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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Effect of fosfomycin, Cynara scolymus extract, deoxynivalenol and their combinations on intestinal health of weaned piglets

Intestinal health of weaning piglets was studied after oral treatments with fosfomycin (FOS), Cynara scolymus extract (CSE), deoxynivalenol (DON) and their combinations. Piglets were divided in groups and received different treatments during 15 days, namely DON (1mg/kg of feed), FOS administered into the drinking water (30 mg/kg b.w.), CSE (300 g/ton of feed) and all possible combinations including a control group that received clean balanced diet. At day 15, three piglets from each group were euthanized and gastrointestinal tract samples were immediately taken to evaluate pH, bacteriology (enterobacteria and lactic acid bacteria), volatile fatty acids concentration (VFAs), disaccharidases activity (lactase, sucrase and maltase), histology (intestinal absorptive area [IAA] and goblet cells count) and adherence of bacteria to intestinal mucus. Animals receiving FOS and CSE treatments exhibited evident beneficial intestinal effects compared to animals receiving diets free from these compounds. This was revealed by a lower enterobacteria population together with a lower E/L, an enhanced production of butyric acid, an increased enzymatic activity (particularly maltase), and a greater IAA and goblet cells count along with an increase in pathogenic bacteria adherence to intestinal mucus. Interactions between both treatments resulted in similar beneficial effects as their individual administration. On the contrary, DON produced detrimental effects on intestinal health as a decrease was observed on volatile fatty acids production, enzymatic activity and goblet cells count in animals receiving diets containing sub- toxic concentrations of this mycotoxin. The knowledge of the intestinal effects of these compounds contributes to understand the physiological and pathological gut changes and their potential productive consequences.

systems biology↗

bioRxiv2018

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

AbstractHypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. An optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm allowed us to perform a systematic study for a large set of HCM mutations. We define different classes of mutations depending on their effects on lever arm compliance, sequestered state stability and motor functions. This work reconciles previous models and explains how distinct HCM mutations can have disparate effects on the motor mechano-chemical parameters and yet lead to the same disease. The framework presented here can guide future investigations aiming at finding HCM treatments.

biophysics↗

bioRxiv2018

Tau monomer encodes strains

Tauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. Aggregates from a single strain reproduce only that strain upon re-inoculation into cells or mice. DS9 and DS10 cell lines propagate distinct synthetic strains. Surprisingly, DS9 monomer inoculated into naive cells encoded an identical \"sub-strain,\" whereas DS10 monomer encoded multiple sub-strains. Sub-strains produced distinct pathology upon inoculation into a tauopathy mouse model (PS19). Brain-derived tau monomer from an Alzheimers brain encoded a single strain. Monomer from a corticobasal degeneration brain encoded three sub-strains in which monomer from each encoded all three upon re-inoculation into cells. Tau monomer thus adopts multiple, stable seed-competent conformations, each of which encodes a limited number of strains. This provides insights into the origins of distinct tauopathies.

biochemistry↗

bioRxiv2018

Type 1 diabetes mellitus-associated genetic variants contribute to overlapping immune regulatory networks

Type 1 diabetes (T1D) is a chronic metabolic disorder characterised by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk loci across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue-and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 298 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, CLEC2B, TYK2, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signalling, and programmed cell death protein-1 (PD-1). These pathways have been implicated in the pancreatic beta-cell inflammation and destruction as observed in T1D. Our results demonstrate that T1D-associated variants contribute to adaptive immune signalling, and immune-cell proliferation and activation through tissue and cell-type specific regulatory networks.\n\nAuthor SummaryAlthough genome-wide association studies have identified risk regions across the human genome that predispose individuals to the development of type 1 diabetes (T1D), the mechanisms through which these regions contribute to disease is unclear. Here, we used population-based genetic data from genome-wide association studies (GWAS) to understand how the three-dimensional (3D) organization of the DNA contributes to the differential expression of genes involved in immune system dysregulation as observed in T1D. We identified interconnected regulatory networks that affect immune pathways (adaptive immune signalling and immune-cell proliferation and activation) in a tissue and cell-type specific manner. Some of these pathways are implicated in the pancreatic beta-cell destruction. However, we observed other regulatory changes in tissues that are not typically considered to be central to the pathology of T1D, which represents a novel insight into the disease. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic and therapeutic interventions in T1D.

genetics↗

bioRxiv2018

Glutathione shapes glutamatergic transmission

Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate, and could influence synaptic excitability. We find that drugs which inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory post synaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter.\n\nSignificanceGlutathione is the principal antioxidant and redox regulator in cells. In addition to its essential roles in redox homeostasis it functions as cofactors for a multitude of enzymes. We show here that glutathione is a reservoir for synaptic glutamate, the excitatory neurotransmitter in the central nervous system. Deficits in glutathione have been linked to multiple neurodegenerative and neuropsychiatric disorders. Accordingly, agents that restore glutathione-glutamate homeostasis may afford therapeutic benefit.

neuroscience↗

bioRxiv2018

Interleukin-17A Secreted from the Lung-infiltrating T Helper 17 Cells Renders Protective Immunity to Pulmonary Cryptococcus neoformans Infection

IL-17A has emerged as a key player in the pathologies of inflammation, autoimmune disease, and immunity to microbes since its discovery two decades ago. In this study, we aim to elucidate the activity of IL-17A in the protection against Cryptococcus neoformans, an opportunistic fungus that causes fatal meningoencephalitis among AIDS patients. For this purpose, we examined if C. neoformans infection triggers IL-17A secretion in the in vitro setting using RAW264.7 murine macrophage cells, and in vivo using wildtype C57BL/6 mice. In addition, an enhanced green fluorescence protein (eGFP) reporter and a knockout (KO) mouse models were used to track the source of IL-17A secretion and explore the protective function of IL-17A, respectively. Our findings showed that both in vivo and in vitro models of C. neoformans infection demonstrated induction of abundant IL-17A secretion. By examining the lung bronchoalveolar lavage fluid (BALF), mediastinal lymph node (mLN) and spleen of the IL-17A- EGFP reporter mice, we showed that intranasal inoculation with C. neoformans promoted leukocytes lung infiltration. A large proportion (~50%) of the infiltrated CD4+ helper T cell population secreted EGFP, indicating vigorous TH17 activity in the C. neoformans-infected lung. The infection study in IL-17A-KO mice, on the other hand, revealed that absence of IL-17A marginally boosted fungal burden in the lung and accelerated the mouse death. Therefore, our data suggest that IL-17A, released predominantly from TH17 cells in vivo, is essential in providing a protective immunity against C. neoformans infection.

immunology↗

bioRxiv2018

Tendon slack length is the primary determinant of plantarflexor muscle-tendon function in computational simulations of gait

1Background: Locomotion is partly dictated by plantarflexor function and structure. Computational simulations are powerful tools capable of testing the isolated effects of muscle-tendon structure on gait function. Research Question: The purpose of this study was to characterize the sensitivity of plantarflexor muscle function based on muscle-tendon unit (MTU) parameters. We hypothesized that plantarflexor metabolics and shortening dynamics would be sensitive to MTU parameters. Methods: Stance phase of gait was simulated using a musculoskeletal model and computed muscle control algorithm. Optimal muscle fiber length, tendon slack length, and tendon stiffness parameters were systematically changed to test the effects on plantarflexor metabolics and shortening dynamics. Results and Significance: Plantarflexor metabolic demands were 8 and 28 times more sensitive to muscle fiber and tendon slack lengths, respectively, compared to the effect of tendon stiffness. Shortened tendon slack lengths induced a large passive plantarflexion moment during early stance, which required non-physiologic dorsiflexor contractions. Conversely, longer muscle fiber and tendon slack lengths increased the shortening demands of the plantarflexors to account for the added length of the MTU. These findings highlight the importance of carefully selecting MTU parameters when modeling gait with musculoskeletal models, especially in pathologic or high-performance athlete populations.

bioengineering↗

bioRxiv2018

Synchrony surfacing: epicortical recording of correlated action potentials

Synchronous spiking of multiple neurons is a key phenomenon in normal brain function and pathologies. Recently, approaches to record spikes from the intact cortical surface using small high-density arrays of microelectrodes have been reported. It remained unaddressed how epicortical spiking relates to intracortical unit activity. We introduce a mesoscale approach using an array of 64 electrodes with intermediate diameter (250 {micro}m) and combined large-coverage epicortical recordings in ferrets with intracortical recordings via laminar probes. Empirical data and modeling strongly suggest that our epicortical electrodes selectively captured synchronized spiking of neurons in the subjacent cortex. As a result, responses to sensory stimulation were more robust and less noisy as compared to intracortical activity, and receptive field properties were well preserved in epicortical recordings. This should promote insights into assembly-coding beyond the informative value of subdural EEG or single-unit spiking, and be advantageous to real-time applications in brain-machine interfacing.\n\nSignificance statementElectrocorticography allows chronic, low-noise recordings from the intact cortical surface - a prerequisite for investigations into brain network dynamics and brain-machine interfaces. Novel electrodes can capture spiking activity at the surface, which should boost precision in the spatial - and time domain, compared to conventional EEG-like measurements. To clarify how surface spiking relates to intracortically fired action potentials, we recorded both types of signal simultaneously from sensory cortices in anesthetized ferrets. Results suggest that mesoscale (250 {micro}m) surface electrodes can selectively capture synchronized spiking from nearby cortical columns, which reduces contamination by non-representative, jittering spikes. Given the high relevance of neural synchrony for sensorimotor and cognitive processing, the novel methodology may improve signal decoding in brain-machine interface approaches.\n\nAuthor contributionsE.G.L., T.B. and A.K.E. conceptualized the research; E.G.L. and F.P. performed experiments; T.B. and E.G.L. wrote Matlab routines for data analysis; T.B. and E.G.L. analyzed the data; T.S. provided technical resources; T.B., E.G.L. and A.K.E. wrote the manuscript; G.E. administrated the project; A.K.E. acquired funding.

neuroscience↗

bioRxiv2018

Evidence for Alternative Complement Cascade Activation in Primary CNS Vasculitis

The central nervous system (CNS) has a dedicated network of blood vessels to support the physiological activity of the brain, spinal cord and meninges. Consequently, inflammation of CNS vasculature can have devastating effects on neurological function. A lack of understanding regarding the molecular pathology of CNS vasculitis impedes the development of better diagnostics and effective therapies. Here, we analyze the proteome of cerebrospinal fluid from patients with biopsy-confirmed Primary Angiitis of the Central Nervous System (PACNS) relative to non-inflammatory control patients and patients with Reversible Cerebral Vasoconstrictive Syndrome (RCVS), a syndrome that clinically mimics PACNS in several aspects. In PACNS, we find significant elevation of apolipoproteins, immunoglobulins and complement cascade components. Notably, we find a bias towards activation of the alternative complement pathway with elevated levels of the terminal cascade component, complement C5. Given the recent treatment successes of Anti-Neutrophil Cytoplasmic Antibody (ANCA) vasculitis with the C5 receptor inhibitor, CCX168 (Avacopan), our results suggest that complement C5 inhibitors may also prove useful as therapeutic interventions for PACNS.

immunology↗

bioRxiv2018

Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

The nuclear receptor NR5A1 (also known as Ad4BP, or SF1) is essential for the initial steps of mammalian gonadal development. The Nr5a1 gene is equally expressed in XX and XY gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We recently reported a case of 46, XX disorder of sex development (DSD) in which ectopically expressed NR5A1 in XX gonads led to an ovo-testicular phenotype, suggesting that excess NR5A1 can direct the development of immature XX gonads towards testicular formation. However, a direct causal relationship has not been demonstrated in an animal model. Here, using a Wt1-BAC (bacterial artificial chromosome) transgene system, we generated two lines of mice overexpressing Nr5a1 in the fetal gonads at different levels. One of these lines (Tg-S), highly expressing Nr5a1, revealed that enforced Nr5a1 expression alone is insufficient to switch the fate of the 46,XX gonads toward testicular formation in mice. In the other line (Tg-A) expressing Nr5a1 at lower level, ovarian development was compromised, with multi-oocyte follicles, reduced number of matured follicles, and impaired expression of Wnt4, resulting in late onset infertility at 20 weeks after birth. The phenotype was similar to that of genetically modified mice with impaired Notch signaling. Indeed, the expression level of Notch2 and 3 was significantly reduced in Tg-A mice, and the ovarian phenotype in Tg-A mice was almost completely rescued by in utero treatment with a Notch2 agonist HMN2-29. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine tuning of Notch signaling levels.\n\nAUTHOR SUMMARYSexual development is a process of differentiation from undifferentiated bipotential gonads, and insight into sexual differentiation will bring important new knowledge to our understanding of organogenesis. The nuclear receptor NR5A1 which is essential for mammalian gonadal development, is equally expressed in both gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We have recently demonstrated that this down-regulation is mediated by ovarian transcription factor, Forkhead box L2 (FOXL2). This finding raised two key questions, whether Nr5a1 can function as a male sex-determining factor, and whether the repression is essential for appropriate ovarian development. By generating two lines Tg mice in XX gonads with different enforced expression levels of Nr5a1, our present study revealed that alterations in Nr5a1 dosage, either reduced or excessive, result in pathological effects in ovarian development and female fertility, indicating that the precise control of Nr5a1 at the transcriptional level is essential for optimal ovarian development. We envisage that the improved understanding of how this pathway regulates ovarian development and female fertility would aid the development of artificial somatic ovarian cells, which in turn may provide a valuable treatment option in reproductive medicine.\n\nABBREVIATIONS

developmental biology↗

bioRxiv2018

A genetically-encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice

Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here we report the development of novel genetically-encoded GPCR-Activation-Based-DA (GRABDA) sensors that enable these measurements. In response to extracellular DA rises, GRABDA sensors exhibit large fluorescence increases ({Delta}F/F0[~]90%) with sub-second kinetics, nanomolar to sub-micromolar affinities, and excellent molecular specificity. Importantly, GRABDA sensors can resolve a single-electrical-stimulus evoked DA release in mouse brain slices, and detect endogenous DA release in the intact brains of flies, fish, and mice. In freely-behaving mice, GRABDA sensors readily report optogenetically-elicited nigrostriatal DA release and depict dynamic mesoaccumbens DA changes during Pavlovian conditioning or during sexual behaviors. Thus, GRABDA sensors enable spatiotemporal precise measurements of DA dynamics in a variety of model organisms while exhibiting complex behaviors.

neuroscience↗

bioRxiv2018

THE ROLE OF DENDRITIC BRAIN-DERIVED NEUROTROPHIC FACTOR TRANSCRIPTS ON ALTERED INHIBITORY CIRCUITRY IN DEPRESSION

BackgroundA parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory {gamma}-amino-butyric acid (GABA) interneurons which target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD), and rodent genetic studies suggests they are linked and both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive.\n\nMethodsWith qPCR, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex (PFC) of MDD patients and matched controls (n=19/group) and of C57BL/6J mice exposed to chronic stress or control conditions (n=12/group). We next suppressed BDNF transcripts with long 3 untranslated region (L-3-UTR) using small hairpin RNA (shRNA) and investigated changes in cell morphology, gene expression and behavior.\n\nResultsL-3-UTR containing BDNF mRNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced and highly correlated with SST expression in the PFC of MDD subjects. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3-UTR knockdown is sufficient to induce (i) dendritic shrinkage in cortical neurons, (ii) cell-specific MDD-like gene changes (including Sst downregulation), and (iii) depressive-/anxiety-like behaviors. The translational validity of the Bdnf L-3-UTR shRNA-treated mice was confirmed by significant cross-species correlation of changes in MDD-associated gene expression.\n\nConclusionThese findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition and mood regulation.

neuroscience↗

bioRxiv2018

Limited One-time Sampling Irregularity Age Map (LOTS-IAM): Automatic Unsupervised Detection of Brain White Matter Abnormalities in Structural Magnetic Resonance Images

We present a complete study of limited one-time sampling irregularity map (LOTS-IM), a fully automatic unsupervised approach to extract brain tissue irregularities in magnetic resonance images (MRI), including its application and evaluation for quantitative assessment of white matter hyperintensities (WMH) of presumed vascular origin and assessing multiple sclerosis (MS) lesion progression. LOTS-IM is unique compared to similar other methods because it yields irregularity map (IM) which represents WMH as irregularity values, not probability values, and retains the original MRIs texture information. We tested and compared the usage of IM for WMH segmentation on T2-FLAIR MRI with various methods, including the well established unsupervised WMH segmentation Lesion Growth Algorithm from the public toolbox Lesion Segmentation Toolbox (LST-LGA), conventional supervised machine learning schemes and state-of-the-art supervised deep neural networks. In our experiments, LOTS-IM outperformed unsupervised method LST-LGA, both in performance and processing speed, thanks to the limited one-time sampling scheme and its implementation on GPU. Our method also outperformed supervised conventional machine learning algorithms (i.e., support vector machine (SVM) and random forest (RF)) and deep neural networks algorithms (i.e., deep Boltzmann machine (DBM) and convolutional encoder network (CEN)), while yielding comparable results to the convolutional neural network schemes that rank top of the algorithms developed up to date for this purpose (i.e., UResNet and UNet). The high sensitivity of IM on depicting signal change deems suitable for assessing MS progression, although care must be taken with signal changes not reflective of a true pathology.

neuroscience↗

bioRxiv2018

ESCRT and autophagy cooperate to repair ESX-1-dependent damage to the Mycobacterium-containing vacuole

Phagocytes capture invader microbes within the bactericidal phagosome. Some pathogens subvert killing by damaging and escaping from this compartment. To prevent and fight bacterial escape, cells contain and repair the membrane damage, or finally eliminate the cytosolic escapees. All eukaryotic cells engage highly conserved mechanisms to ensure integrity of membranes in a multitude of physiological and pathological situations, including the Endosomal Sorting Complex Required for Transport (ESCRT) and autophagy machineries. In Dictyostelium discoideum, recruitment of the ESCRT-III protein Snf7/Chmp4/Vps32 and the ATPase Vps4 to sites of membrane repair relies on the ESCRT-I component Tsg101 and occurs in absence of Ca2+. The ESX-1 dependent membrane perforations produced by the pathogen Mycobacterium marinum separately engage both ESCRT and autophagy. In absence of Tsg101, M. marinum escapes earlier to the cytosol, where it is restricted by xenophagy. We propose that ESCRT has an evolutionary conserved function in containing intracellular pathogens in intact compartments.

microbiology↗

bioRxiv2018

Stress-induced alterations of norepinephrine release in the bed nucleus of the stria terminalis of mice

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated noradrenergic release across multiple stimulation parameters, and reduced sensitivity to the 2-adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/335653_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@75ef4aorg.highwire.dtl.DTLVardef@b0fd27org.highwire.dtl.DTLVardef@1bc3afborg.highwire.dtl.DTLVardef@c469f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2018

Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain

Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (TRAP) to comprehensively characterize up-and down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.\n\nOne Sentence SummaryCell-specific sequencing of translating mRNAs elucidates signaling pathology that can be targeted to reverse neuropathic pain

neuroscience↗

bioRxiv2018

Disruption of cortical dopaminergic modulation delays licking initiation

Dysfunction of motor cortices is thought to contribute to motor disorders such as Parkinsons disease (PD). However, little is known on the link between cortical dopaminergic loss, abnormalities in motor cortex neural activity and motor deficits. We address the role of dopamine in modulating motor cortical activity by focusing on the anterior lateral motor cortex (ALM) of mice performing a cued-licking task. We first demonstrate licking deficits and concurrent alterations of spiking activity in ALM of mice with unilateral depletion of dopaminergic neurons (i.e., mice injected with 6-OHDA into the medial forebrain bundle). Hemi-lesioned mice displayed delayed licking initiation, shorter duration of licking bouts, and lateral deviation of tongue protrusions. In parallel with these motor deficits, we observed a reduction in the prevalence of cue responsive neurons and altered preparatory activity. Acute and local blockade of D1 receptors in ALM recapitulated some of the key behavioral and neural deficits observed in hemi-lesioned mice. Altogether, our data show a direct relationship between cortical D1 receptor modulation, cue-evoked and preparatory activity in ALM, and licking initiation.\n\nSIGNIFICANCE STATEMENTThe link between dopaminergic signaling, motor cortical activity and motor deficits is not fully understood. This manuscript describes alterations in neural activity of the anterior lateral motor cortex (ALM) that correlate with licking deficits in mice with unilateral dopamine depletion or with intra-ALM infusion of dopamine antagonist. The findings emphasize the importance of cortical dopaminergic modulation in motor initiation. These results will appeal not only to researchers interested in cortical control of licking, but also to a broader audience interested in motor control and dopaminergic modulation in physiological and pathological conditions. Specifically, our data suggest that dopamine deficiency in motor cortex could play a role in the pathogenesis of the motor symptoms of Parkinsons disease.

neuroscience↗

bioRxiv2018

MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

The genetically heterogeneous Spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically-approved Src inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.\n\nSignificance StatementThe Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system function, and may contribute to neurodegeneration. Spinocerebellar ataxias (SCAs) are neurodegenerative diseases where Purkinje neurons fire irregularly and degenerate leading to motor problems. We show that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia gene that links multiple SCAs. MTSS1 loss results in increased SFK activity, degenerating Purkinje neurons with low basal firing rates, and cell death. Surprisingly, mouse models for three different SCAs show elevated SFK activity, with SCA1 and SCA2 models displaying dramatically reduced MTSS1 protein levels. Treatment of each SCA model with SFK inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common link among disparate neurodegenerative diseases.

neuroscience↗