Search

BACKGROUND: A number of rare copy number variants (CNVs) have been linked to neurodevelopmental disorders. However, because CNVs encompass many genes, it is often difficult to identify the mechanisms that lead to developmental perturbations.METHODS: We used 15q13.3 microdeletion to propose and validate a novel strategy to predict the impact of CNV genes on brain development that could further guide functional studies. We analyzed single-cell transcriptomics datasets containing cortical interneurons to identify their developmental vulnerability to 15q13.3 microdeletion, which was validated in mouse models.RESULTS: We found that Klf13-but not other 15q13.3 genes-is expressed by precursors and neuroblasts in the medial and caudal ganglionic eminences during development, with a peak of expression at embryonic day (E)13.5 and E18.5, respectively. In contrast, in the adult mouse brain, Klf13 expression is negligible. Using Df(h15q13.3)/+ and Klf13+/- embryos, we observed a precursor subtype-specific impairment in proliferation in the medial ganglionic eminence and caudal ganglionic eminence at E13.5 and E17.5, respectively, corresponding to vulnerability predicted by Klf13 expression patterns. Finally, Klf13+/- mice showed a layer-specific decrease in parvalbumin and somatostatin cortical interneurons accompanied by changes in locomotor and anxiety-related behavior.CONCLUSIONS: We show that the impact of 15q13.3 microdeletion on precursor proliferation is grounded in a reduction in Klf13 expression. The lack of Klf13 in Df(h15q13.3)/+ cortex might be the major reason for perturbed density of cortical interneurons. Thus, the behavioral defects seen in 15q13.3 microdeletion could stem from a developmental perturbation owing to selective vulnerability of cortical interneurons during sensitive stages of their development.

Oxidative stress is a major risk factor for Alzheimer's disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. 8-oxo-2´-deoxyguanosine triphosphatase (MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MTH1 and/or OGG1 may suppress the pathogenesis of AD; however, their exact roles remain unclear. We evaluated the roles of MTH1 and OGG1 during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice (a preclinical AD model). Six-month-old female AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged; the alteration was less evident in 12-month-old mice. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex of six-month-old mice; the alteration was less evident in 12-month-old mice. Astrocytes and neurons were not influenced. We showed that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, and the effects are age-dependent. MTH1 and/or OGG1 deficiency reduced anxiety-related behavior in AppNL-G-F/NL-G-F mice with a significant acceleration of the 8-oxoG burden and microgliosis, especially in the cortex and amygdala.

Background Age of onset may be an important feature associated with distinct subtypes of obsessive-compulsive disorder (OCD). The amygdala joined neurocircuitry models of OCD for its role in mediating fear and regulating anxiety. The present study aims to identify the underlying pathophysiological specifics in OCD with different onset times by assessing amygdala subregional functional connectivity (FC) alterations in early-onset OCD (EO-OCD) and late-onset OCD (LO-OCD). Methods Resting-state functional magnetic resonance imaging data were acquired from 88 medication-free OCD patients (including 30 EO-OCD and 58 LO-OCD) and age- and sex-matched healthy controls (HC) for each patient group. Onset-by-diagnosis interactions were examined and comparisons between each OCD group and the corresponding HC group were performed regarding the FC of amygdala subregions including the basolateral amygdala (BLA), centromedial amygdala (CMA), superficial amygdala (SFA) and amygdalostriatal transition area (Astr). Results Significant onset-by-diagnosis interactions were found in FC between bilateral SFA, right CMA, left Astr and the cerebellum. EO-OCD patients showed abnormally increased BLA/SFA-cerebellum, BLA-precuneus and BLA/SFA-fusiform connectivity in addition to decreased BLA/SFA-orbitofrontal cortex connectivity. In contrast, LO-OCD patients exhibited increased CMA/Astr-precentral/postcentral gyrus and CMA-cuneus connectivity as well as decreased CMA/Astr-cerebellum and BLA-striatum connectivity. Limitations The exclusion of comorbidity may reduce the generalizability of our results. Conclusions These findings emphasized the different patterns of amygdala subregional connectivity alterations associated with EO-OCD and LO-OCD patients. These results provide unique insights into constructing evidence-based distinct OCD subtypes based on brain intrinsic connectivity and point to the need of specified management for EO-OCD and LO-OCD in clinical setting.

Aneuploidy is the leading genetic cause of miscarriage and infertility in women and occurs frequently in oocytes. Spindle formation and positioning are two critical events that must be regulated tightly to avoid erroneous chromosome segregation. Following nuclear envelope breakdown (NEBD), the spindle is assembled centrally before migrating towards the cortex to allow the first asymmetric division. The biological significance of the primary central positioning of the spindle is unknown. Because the spindle forms where NEBD occurs, whether positioned at the center or at the cortex of the cell, full-grown GV (prophase I) oocytes were collected from CF-1 mice (6-8 weeks old) and sorted according to the position of the GV into three groups: central, intermediate, and peripheral. Approximately 50% of the cells exhibited a central GV position, while 25% of cells showed a peripheral GV position. These proportions were similar to those obtained by histological evaluation of ovarian oocytes in 6-8 week mice, but not to those of mice aged less than 5 weeks, which tended to have a majority of peripherally positioned GVs. When peripheral GV oocytes were matured in vitro, GVs (88%) migrated towards the center and NEBD (and spindle assembly) occurred either at the center of the cell or during migration. The percentages of NEBD and polar body (PB) extrusion did not vary significantly among groups. Importantly, peripheral GV oocytes had a significant increase of abnormal K-MT attachments at metaphase I (Met I) and showed a significant increase of aneuploidy at metaphase II (Met II) when compared to central GV oocytes. Interestingly, peripheral GV oocytes that were able to achieve full GV relocation to the center were half as likely to experience aneuploidy when compared to peripheral GV oocytes unable to achieve relocation. These results indicate that preferential central spindle formation is an insurance mechanism to protect against incorrect K-MT attachments and aneuploidy.

Lodging is a major problem limiting maize yield worldwide. However, the mechanisms of lodging resistance remain incompletely understood for maize. Here, we evaluated 443 maize accessions for lodging resistance in the field. Five lodging-resistant accessions and five lodging-sensitive accessions were selected for further research. The leaf number, plant height, stem diameter, and rind penetrometer resistance were similar between lodging-resistant and -sensitive inbred lines. The average thickness of sclerenchymatous hypodermis layer was thicker and the vascular area was larger in the lodging-resistant lines compared with lodging-sensitive lines. Although total lignin content in stem tissue did not significantly differ between lodging-resistant and -sensitive lines, phloroglucinol staining revealed that the lignin content of the cell wall in the stem cortex and in the stem vascular tissue near the cortex was higher in the lodging-resistant lines than in the lodging-sensitive lines. Analysis of strand-specific RNA-seq transcriptome showed that a total of 793 genes were up-regulated and 713 genes were down-regulated in lodging-resistant lines relative to lodging-sensitive lines. The up-regulated genes in lodging-resistant lines were enriched in cell wall biogenesis. These results indicated that modification of cell wall biosynthesis would contribute to lodging resistance of maize.

The accurate definition of an epitranscriptome is endangered by artefacts resulting from RNA degradation after cell death, a ubiquitous yet little investigated process. By tracing RNA marker modifications through tissue preparation protocols, we identified a major blind spot from daily lab routine, that has massive impact on modification analysis in small RNAs. In particular, m6,6A and Am as co-varying rRNA marker modifications, appeared in small RNA fractions following rRNA degradation in vitro and in cellulo. Analysing mouse tissue at different time points post mortem, we tracked the progress of intracellular RNA degradation after cell death, and found it reflected in RNA modification patterns. Differences were dramatic between liver, where RNA degradation commenced immediately after death, and brain, yielding essentially undamaged RNA. RNA integrity correlated with low amounts of co-varying rRNA markers. Thus validated RNA preparations featured differentially modified tRNA populations whose information content allowed a distinction even among the related brain tissues cortex, cerebellum and hippocampus. Inversely, advanced cell death correlated with high rRNA marker content, and correspondingly little with the naïve state of living tissue. Therefore, unless RNA and tissue preparations are executed with utmost care, interpretation of modification patterns in tRNA and small RNA are prone to artefacts.

1AbstractComputational models which predict the neurophysiological response from experimental stimuli have played an important role in human neuroimaging. One type of computational model, the population receptive field (pRF), has been used to describe cortical responses at the millimeter scale using functional magnetic resonance imaging (fMRI) and electrocorticography (ECoG). However, pRF models are not widely used for non-invasive electromagnetic field measurements (EEG/MEG), because individual sensors pool responses originating from several centimeter of cortex, containing neural populations with widely varying spatial tuning. Here, we introduce a forward-modeling approach in which pRFs estimated from fMRI data are used to predict MEG sensor responses. Subjects viewed contrast-reversing bar stimuli sweeping across the visual field in separate fMRI and MEG sessions. Individual subject’s pRFs were modeled on the cortical surface at the millimeter scale using the fMRI data. We then predicted cortical time series and projected these predictions to MEG sensors using a biophysical MEG forward model, accounting for the pooling across cortex. We compared the predicted MEG responses to observed visually evoked steady-state responses measured in the MEG session. We found that pRF parameters estimated by fMRI could explain a substantial fraction of the variance in steady-state MEG sensor responses (up to 60% in individual sensors). Control analyses in which we artificially perturbed either pRF size or pRF position reduced MEG prediction accuracy, indicating that MEG data are sensitive to pRF properties derived from fMRI. Our model provides a quantitative approach to link fMRI and MEG measurements, thereby enabling advances in our understanding of spatiotemporal dynamics in human visual field maps.

Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.

Current models to explain how signals emanating from cutaneous mechanoreceptors generate representations of touch are based on comparisons of the tactile responses of mechanoreceptor subtypes and neurons in somatosensory cortex1–8. Here we used mouse genetic manipulations to investigate the contributions of peripheral mechanoreceptor subtypes to cortical responses to touch. Cortical neurons exhibited remarkably homogeneous and transient responses to skin indentation that resembled rapidly adapting (RA) low-threshold mechanoreceptor (LTMR) responses. Concurrent disruption of signals from both Aβ RA-LTMRs and Aβ slowly adapting (SA)-LTMRs eliminated cortical responses to light indentation forces. However, disruption of either LTMR subtype alone caused opposite shifts in cortical sensitivity but otherwise largely unaltered tactile responses, indicating that both subtypes contribute to normal cortical responses. Selective optogenetic activation of single action potentials in Aβ RA-LTMRs or Aβ SA-LTMRs drove low-latency responses in most mechanically sensitive cortical neurons. Similarly, most somatosensory thalamic neurons were also driven by activation of Aβ RA-LTMRs or Aβ SA-LTMRs. These findings support a model in which signals from physiologically distinct mechanoreceptor subtypes are extensively integrated and transformed within the subcortical somatosensory system to generate cortical representations of touch. Genetic manipulation of skin peripheral sensory neurons in mice shows that cortical neuron responses to touch reflect subcortical mixing of signals from both rapidly adapting and slowly adapting low-threshold mechanoreceptors.

Regulation of microglial activation and neuroinflammation are critical factors in the pathogenesis of ischemic brain injury. Interest in protease-activated receptor 2 (PAR2) as a pharmaceutical target for various diseases is creasing. However, it is unclear the expression and functions of PAR2 in hypoxia-ischemic (HI) brain injury. Mice with HI and cells with oxygen-glucose deprivation and reoxygenation (OGD/R) were studied. Immunoblot and qRT-PCR were used to study the differential gene expression in cultured microglia and neurons. Immunofluorescent staining was used to study the expression pattern of PAR2 in the HI brain and phagocytotic activity of microglia after OGD/R. In neonatal mice brain after HI, we found PAR2 expression was abundant in neurons, but barely in microglia from the contralateral side of cortex and hippocampus. Conversely, PAR2 expression was barely in neurons while significantly increased in activated microglia from the ipsilateral side of cortex and hippocampus. The activations of PAR2 were increased in both microglia and neuron in a cell model of OGD/R. PAR2 activation mediated the cross-talk between microglia and neurons including the following: microglial PAR2 mediated inflammatory responses that induced neuronal damage; neuronal PAR2 regulated chemokines that recruited activated microglia to damage area; microglia PAR2 controlled the phagocytosis of degenerating neurons. These data suggested differential expression and distinct roles of PAR2 in microglia and neurons after HI injury; thereby, interventions targeting PAR2 may provide insights into the inflammatory-related diseases.

The fate of neurons in the developing brain is largely determined by the combination of transcription factors they express. In particular, stem cells must follow different transcriptional cascades during differentiation in order to generate neurons with different neurotransmitter properties, such as glutamatergic and GABAergic neurons. In the mouse cerebral cortex, it has been shown that large Maf family proteins, MafA, MafB and c-Maf, regulate the development of specific types of GABAergic interneurons but are not expressed in glutamatergic neurons. In this study, we examined the expression of large Maf family proteins in the developing mouse olfactory bulb by immunohistochemistry and found that the cell populations expressing MafA and MafB are almost identical, and most of them express Tbr2. Since Tbr2 is expressed in glutamatergic neurons in the olfactory bulb, we further examined the expression of glutamatergic and GABAergic neuronal markers in MafA and MafB positive cells. The results showed that in the olfactory bulb, MafA and MafB are expressed exclusively in glutamatergic neurons, but not in GABAergic neurons. We also found that few cells express c-Maf in the olfactory bulb. These results indicate that, unlike the cerebral cortex, MafA and/or MafB may regulate the development of glutamatergic neurons in the developing olfactory bulb. This study advances our knowledge about the development of glutamatergic neurons in the olfactory bub, and also provides insight into the mechanism by which the cortex and olfactory bulb, although both generated from the telencephalon, generate projection and interneurons with different properties.

Background Previous studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation. Results Data showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What’s more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats. Conclusions These results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.

BackgroundFragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differentiation in human stem cells.ResultsWe show here that NMD is hyperactivated during the development of the cerebral cortex, hippocampus, and cerebellum in theFmr1-knockout (KO) mouse during embryonic and early postnatal periods. Our findings demonstrate that NMD regulates many neuronal mRNAs that are important for mouse brain development.ConclusionsWe reveal the abnormal regulation of these mRNAs in theFmr1-KO mouse, a model of FXS, and highlight the importance of early intervention.

Previous evidence suggests that α2-adrenoceptors (α2-AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α2-AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α2A-AR and α2C-AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α2-AR to Gα proteins induced by the agonist UK14304 was also tested. Additionally, Gα protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α2A-AR and α2C-AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α2A-AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α2C-AR. [35S]GTPγS SPA experiments showed a significant lower stimulation of Gαi2 and Gαi3 proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. Gαo protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of Gαi3 protein did not differ between groups, whereas Gαi2 levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. Gαo protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α2A-AR in the cortex of schizophrenia patients.

The distribution of essential nutrients such as potassium (K), phosphorous (P), calcium (Ca), sulfur (S) and chlorine (Cl) within root tissues is crucial aspect of plant growth but nothing is known regarding this subject in seedlings of dicotyledons such as peanut (Arachis hypogaea). We used scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS) and inductively coupled plasma optical emission spectrometry (ICP-OES) to analyze element distributions in developing root tissues. Distribution patterns and concentrations of endogenous K, P, S and exogenous Ca from seeds grown in water varied along the length of peanut radicle and were tissue specific. Semi-quantitative SEM/EDS data indicated 24 mM K in the cortex and 46 mM K in the stele at a distance of 5 mm from the root tip. The P concentration in the same region was 15 mM in cortex and 22 mM in stele. The concentration of K and P decreased in the more mature parts of the root. SEM–EDS element concentrations values were lower for K and higher for P when compared with the ICP-OES data of root segments. Peanut roots grown in 10 mM Ca(NO3)2 solution for hours showed tissue-specific Ca distribution at 25 mm from the root tip with the highest levels detected in portions of the cortex. The parent root cortex centrifugal to the tip of developing lateral root primordia had lower levels of calcium than could be detected by SEM/EDS.

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease threatening the health of the elderly, but the available therapeutic and preventive drugs remain suboptimal. Loganin, an iridoid glycoside extracted from Cornus officinalis, is reported to have anti-inflammatory and memory-enhancing properties. This study is aimed to explore the influence of loganin on cognitive function in 3xTg-AD mice and the underlying mechanism associated with its neuroprotection. According to the results of behavioral tests, we found that administration of loganin could significantly alleviate anxiety behavior and improve memory deficits of 3xTg-AD mice. Furthermore, immunohistochemical analysis displayed that there were decreased Aβ deposition in the hippocampus and cortex of 3xTg-AD mice treated with loganin compared with the control mice. Importantly, the Aβ-related pathological change was mainly involved in altering APP expression and processing. And loganin was also found to reduce the levels of phosphorylated tau (i.e. pTauS396 and pTauS262) in 3xTg-AD mice. By performing 2D-DIGE combined with MALDI-TOF-MS/MS, we revealed 28 differentially expressed proteins in the 3xTg-AD mice treated with loganin compared with the control mice. Notably, 10 proteins largely involved in energy metabolism, synaptic proteins, inflammatory response, and ATP binding were simultaneously detected in 3xTg-AD mice compared to WT mice. The abnormal changes of energy metabolism (PAGM1 and ENO1), synaptic proteins (SYN2 and Cplx2), inflammatory response (1433Z) were verified by western blot. Overall, our study suggested that loganin could be used as a feasible candidate drug to ameliorate molecular deficits, pathologies and cognitive impairment for prevention and treatment of AD.

Summary The specification of inhibitory neurons has been described for the mouse and human brain, and many studies have shown that pluripotent stem cells (PSCs) can be used to create interneurons in vitro. It is unclear whether in vitro methods to produce human interneurons generate all the subtypes found in brain, and how similar in vitro and in vivo interneurons are. We applied single-nuclei and single-cell transcriptomics to model interneuron development from human cortex and interneurons derived from PSCs. We provide a direct comparison of various in vitro interneuron derivation methods to determine the homogeneity achieved. We find that PSC-derived interneurons capture stages of development prior to mid-gestation, and represent a minority of potential subtypes found in brain. Comparison with those found in fetal or adult brain highlighted decreased expression of synapse-related genes. These analyses highlight the potential to tailor the method of generation to drive formation of particular subtypes., Highlights • Comparison of interneurons derived from human pluripotent cells by various methods • Single-cell analyses define heterogeneity of in vitro-derived interneurons • Direct comparison of in vitro- and in vivo-derived interneurons • Identification of transcriptional modules that developmentally define interneurons, Plath, Lowry and colleagues profile interneurons generated from human pluripotent stem cells by various methods to understand the heterogeneity and cellular state of interneuron cultures in vitro. Using single-cell analyses, the authors define the homogeneity and maturity achieved with each in vitro method. By directly comparing these interneurons with those born in the human brain, the authors highlight distinctions particularly in synaptic genes and transcription factor modules that distinguish in vitro- and in vivo-derived neurons.

Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington’s disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.

There is solid epidemiological evidence that arsenic exposure leads to cognitive impairment, while experimental work supports the hypothesis that it also contributes to neurodegeneration. Energy deficit, oxidative stress, demyelination, and defective neurotransmission are demonstrated arsenic effects, but it remains unclear whether synaptic structure is also affected. Employing both a triple-transgenic Alzheimer’s disease model and Wistar rats, the cortical microstructure and synapses were analyzed under chronic arsenic exposure. Male animals were studied at 2 and 4 months of age, after exposure to 3 ppm sodium arsenite in drinking water during gestation, lactation, and postnatal development. Through nuclear magnetic resonance, diffusion-weighted images were acquired and anisotropy (integrity; FA) and apparent diffusion coefficient (dispersion degree; ADC) metrics were derived. Postsynaptic density protein and synaptophysin were analyzed by means of immunoblot and immunohistochemistry, while dendritic spine density and morphology of cortical pyramidal neurons were quantified after Golgi staining. A structural reorganization of the cortex was evidenced through high-ADC and low-FA values in the exposed group. Similar changes in synaptic protein levels in the 2 models suggest a decreased synaptic connectivity at 4 months of age. An abnormal dendritic arborization was observed at 4 months of age, after increased spine density at 2 months. These findings demonstrate alterations of cortical synaptic connectivity and microstructure associated to arsenic exposure appearing in young rodents and adults, and these subtle and non-adaptive plastic changes in dendritic spines and in synaptic markers may further progress to the degeneration observed at older ages.

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We also assessed regional neurochemical and functional statuses related to spontaneous neural firing by measuring MRS signals and neuronal activities in a mouse model of Dravet syndrome under a resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that the MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

The pathological form of a-synuclein (a-syn) is transmitted through neural circuits in the brains of Parkinson disease (PD) patients and amplifies misfolded a-syn, further forming intracellular deposits. However, the details of a-syn pre-formed fibrils (PFFs) transmission in vivo have not been fully elucidated. By inoculating Quantum dots (QD)-labeled a-syn PFFs (QD-a-syn PFFs) into the unilateral striatum, we detected QD-a-syn PFFs in brain homogenates obtained from the ipsilateral and contralateral sides of the inoculated site and further obtained QD-a-syn PFFs enriched-particles with fluorescence-activated organelle sorting. Proteomic analysis suggested that QD-a-syn PFFs-enriched particles in the contralateral side were associated with component proteins of synapse. In contrast, QD-a-syn PFFs-enriched particles in the ipsilateral side were associated with proteins belonging to ER components. Immunostaining of brain sections confirmed that QD-a-syn PFFs in the contralateral side were co-localized with synaptic vesicle marker proteins in the cortex and striatum. Additionally, QD-a-syn PFFs in the ipsilateral side were more co-localized with ER marker proteins compared to the contralateral side. These results correspond to proteomic analysis. This study provides potential candidates for the subcellular localization of a-syn PFFs in vivo during the dissemination phase of seeds. These subcellular compartments could be involved in the transmission of seeds.

Neonatal hypoxic-ischaemic (HI) injury is a serious complication of neonatal asphyxia and the leading cause of neonatal acute death and chronic neurological injury, and the effective therapeutic method is lacking to improve patients' outcomes. We reported in this study that panax notoginseng saponin (PNS) may provide a treatment option for HI. HI model was established using neonatal Sprague-Dawley rats and then intraperitoneally injected with different dosage of PNS, once a day for 7 days. Histological staining and behavioural evaluations were performed to elucidate the pathological changes and neurobehavioural variation after PNS treatment. We found PNS administration significantly reduced the infarct volume of brain tissues and improved the autonomous activities of neonatal rats, especially with higher dosage. PNS treatment at 40 mg/kg reduced neuronal damage, suppressed neuronal apoptosis and depressed astroglial reactive response. Moreover, the long-term cognitive and motor functions were also improved after PNS treatment at 40 mg/kg. Importantly, PNS treatment elevated the levels of BDNF and TrkB but decreased the expression of p75NTR both in the cortex and hippocampus of HI rats. The therapeutic efficacy of PNS might be correlated with PNS-activated BDNF/TrkB signalling and inactivation of p75NTR expression, providing a novel potential therapy for alleviating HI injury.

Traumatic brain injury (TBI) is one of the leading causes of disability and paralysis around the world. Secondary injury, characterized by progressive neuronal loss and astrogliosis, plays important roles in the post-TBI cognitive impairment and mood disorder. Unfortunately, there still lacks effective treatments, particularly surgery interferences for it. Recent findings of intercellular mitochondria transfer implies a potential therapeutic value of mitochondria transplantation for TBI, which has not been tested yet. In the present study, we demonstrated a quick dysfunction of mitochondria, up-regulation of Tom20 in the injured cortex and subsequent cognitive and mood impairment. Our data demonstrated that mitochondria derived from allogeneic liver or autogeneic muscle stimulated similar microglial activation in brain parenchyma. In vitro experiments showed that exogenous mitochondria could be easily internalized by neurons, astrocytes, and microglia, except for oligodendrocytes. Mitochondria transplantation effectively rescued neuronal apoptosis, restored the expression of Tom20 and the phosphorylation of JNK. Further analysis revealed that mitochondria transplantation in injured cortex induced a significant up-regulation of BDNF in reactive astrocytes, improved animals' spatial memory and alleviated anxiety. In together, our data indicate that mitochondria transplantation may has the potential of clinical translation for TBI treatment, in combination with surgery.

The neurophysiological mechanisms underlying the behavioural improvements usually associated with an external (EF) compared with an internal focus of attention (IF) remain poorly investigated. Surround inhibition in the primary cortex has been shown to be more pronounced with an EF, indicating a more spatial restriction of the motor command. However, the influence of different foci on the temporal aspect of the motor command, such as the modulation of fast versus slow(er) motor pathways, remains unknown and was therefore investigated in this study. Fourteen participants were asked to press on a pedal with the right foot to match its position with a target line displayed on a screen. The deviation of the pedal from the target line was used as a behavioural parameter and compared between both foci (EF vs IF). Additionally, conditioned H-reflexes were evoked during the motor task to assess the excitability of fast (direct) and slower (more indirect) motor pathways when adopting an EF or IF. With an EF compared to an IF, the motor performance was enhanced (P = .001; + 24%) and the activation of slow(er) motor pathways was reduced (P

Alzheimer’s disease (AD) is defined by the presence of abundant amyloid-β (Aβ) and tau neuropathology. While this neuropathology is necessary for AD diagnosis, it is not sufficient for causing cognitive impairment. Up to one third of community dwelling older adults harbor intermediate to high levels of AD neuropathology at death yet demonstrate no significant cognitive impairment. Conversely, there are individuals who exhibit dementia with no gross explanatory neuropathology. In prior studies, synapse loss correlated with cognitive impairment. To understand how synaptic composition changes in relation to neuropathology and cognition, multiplexed liquid chromatography mass-spectrometry was used to quantify enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting levels of AD pathology and cognitive performance. 123 unique proteins were significantly associated with diagnostic category. Functional analysis showed enrichment of serotonin release and oxidative phosphorylation categories in normal (cognitively unimpaired, low neuropathology) and “resilient” (unimpaired despite AD pathology) individuals. In contrast, frail individuals, (low pathology, impaired cognition) showed a metabolic shift towards glycolysis and increased presence of proteasome subunits.