Cortical Model Research Articles

Computational analysis of the effects of interprosthetic distance on normal and reduced cortical thickness femur models.

Distal femoral fractures associated with the femoral stem in a well-fixed hip arthroplasty pose a risk of an interprosthetic fracture, the treatment of which is known as difficult. To effectively prevent and treat IP fractures, biomechanical effects must be demonstrated. We defined eight variations of the interprosthetic distance ranging from 48 mm overlap to 128 mm gap. Femoral geometries with normal and reduced cortical thickness were modeled to evaluate the effects of cortical thickness. In addition to the intact model, a total of 16 finite element models were analyzed under physiological boundary conditions. Maximum and minimum principal strains on the lateral and medial cortex surfaces were always found to be greater in models with reduced cortical thickness than in normal femurs. The model with 48 mm overlapping interprosthetic distance produced the least peak strain and the model with 16 mm interprosthetic gap produced the greatest strain with both normal and reduced cortical thickness. The screw holes produced local strain concentrations and increased the peak strains on the cortex surfaces, especially close to the stem tip. Statistically, a significant correlation (R2 = 0.9483) was found between strain shielding and interprosthetic distance. Axial stiffness, interfragmentary shear motion, and maximum von-Mises stress on the distal plate showed a high correlation with the interprosthetic distance. It was concluded that the overlapping structures are superior to other fixations we analyzed in that they offer better mechanical stability and eliminates the local strain concentrations.

Blockade of TRPC Channels Limits Cholinergic-Driven Hyperexcitability and Seizure Susceptibility After Traumatic Brain Injury.

We investigated the contribution of excitatory transient receptor potential canonical (TRPC) cation channels to posttraumatic hyperexcitability in the brain 7 days following controlled cortical impact model of traumatic brain injury (TBI) to the parietal cortex in male adult mice. We investigated if TRPC1/TRPC4/TRPC5 channel expression is upregulated in excitatory neurons after TBI in contribution to epileptogenic hyperexcitability in key hippocampal and cortical circuits that have substantial cholinergic innervation. This was tested by measuring TRPC1/TRPC4/TRPC5 protein and messenger RNA (mRNA) expression, assays of cholinergic function, neuronal Ca2+ imaging in brain slices, and seizure susceptibility after TBI. We found region-specific increases in expression of TRPC1, TRPC4, and TRPC5 subunits in the hippocampus and cortex following TBI. The dentate gyrus, CA3 region, and cortex all exhibited robust upregulation of TRPC4 mRNA and protein. TBI increased cFos activity in dentate gyrus granule cells (DGGCs) and layer 5 pyramidal neurons both at the time of TBI and 7 days post-TBI. DGGCs displayed greater magnitude and duration of acetylcholine-induced rises in intracellular Ca2+ in brain slices from mice subjected to TBI. The TBI mice also exhibited greater seizure susceptibility in response to pentylenetetrazol-induced kindling. Blockade of TRPC4/TRPC5 channels with M084 reduced neuronal hyperexcitation and impeded epileptogenic progression of kindling. We observed that the time-dependent upregulation of TRPC4/TRPC5-containing channels alters cholinergic responses and activity of principal neurons acting to increase proexcitatory sensitivity. The underlying mechanism includes acutely decreased acetylcholinesterase function, resulting in greater Gq/11-coupled muscarinic receptor activation of TRPC channels. Overall, our evidence suggests that TBI-induced plasticity of TRPC channels strongly contributes to overt hyperexcitability and primes the hippocampus and cortex for seizures.

Krüppel-like factor 7 attenuates hippocampal neuronal injury after traumatic brain injury.

Our previous study has shown that the transcription factor Krüppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2'-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018.

Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury.

MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.

Impact of gyral geometry on cortical responses to surface electrical stimulation: insights from experimental and modeling studies

Objective. Invasive simultaneous stimulation and recording from intracranial electrodes and microwire arrays were used to investigate direct cortical responses to single pulses of electrical stimulation in humans. Approach. Microwire contacts measured surface potentials in cortical microdomains at a distance of 2–6 mm from the intracranial electrode. Direct cortical responses to stimulation (<20 ms) consisted of a larger surface negative potentials. Main results. The latencies of these responses were directly or inversely correlated with distances between the intracranial electrode and microwire contacts. We hypothesize that surface negative potentials reflected local synchronous depolarization of apical dendrites of pyramidal neurons in cortical microdomains in the superficial cortical layer and resulted from the activation of gray matter axons that delivered excitatory inputs to apical dendrites after cortical stimulation. We further hypothesized that the positive or inverse distance-latency correlations of the recorded negative responses were measured depending on whether activation of neurons originated at one (crown) or multiple (crown, lip, bank) sites throughout the gyrus simultaneously. The inverse distance-latency correlations then reflected the spatiotemporal superposition of different nearby sources of neuronal recruitment in the gyrus. To prove this hypothesis, we built an anatomically informed and biophysically realistic cortical network model and simulated early responses of cortical neurons to electrical stimulation in this cortical network model. The model simulations yielded negative potentials in simulated microdomains in the cortical model consistent with those recorded from humans. The model predicted sensitivity of cortical responses to the alignment of the stimulating electrode and microwire array with respect to the cortical gyrus and confirmed that gyral geometry has a major impact on direct neuronal recruitment, the timing, and the time course of neuronal activation in cortical microdomains. Significance. In this work, we demonstrated how the high-resolution forward network models can be used for better understanding and detailed prediction of cortical stimulation effects. Accurate predictive modeling tools are needed for the progress of brain stimulation therapies.

Investigation of tissue level tolerance for cerebral contusion in a controlled cortical impact porcine model

Objective Cerebral contusions (CC) represent a frequent lesion in traumatic brain injury, with potential morbidity from mass effect and tissue loss. Better understanding of the mechanical etiology will help to improve head protection. The goal of this study is to investigate the threshold for mechanical impact parameters to induce CC in an in vivo porcine controlled cortical impact model. Methods Thirty-four adult male pigs underwent craniotomy and controlled cortical impact with a hemispherical tip on intact dura under general anesthesia. Peak impact depth varied between 1.1 and 12.6 mm, and impact velocity between 0.4 and 2.2 m/s while the dwell time was kept at 200 ms. Two days following impact, the animals underwent magnetic resonance (MR) imaging of the brain, and were subsequently sacrificed for brain extraction. CC damage was investigated by magnetic resonance imaging and histology. Results All animals recovered from the impact without overt neurological deficit. Provoked injuries were histologically confirmed to be CC. Decreasing probability of cortical damage and white matter edema volume was observed with decreasing impact depth and velocity. No CC could be demonstrated below a product of impact depth and velocity of 0.8 mm*m/s, whereas the probability for CC was one third below 15 mm*m/s. The threshold for CC development as estimated from the current series of experiments, was situated at an impact depth of 2.0 mm and impact velocity of 0.4 m/s Conclusion Mechanical thresholds for CC development could be explored in the current porcine controlled cortical impact model. Findings will be used to further refine a cerebral contusion porcine model with volumetric histology data in light of future finite element cerebral contusion validation studies.

Dexmedetomidine Ameliorates Perioperative Neurocognitive Disorders by Suppressing Monocyte-Derived Macrophages in Mice With Preexisting Traumatic Brain Injury.

Traumatic brain injury (TBI) initiates immune responses involving infiltration of monocyte-derived macrophages (MDMs) in the injured brain tissue. These MDMs play a key role in perioperative neurocognitive disorders (PNDs). We tested the hypothesis that preanesthetic treatment with dexmedetomidine (DEX) could suppress infiltration of MDMs into the hippocampus of TBI model mice, ameliorating PND. We first performed bone marrow transplantation from green fluorescent protein-transgenic mice to C57BL/6 mice to identify MDMs. We used only male mice for homogeneity. Four weeks after transplantation, a controlled cortical impact model of TBI was created using recipient mice. Four weeks after TBI, mice received pretreatment with DEX before general anesthesia (GA). Mice performed the Barnes maze test (8-12 mice/group) 2 weeks after GA and were euthanized for immunohistochemistry (4-5 mice/group) or immunoblotting (7 mice/group) 4 weeks after GA. In Barnes maze tests, TBI model mice showed longer primary latency (mean difference, 76.5 [95% confidence interval, 41.4-111.6], P < .0001 versus Naïve), primary path length (431.2 [98.5-763.9], P = .001 versus Naïve), and more primary errors (5.7 [0.62-10.7], P = .017 versus Naïve) than Naïve mice on experimental day 3. Expression of MDMs in the hippocampus was significantly increased in TBI mice compared to Naïve mice (2.1 [0.6-3.7], P = .003 versus Naïve). Expression of monocyte chemotactic protein-1 (MCP1)-positive areas in the hippocampus was significantly increased in TBI mice compared to Naïve mice (0.38 [0.09-0.68], P = .007 versus Naïve). Immunoblotting indicated significantly increased expression of interleukin-1β in the hippocampus in TBI mice compared to Naïve mice (1.59 [0.08-3.1], P = .035 versus Naïve). In contrast, TBI mice pretreated with DEX were rescued from these changes and showed no significant difference from Naïve mice. Yohimbine, an α2 receptor antagonist, mitigated the effects of DEX (primary latency: 68.3 [36.5-100.1], P < .0001 versus TBI-DEX; primary path length: 414.9 [120.0-709.9], P = .0002 versus DEX; primary errors: 6.6 [2.1-11.2], P = .0005 versus TBI-DEX; expression of MDMs: 2.9 [1.4-4.4], P = .0001 versus TBI-DEX; expression of MCP1: 0.4 [0.05-0.67], P = .017 versus TBI-DEX; expression of interleukin-1β: 1.8 [0.34-3.35], P = .01 versus TBI-DEX). Preanesthetic treatment with DEX suppressed infiltration of MDMs in the hippocampus and ameliorated PND in TBI model mice. Preanesthetic treatment with DEX appears to suppress infiltration of MDMs in the hippocampus and may lead to new treatments for PND in patients with a history of TBI.

Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD.

Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically induced effects. Previously, using pharmacological neuroimaging, we found that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to agonism of the serotonin-2A receptor (Preller et al., 2018). Here, we integrate brain-wide transcriptomics with biophysically based circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical large-scale spatiotemporal dynamics. Our model captures the inter-areal topography of LSD-induced changes in cortical blood oxygen level-dependent (BOLD) functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal-neuronal gain is a circuit mechanism through which LSD alters cortical functional topography. Individual-subject model fitting captures patterns of individual neural differences in pharmacological response related to altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to systems-level functional alterations, with implications for precision medicine.

Genome-wide interrogation of transfer RNA-derived small RNAs in a mouse model of traumatic brain injury.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are a recently established family of regulatory small non-coding RNAs that modulate diverse biological processes. Growing evidence indicates that tsRNAs are involved in neurological disorders and play a role in the pathogenesis of neurodegenerative disease. However, whether tsRNAs are involved in traumatic brain injury-induced secondary injury remains poorly understood. In this study, a mouse controlled cortical impact model of traumatic brain injury was established, and integrated tsRNA and messenger RNA (mRNA) transcriptome sequencing were used. The results revealed that 103 tsRNAs were differentially expressed in the mouse model of traumatic brain injury at 72 hours, of which 56 tsRNAs were upregulated and 47 tsRNAs were downregulated. Based on microRNA-like seed matching and Pearson correlation analysis, 57 differentially expressed tsRNA-mRNA interaction pairs were identified, including 29 tsRNAs and 26 mRNAs. Moreover, Gene Ontology annotation of target genes revealed that the significantly enriched terms were primarily associated with inflammation and synaptic function. Collectively, our findings suggest that tsRNAs may be associated with traumatic brain injury-induced secondary brain injury, and are thus a potential therapeutic target for traumatic brain injury. The study was approved by the Beijing Neurosurgical Institute Animal Care and Use Committee (approval No. 20190411) on April 11, 2019.

A cortical injury model in a non-human primate to assess execution of reach and grasp actions: implications for recovery after traumatic brain injury

BackgroundTechnological advances in developing experimentally controlled models of traumatic brain injury (TBI) are prevalent in rodent models and these models have proven invaluable in characterizing temporal changes in brain and behavior after trauma. To date no long-term studies in non-human primates (NHPs) have been published using an experimentally controlled impact device to follow behavioral performance over time. New methodWe have employed a controlled cortical impact (CCI) device to create a focal contusion to the hand area in primary motor cortex (M1) of three New World monkeys to characterize changes in reach and grasp function assessed for 3 months after the injury. ResultsThe CCI destroyed most of M1 hand representation reducing grey matter by 9.6 mm3, 12.9 mm3, and 15.5 mm3 and underlying corona radiata by 7.4 mm3, 6.9 mm3, and 5.6 mm3 respectively. Impaired motor function was confined to the hand contralateral to the injury. Gross hand-use was only mildly affected during the first few days of observation after injury while activity requiring skilled use of the hand was impaired over three months. Comparison with existing method(s)This study is unique in establishing a CCI model of TBI in an NHP resulting in persistent impairments in motor function evident in volitional use of the hand. ConclusionsEstablishing an NHP model of TBI is essential to extend current rodent models to the complex neural architecture of the primate brain. Moving forward this model can be used to investigate novel therapeutic interventions to improve or restore impaired motor function after trauma.

Multiscale Computational Model Reveals Nerve Response in a Mouse Model for Temporal Interference Brain Stimulation.

There has been a growing interest in the non-invasive stimulation of specific brain tissues, while reducing unintended stimulation in surrounding regions, for the medical treatment of brain disorders. Traditional methods for non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), can stimulate brain regions, but they also simultaneously stimulate the brain and non-brain regions that lie between the target and the stimulation site of the source. Temporal interference (TI) stimulation has been suggested to selectively stimulate brain regions by superposing two alternating currents with slightly different frequencies injected through electrodes attached to the scalp. Previous studies have reported promising results for TI applied to the motor area in mice, but the mechanisms are yet to be clarified. As computational techniques can help reveal different aspects of TI, in this study, we computationally investigated TI stimulation using a multiscale model that computes the generated interference current pattern effects in a neural cortical model of a mouse head. The results indicated that the threshold increased with the carrier frequency and that the beat frequency did not influence the threshold. It was also found that the intensity ratio between the alternating currents changed the location of the responding nerve, which is in agreement with previous experiments. Moreover, particular characteristics of the envelope were investigated to predict the stimulation region intuitively. It was found that regions with high modulation depth (| maximum| − | minimum| values of the envelope) and low minimum envelope (near zero) corresponded with the activation region obtained via neural computation.

Roles of Cytokines in the Temporal Changes of Microglial Membrane Currents and Neuronal Excitability and Synaptic Efficacy in ATP-Induced Cortical Injury Model.

Cytokines are important neuroinflammatory modulators in neurodegenerative brain disorders including traumatic brain injury (TBI) and stroke. However, their temporal effects on the physiological properties of microglia and neurons during the recovery period have been unclear. Here, using an ATP-induced cortical injury model, we characterized selective effects of ATP injection compared to needle-control. In the damaged region, the fluorescent intensity of CX3CR1-GFP (+) cells, as well as the cell density, was increased and the maturation of newborn BrdU (+) cells continued until 28 day-post-injection (dpi) of ATP. The excitability and synaptic E/I balance of neurons and the inward and outward membrane currents of microglia were increased at 3 dpi, when expressions of tumor necrosis factor (TNF)-α/interleukin (IL)-1β and IL-10/IL-4 were also enhanced. These changes of both cells at 3 dpi were mostly decayed at 7 dpi and were suppressed by any of IL-10, IL-4, suramin (P2 receptor inhibitor) and 4-AP (K+ channel blocker). Acute ATP application alone induced only small effects from both naïve neurons and microglial cells in brain slice. However, TNF-α alone effectively increased the excitability of naïve neurons, which was blocked by suramin or 4-AP. TNF-α and IL-1β increased and decreased membrane currents of naïve microglia, respectively. Our results suggest that ATP and TNF-α dominantly induce the physiological activities of 3 dpi neurons and microglia, and IL-10 effectively suppresses such changes of both activated cells in K+ channel- and P2 receptor-dependent manner, while IL-4 suppresses neurons preferentially.

NetPyNE Implementation and Scaling of the Potjans-Diesmann Cortical Microcircuit Model.

The Potjans-Diesmann cortical microcircuit model is a widely used model originally implemented in NEST. Here, we reimplemented the model using NetPyNE, a high-level Python interface to the NEURON simulator, and reproduced the findings of the original publication. We also implemented a method for scaling the network size that preserves first- and second-order statistics, building on existing work on network theory. Our new implementation enabled the use of more detailed neuron models with multicompartmental morphologies and multiple biophysically realistic ion channels. This opens the model to new research, including the study of dendritic processing, the influence of individual channel parameters, the relation to local field potentials, and other multiscale interactions. The scaling method we used provides flexibility to increase or decrease the network size as needed when running these CPU-intensive detailed simulations. Finally, NetPyNE facilitates modifying or extending the model using its declarative language; optimizing model parameters; running efficient, large-scale parallelized simulations; and analyzing the model through built-in methods, including local field potential calculation and information flow measures.

A comparison of six numerical methods for integrating a compartmental Hodgkin-Huxley type model

We compare six numerical integrators' performance when simulating a regular spiking cortical neuron model whose 74-compartments are equipped with eleven membrane ion channels and Calcium dynamics. Four methods are explicit and two are implicit; three are finite difference PDE methods, two are Runge-Kutta methods, and one an exponential time differencing method. Three methods are first-, two commonly considered second-, and one commonly considered fourth-order. Derivations show, and simulation data confirms, that Hodgkin-Huxley type cable equations render multiple order explicit RK methods as first-order methods. Illustrations compare accuracy, stability, variations of action potential phase and waveform statistics. Explicit methods were found unsuited for our model given their inability to control spiking waveform consistency up to 10μs less than the step size for onset of instability. While the backward-time central space method performed satisfactorily as a first order method for step sizes up to 80μs, performance of the Hines-Crank-Nicolson method, our only true second order method, was unmatched for step sizes of 1−100μs.

Single cell RNA sequencing detects persistent cell type- and methylmercury exposure paradigm-specific effects in a human cortical neurodevelopmental model

The developing human brain is uniquely vulnerable to methylmercury (MeHg) resulting in lasting effects especially in developing cortical structures. Here we assess by single-cell RNA sequencing (scRNAseq) persistent effects of developmental MeHg exposure in a differentiating cortical human-induced pluripotent stem cell (hiPSC) model which we exposed to in vivo relevant and non-cytotoxic MeHg (0.1 and 1.0 μM) concentrations. The cultures were exposed continuously for 6 days either once only during days 4–10, a stage representative of neural epithelial- and radial glia cells, or twice on days 4–10 and days 14–20, a somewhat later stage which includes intermediate precursors and early postmitotic neurons. After the completion of MeHg exposure the cultures were differentiated further until day 38 and then assessed for persistent MeHg-induced effects by scRNAseq. We report subtle, but significant changes in the population size of different cortical cell types/stages and cell cycle. We also observe MeHg-dependent differential gene expression and altered biological processes as determined by Gene Ontology analysis. Our data demonstrate that MeHg results in changes in gene expression in human developing cortical neurons that manifest well after cessation of exposure and that these changes are cell type-, developmental stage-, and exposure paradigm-specific.

HGG-22. EVALUATING THE REGULATION OF BLOOD-BRAIN BARRIER INTEGRITY IN DIPG MOUSE MODELS

Diffuse intrinsic pontine gliomas (DIPGs) are considered to maintain a fairly intact blood-brain barrier (BBB) based on patient imaging tumor histology. In characterizing recently developed DIPG and HGG mouse models, we identified differences in BBB function and increased Angiopoietin1 (Angpt1) in H3 K27M DIPG models. We hypothesize that H3 K27M mutations promote the maintenance of DIPG BBB integrity through upregulation of Angpt1. To determine DIPG and HGG BBB phenotypes we performed an intergrative analysis of vascular histology and endothelial transcriptomes Ongoing studies using electroporation based DIPG mouse models are being performed examine the regulation and function of Angpt1 in DIPG BBB integrity. We have initiated studies comparing H3 K27M DIPG mouse models to H3 WT and G34R cortical HGG mouse models, demonstrating that DIPG models show minimal changes in vascular phenotype, including vessel density, branching, and diameter compared to cortical HGG models. Comparing DIPG and HGG purified endothelial transcriptomes, HGG ECs displayed enrichments of inflammatory signals and proliferation gene sets, and increased expression of tip cell identity genes. We identified Angpt1 as selectively upregulated in H3 K27M mouse models and derived cell lines. Preliminary data suggests Angpt1 supports the maintenance of BBB integrity in DIPG models. BBB phenotype differences are present in DIPG and HGG mouse models. Uncovering mutation specific mechanisms that regulate BBB function in brain tumors will be critical to advance our understanding of brain tumor pathogenesis and treatment response.

Striatum and language processing: Where do we stand?

More than a century ago, Broca (1861), Wernicke (1874) and Lichteim (1885) laid the foundations for the first anatomo-functional model of language, secondarily enriched by Geschwind (1967), leading to the Broca-Wernicke-Lichteim-Geschwind model. This model included the frontal, parietal, and temporal cortices as well as a subcortical structure, which could be the striatum, whose nature and role have remained unclear. Although the emergence of language deficits in patients with striatal injury has challenged the cortical language models developed over the past 30 years, the integration of the striatum into language processing models remains rare. The main argument for not including the striatum in language processing is that the disorders observed in patients with striatal dysfunction may result from the striatal role in cognitive functions beyond language, and not from the impairment of language itself. Indeed, unraveling the role of the striatum and the frontal cortex, linked by the fronto-striatal pathway, is a challenge. Here, we first reviewed the studies that explored the link between striatal functions and the different levels of language (phonetics, phonology, morphology, syntax, and lexico-semantics). We then looked at the language models, which included the striatum, and found that none of them captured the diversity of experimental data in this area. Finally, we propose an integrative anatomo-functional model of language processing combining traditional language processing levels and some “executive” functions, known to improve the efficiency and fluidity of language: control, working memory, and attention. We argue that within this integrative model, the striatum is a central node of a verbal executive network that regulates, monitors, and controls the allocations of limited cognitive resources (verbal working memory and verbal attention), whatever the language level. This model combines data from neurology, psycholinguistics, and cognitive science.

Cellular connectomes as arbiters of local circuit models in the cerebral cortex

With the availability of cellular-resolution connectivity maps, connectomes, from the mammalian nervous system, it is in question how informative such massive connectomic data can be for the distinction of local circuit models in the mammalian cerebral cortex. Here, we investigated whether cellular-resolution connectomic data can in principle allow model discrimination for local circuit modules in layer 4 of mouse primary somatosensory cortex. We used approximate Bayesian model selection based on a set of simple connectome statistics to compute the posterior probability over proposed models given a to-be-measured connectome. We find that the distinction of the investigated local cortical models is faithfully possible based on purely structural connectomic data with an accuracy of more than 90%, and that such distinction is stable against substantial errors in the connectome measurement. Furthermore, mapping a fraction of only 10% of the local connectome is sufficient for connectome-based model distinction under realistic experimental constraints. Together, these results show for a concrete local circuit example that connectomic data allows model selection in the cerebral cortex and define the experimental strategy for obtaining such connectomic data.

Single intracerebroventricular progranulin injection adversely affects the blood-brain barrier in experimental traumatic brain injury.

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor with protective effects in animal models of ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury (TBI). Administration of recombinant (r) PGRN prevents exaggerated brain pathology after TBI in Grn-deficient mice, suggesting that local injection of recombinant progranulin (rPGRN) provides therapeutic benefit in the acute phase of TBI. To test this hypothesis, we subjected adult male C57Bl/6N mice to the controlled cortical impact model of TBI, administered a single dose of rPGRN intracerebroventricularly (ICV) shortly before the injury, and examined behavioral and biological effects up to 5days post injury (dpi). The anti-inflammatory bioactivity of rPGRN was confirmed by its capability to inhibit the inflammation-induced hypertrophy of murine primary microglia and astrocytes in vitro. In C57Bl/6N mice, however, ICV administration of rPGRN failed to attenuate behavioral deficits over the 5-day observation period. (Immuno)histological gene and protein expression analyses at 5dpi did not reveal a therapeutic benefit in terms of brain injury size, brain inflammation, glia activation, cell numbers in neurogenic niches, and neuronal damage. Instead, we observed a failure of TBI-induced mRNA upregulation of the tight junction protein occludin and increased extravasation of serum immunoglobulin G into the brain parenchyma at 5dpi. In conclusion, single ICV administration of rPGRN had not the expected protective effects in the acute phase of murine TBI, but appeared to cause an aggravation of blood-brain barrier disruption. The data raise questions about putative PGRN-boosting approaches in other types of brain injuries and disease.

Siamese networks and multi-scale local extrema scheme for multimodal brain medical image fusion

Multimodal medical image fusion is an auxiliary approach to help doctors diagnose diseases accurately leveraging information enhancement technology. Up to now, none of the fusion strategies is authoritative. Exploring methods with excellent performance is still the theme of image fusion works. The local extrema scheme (LES) and convolutional neural networks (CNNs) perform remarkable in medical image fusion tasks. However, the low decomposition efficiency of the LES and the limitations of CNNs should be addressed. Therefore, a novel framework proposed by combining the local extrema scheme and a Siamese network. This paper tried to solve the mentioned issues by improving the decomposition efficiency of LES and customizing the fusion strategy. Initially, the multi-scale local extrema scheme (MSLES) is introduced to decompose the source image into a series of detailed layers and a smoothed layer. Simultaneously, an adaptive dual-channel spiking cortical model (ADCSCM) based on the image information entropy (EN) is constructed to fuse the smoothed layer, and subsequently a feasible weight allocation strategy is designed by combining the Siamese network and EN to fuse the detailed layers. Ultimately, the informative image is reconstructed with the fused smoothed layer and detailed layers. By analyzing the extensive experimental results and metrics, the proposed framework achieves better performance against other state-of-art methods.