenitor origin significantly impacts long-range excitatory input strength, with medial prefrontal cortex preferentially driving aIP-derived SPNs and visual cortex preferentially driving OP-derived SPNs. In contrast, the strength of local inhibitory inputs among SPNs is controlled by birthdate rather than progenitor origin. Combined, these results demonstrate distinct roles for embryonic progenitor origin in shaping neuronal and circuit properties of the postnatal striatum.

The Functional Role of Spinal Interneurons Following Traumatic Spinal Cord Injury.

Traumatic spinal cord injury (SCI) impedes signal transmission by disrupting both the local neurons and their surrounding synaptic connections. Although the majority of SCI patients retain spared neural tissue at the injury site, they predominantly suffer from complete autonomic and sensorimotor dysfunction. While there have been significant advances in the characterization of the spared neural tissue following SCI, the functional role of injury-induced interneuronal plasticity remains elusive. In healthy individuals, spinal interneurons are responsible for relaying signals to coordinate both sympathetic and parasympathetic functions. However, the spontaneous synaptic loss following injury alters these intricate interneuronal networks in the spinal cord. Here, we propose the synaptopathy hypothesis of SCI based on recent findings regarding the maladaptive role of synaptic changes amongst the interneurons. These maladaptive consequences include circuit inactivation, neuropathic pain, spasticity, and autonomic dysreflexia. Recent preclinical advances have uncovered the therapeutic potential of spinal interneurons in activating the dormant relay circuits to restore sensorimotor function. This review will survey the diverse role of spinal interneurons in SCI pathogenesis as well as treatment strategies to target spinal interneurons.

Taurine Protects Retinal Cells and Improves Synaptic Connections in Early Diabetic Rats.

Purpose: Taurine has long been thought to be involved in retinal protection from retinal degenerative diseases, but the underlying molecular mechanisms remain unclear. Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR) that precedes and participates in the microcirculatory abnormalities that occur in DR. Our objective was to investigate the role and mechanisms of taurine in early diabetic retinas.Methods: Eight-week-old STZ-induced diabetic rats and control animals were randomly assigned to receive taurine or vehicle by intraperitoneal injection or by intragastric administration. The retinal function and retinal cell counts were evaluated using an electroretinography (ERG) and immunofluorescence microscopy. Plasma amino acids were measured by ion-exchange chromatography (IEC). The expression levels of retinal taurine transporter (Tau-T), mitochondria-dependent apoptosis-associated genes and reactive gliosis markers were studied by western blotting and immunofluorescence. Pre- and post-synaptic markers (PSD95 and mGluR6) in outer plexiform layer (OPL), and the bipolar cell marker protein kinase C alpha (PKCα) were localized by immunofluorescence. Levels of PSD95 and mGluR6 were determined by quantitative western blot.Results: Taurine significantly prevented the reduction of photopic b-wave amplitude and retinal cone cells and ganglion cells loss and maintained the Bcl-2/Bax ratio balance in diabetic rats. Taurine also prevented the upregulation of glial fibrillary acidic protein (GFAP) and reduced retinal reactive gliosis. Taurine reduced plasma glutamate and tyrosine levels, which were elevated in diabetic rats. Moreover, mGluR6 levels reduction detected by western blot and immunofluorescence in diabetic retinas was inhibited and the displacement of mGluR6 in OPL into the inner nuclear layer (INL) detected by immunofluorescence was reduced by Taurine treatment.Conclusion: Taurine may protect retinal cells from diabetic attacks by activating Tau-T, reducing retinal reactive gliosis, improving retinal synaptic connections and decreasing retinal cell apoptosis. Thus, taurine treatment may be a novel approach for early DR.

Functional Reorganization of Local Circuit Connectivity in Superficial Spinal Dorsal Horn with Neuropathic Pain States.

The spinal dorsal horn is the first relay structure coding for pain transmission and modulation. Previous anatomical and electrophysiological studies have examined spinal dorsal horn circuit connections and network activity. Further work is required to understand spinal cord sensory information processing that underlies pathological neuropathic pain states. Our previous studies suggest that peripheral nerve injury enhances presynaptic excitatory input onto spinal superficial dorsal horn neurons, which in turn contributes to pathologic nociception. The potential changes in local postsynaptic circuits in the dorsal horn that lead to pathologically heightened behavioral responses to pain remain largely unexplored. We combined whole-cell electrophysiological recordings with laser-scanning photostimulation to test whether peripheral nerve injury in the spinal nerve ligation (SNL) mouse model of neuropathic pain leads to alterations in the functional connectivity of spinal cord circuits including lamina II excitatory interneurons. Here we show that SNL enhances excitation and decreases inhibition to lamina II excitatory interneurons along with their increased glutamate-evoked excitability. The enhanced excitatory postsynaptic input and connectivity evoked by SNL eventually return to normal levels concurrently with the resolution of the neuropathic pain states. The physiological pattern highly correlates with mouse pain behaviors following SNL, supporting a neurophysiological mechanism of central sensitization and neuropathic pain that is functionally localized to the spinal dorsal horn. Together, these data support that SNL induces functional changes in synaptic input and connectivity to lamina II excitatory interneurons that code for pain perception, and thus provide new insights into the mechanism and locus of pain hypersensitivity.