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Neuroscience
Fast nonconvex deconvolution of calcium imaging data.
Feb 12, 2019   Biostatistics (Oxford, England)
Jewell SW, Hocking TD, Fearnhead P, Witten DM
Fast nonconvex deconvolution of calcium imaging data.
Feb 12, 2019
Biostatistics (Oxford, England)
Calcium imaging data promises to transform the field of neuroscience by making it possible to record from large populations of neurons simultaneously. However, determining the exact moment in time at which a neuron spikes, from a calcium imaging data set, amounts to a non-trivial deconvolution problem which is of critical importance for downstream analyses. While a number of formulations have been proposed for this task in the recent literature, in this article, we focus on a formulation recently proposed in Jewell and Witten (2018. Exact spike train inference via $\ell_{0} $ optimization. The Annals of Applied Statistics12(4), 2457-2482) that can accurately estimate not just the spike rate, but also the specific times at which the neuron spikes. We develop a much faster algorithm that can be used to deconvolve a fluorescence trace of 100 000 timesteps in less than a second. Furthermore, we present a modification to this algorithm that precludes the possibility of a "negative spike". We demonstrate the performance of this algorithm for spike deconvolution on calcium imaging datasets that were recently released as part of the $\texttt{spikefinder}$ challenge (http://spikefinder.codeneuro.org/). The algorithm presented in this article was used in the Allen Institute for Brain Science's "platform paper" to decode neural activity from the Allen Brain Observatory; this is the main scientific paper in which their data resource is presented. Our $\texttt{C++}$ implementation, along with $\texttt{R}$ and $\texttt{python}$ wrappers, is publicly available. $\texttt{R}$ code is available on $\texttt{CRAN}$ and $\texttt{Github}$, and $\texttt{python}$ wrappers are available on $\texttt{Github}$; see https://github.com/jewellsean/FastLZeroSpikeInference.
Inflammatory and anti-inflammatory markers in plasma: from late pregnancy to early postpartum.
Feb 13, 2019   Scientific Reports
Bränn E, Edvinsson Å, Rostedt Punga A, Sundström-Poromaa I, Skalkidou A
Inflammatory and anti-inflammatory markers in plasma: from late pregnancy to early postpartum.
Feb 13, 2019
Scientific Reports
During pregnancy, the woman's body undergoes tremendous changes in immune system adaptation. The immunological shifts that occur in pregnancy can partially be explained by alterations in hormonal levels. Furthermore, during pregnancy, many autoimmune diseases go into remission, only to flare again in the early postpartum period. Given these important changes in the clinical course of a number of autoimmune disorders, surprisingly little has been done to investigate the inflammatory profile changes across pregnancy and the postpartum period. Thus, the aim of this study was to describe how inflammatory and anti-inflammatory markers change from late pregnancy to the early postpartum period, using a multiplexed assay consisting of both well-known as well as exploratory proteins. Two-hundred-and-ninety women were included in this study and donated a total of 312 blood samples; 198 in late pregnancy (~gw38) and 114 in the postpartum period (~w8). The plasma blood samples were analyzed for 92 immune system related protein markers using Proseek Multiplex Inflammation I panel, a high-sensitivity assay based on proximity extension assay technology. Fifty-six inflammatory and anti-inflammatory markers were significantly different between pregnancy and the postpartum, of which 50 survived corrections for multiple comparisons. Out of these 50 markers, 41 decreased from pregnancy to postpartum, while the remaining 9 increased in the postpartum period. The top five markers with the greatest decrease in the postpartum period were Leukemia inhibitory factor receptor (LIF-R), Latency-associated peptide Transforming growth factor beta-1 (LAP TGF-beta-1), C-C motif chemokine 28 (CCL28), Oncostatin M (OSM) and Fibroblast growth factor 21 (FGF21). Top three markers that increased in the postpartum period were Tumor necrosis factor ligand superfamily member 11 (TRANCE), Tumor necrosis factor ligand superfamily member 12 (TWEAK), and C-C motif chemokine/Eotaxin (CCL11). This study revealed that the majority of the markers decreased from pregnancy to postpartum, and only a few increased. Several of the top proteins that were higher in pregnancy than postpartum have anti-inflammatory and immune modulatory properties promoting pregnancy progress. These results clearly reflect the tremendous change in the immune system in the pregnancy to postpartum transition.
Neurobiology of maternal regulation of infant fear: the role of mesolimbic dopamine and its disruption by maltreatment.
Feb 13, 2019   Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology
Opendak M, Robinson-Drummer P, Blomkvist A, Zanca RM, Wood K,   . . . . . .   , Kirschner E, Lundström JN, Wilson DA, Serrano PA, Sullivan RM
Neurobiology of maternal regulation of infant fear: the role of mesolimbic dopamine and its disruption by maltreatment.
Feb 13, 2019
Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology
Child development research highlights caregiver regulation of infant physiology and behavior as a key feature of early life attachment, although mechanisms for maternal control of infant neural circuits remain elusive. Here we explored the neurobiology of maternal regulation of infant fear using neural network and molecular levels of analysis in a rodent model. Previous research has shown maternal suppression of amygdala-dependent fear learning during a sensitive period. Here we characterize changes in neural networks engaged during maternal regulation and the transition to infant self-regulation. Metabolic mapping of 2-deoxyglucose uptake during odor-shock conditioning in postnatal day (PN)14 rat pups showed that maternal presence blocked fear learning, disengaged mesolimbic circuitry, basolateral amygdala (BLA), and plasticity-related AMPA receptor subunit trafficking. At PN18, when maternal presence only socially buffers threat learning (similar to social modulation in adults), maternal presence failed to disengage the mesolimbic dopaminergic system, and failed to disengage both the BLA and plasticity-related AMPA receptor subunit trafficking. Further, maternal presence failed to block threat learning at PN14 pups following abuse, and mesolimbic dopamine engagement and AMPA were not significantly altered by maternal presence-analogous to compromised maternal regulation of children in abusive relationships. Our results highlight three key features of maternal regulation: (1) maternal presence blocks fear learning and amygdala plasticity through age-dependent suppression of amygdala AMPA receptor subunit trafficking, (2) maternal presence suppresses engagement of brain regions within the mesolimbic dopamine circuit, and (3) early-life abuse compromises network and molecular biomarkers of maternal regulation, suggesting reduced social scaffolding of the brain.
Dystroglycan is a scaffold for extracellular axon guidance decisions.
Feb 16, 2019   ELife
Lindenmaier LB, Parmentier N, Guo C, Tissir F, Wright KM
Dystroglycan is a scaffold for extracellular axon guidance decisions.
Feb 16, 2019
ELife
Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.
Targets for improving dispatcher identification of acute stroke.
Feb 14, 2019   International Journal Of Stroke : Official Journal Of The International Stroke Society
Mattila OS, Puolakka T, Ritvonen J, Pihlasviita S, Harve H, Alanen A, Sibolt G, Curtze S, Strbian D, Pystynen M, Tatlisumak T, Kuisma M, Lindsberg PJ
Targets for improving dispatcher identification of acute stroke.
Feb 14, 2019
International Journal Of Stroke : Official Journal Of The International Stroke Society
BACKGROUND: Accurate identification of acute stroke by Emergency Medical Dispatchers (EMD) is essential for timely and purposeful deployment of Emergency Medical Services (EMS), and a prerequisite for operating mobile stroke units. However, precision of EMD stroke recognition is currently modest. AIMS: We sought to identify targets for improving dispatcher stroke identification. METHODS: Dispatch codes and EMS patient records were cross-linked to investigate factors associated with an incorrect dispatch code in a prospective observational cohort of 625 patients with a final diagnosis of acute stroke or transient ischemic attack (TIA), transported to our stroke center as candidates for recanalization therapies. Call recordings were analyzed in a subgroup that received an incorrect low-priority dispatch code indicating a fall or unknown acute illness ( n = 46). RESULTS: Out of 625 acute stroke/TIA patients, 450 received a high-priority stroke dispatch code (sensitivity 72.0%; 95% CI, 68.5-75.5). Independent predictors of dispatcher missed acute stroke included a bystander caller (aOR, 3.72; 1.48-9.34), confusion (aOR, 2.62; 1.59-4.31), fall at onset (aOR, 1.86; 1.24-2.78), and older age (aOR [per year], 1.02; 1.01-1.04). Of the analyzed call recordings, 71.7% revealed targets for improvement, including failure to recognize a Face Arm Speech Time (FAST) test symptom (21/46 cases, 18 with speech disturbance), or failure to thoroughly evaluate symptoms (12/46 cases). CONCLUSIONS: Based on our findings, efforts to improve dispatcher stroke identification should primarily focus on improving recognition of acute speech disturbance, and implementing screening of FAST-symptoms in emergency phone calls revealing a fall or confusion. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02145663.
Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2-mediated signaling.
Feb 13, 2019   Experimental Dermatology
Nguyen MB, Valdes VJ, Cohen I, Pothula V, Zhao D, Zheng D, Ezhkova E
Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2-mediated signaling.
Feb 13, 2019
Experimental Dermatology
Merkel cells are mechanosensory cells involved in tactile discrimination. Merkel cells have been primarily studied in the murine back skin, where they are found in specialized structures called touch domes located around primary hair follicles. Yet, little is known about the morphogenesis of Merkel cells in areas of the skin devoid of hair, such as the glabrous paw skin. Here, we describe Merkel cell formation in the glabrous paw skin during embryogenesis. We first found in the glabrous paw skin that Merkel cells were specified at E15.5, 24 hours later, compared to in the back skin. Additionally, by performing lineage-tracing experiments, we found that unlike in the back skin, SOX9(+) cells do not give rise to Merkel cells in the glabrous paw skin. Finally, we compared the transcriptomes of Merkel cells in the back and the glabrous paw skin and showed that they are similar. Genetic and transcriptome studies showed that the formation of Merkel cells in both regions was controlled by similar regulators. Among them was FGFR2, an upstream factor of MAPK signaling that was reported to have a critical function in Merkel cell formation in the back skin. Here, we showed that FGFR2 is also required for Merkel cell development in the glabrous paw skin. Taken together, our results demonstrate that Merkel cells in the murine back skin and glabrous paw skin are similar, and even though their formation is controlled by a common genetic program, their precursor cells might differ. This article is protected by copyright. All rights reserved.
Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer's Disease and Systemic Inflammation.
Feb 13, 2019   Neurochemical Research
Zhou J, Yu W, Zhang M, Tian X, Li Y, Lü Y
Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer's Disease and Systemic Inflammation.
Feb 13, 2019
Neurochemical Research
Clinically, superimposed systemic inflammation generally has significant deleterious effects on the Alzheimer's disease (AD) progression. However, the related molecular mechanisms remain poorly understood. Microglial toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2) are two key regulators of inflammation that may play an essential role in this complex pathophysiological process. In this study, intraperitoneal injection of lipopolysaccharide (LPS) into APP/PS1 transgenic AD model was used to mimic systemic inflammation in the development of AD. Initial results from the cortex showed that compared with wild-type mice, APP/PS1 mice exhibited elevated gene and protein expression levels of both TLR4 and TREM2 with different degree. Interestingly, after LPS treatment, TLR4 expression was persistently up-regulated, while TREM2 expression was significantly down-regulated in APP/PS1 mice, suggesting that the negative regulatory effect of TREM2 on inflammation might be suppressed by LPS-induced hyperactive TLR4. This imbalance of TLR4/TREM2 contributed to microglial over-activation, followed by increased neuronal apoptosis in the cortex of APP/PS1 mice; these changes did not alter the expression level of Aβ1-42. Similar alterations were observed in our in vitro experiment with β-amyloid1-42 (Aβ1-42)-treated N9 microglia. Further, Morris water maze (MWM) testing data indicated that LPS administration acutely aggravated cognitive impairment in APP/PS1 mice, suggesting that the addition of systemic inflammation can potentially accelerate the progression of AD. Collectively, we conclude that an imbalance of TLR4/TREM2 may be a potential link between AD and systemic inflammation. TREM2 can serve as a potential therapeutic target for treating systemic inflammation in AD progression.
Jawless fish can regrow their spinal cords - twice.
Feb 13, 2019   Nature Add nature.com free-link Cancel
Baseline and follow-up activity and functional connectivity in reward neural circuitries in offspring at risk for bipolar disorder.
Feb 13, 2019   Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology
Acuff HE, Versace A, Bertocci MA, Ladouceur CD, Hanford LC,   . . . . . .   , Goldstein TR, Sakolsky D, Axelson D, Birmaher B, Phillips ML
Baseline and follow-up activity and functional connectivity in reward neural circuitries in offspring at risk for bipolar disorder.
Feb 13, 2019
Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology
Bipolar disorder (BD) is a serious psychiatric illness with demonstrated abnormalities in reward processing circuitry. Examining this circuitry in youth at familial risk for BD may provide further insight into the underlying mechanisms of BD development. In this study, we compared offspring of bipolar parents (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 36), and offspring of healthy parents (OHP, n = 39) during a functional magnetic resonance imaging reward processing task. Elastic net regression analyses identified 26 activity, functional connectivity (FC), and demographic variables that explained 34.24% of the variance in group (λ = 0.224). ANOVA and post-hoc analyses revealed that OBP had significantly lower right ventral striatum-left caudal anterior cingulate FC to loss (OBP versus OCP: p = 0.028, OBP versus OHP: p = 0.015) and greater right pars orbitalis-left (OBP versus OCP: p = 0.003, OBP versus OHP: p = 0.036) and -right (OBP versus OCP: p = 0.001, OBP versus OHP: p = 0.038) orbitofrontal cortex FC to reward versus OCP and OHP, respectively. These findings were not affected by non-BD psychopathology, psychotropic medication use, or symptomatology. There were no changes in, or relationships between, neuroimaging or symptom measures at follow-up (mean(SD) = 2.70(1.22) year inter-scan interval) in a subset of youth with follow-up data (OBP, n = 14; OCP, n = 8; OHP, n = 19). These findings suggest that lower right ventral striatum-left caudal anterior cingulate FC to loss and greater right pars orbitalis-orbitofrontal cortex FC to reward may be trait-level neural markers that may reflect risk for BD in at-risk youth. These findings comprise important steps toward identifying neural markers of BD risk, which may enhance early identification and guide interventions for youth at familial risk for BD.
A hypothalamus-habenula circuit controls aversion.
Feb 13, 2019   Molecular Psychiatry
Lazaridis I, Tzortzi O, Weglage M, Märtin A, Xuan Y,   . . . . . .   , Ramakrishnan C, Silberberg G, Deisseroth K, Carlén M, Meletis K
A hypothalamus-habenula circuit controls aversion.
Feb 13, 2019
Molecular Psychiatry
Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.
Non-alcoholic fatty liver disease and cerebral small vessel disease in Korean cognitively normal individuals.
Feb 13, 2019   Scientific Reports
Jang H, Kang D, Chang Y, Kim Y, Lee JS, Kim KW, Jang YK, Kim HJ, Na DL, Shin HY, Kang M, Guallar E, Cho J, Seo SW
Non-alcoholic fatty liver disease and cerebral small vessel disease in Korean cognitively normal individuals.
Feb 13, 2019
Scientific Reports
We aimed to investigate the association between nonalcoholic fatty liver disease (NAFLD) and cerebral small vessel disease (CSVD) burden, especially according to the NAFLD severity. A total of 1,260 participants were included. The CSVD burden was assessed with white matter hyperintensities (WMH), lacunes, and microbleeds (MBs) on brain MRI. An ultrasound diagnosis of fatty liver was made based on standard criteria, and the Fibrosis-4 (FIB-4) index was used to classify participants with NAFLD with having a high-intermediate (FIB-4 ≥1.45) or low (FIB-4 
Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.
Feb 13, 2019   Scientific Reports
Araya C, Häkkinen HM, Carcamo L, Cerda M, Savy T, Rookyard C, Peyriéras N, Clarke JDW
Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.
Feb 13, 2019
Scientific Reports
Tissue internalisation is a key morphogenetic mechanism by which embryonic tissues generate complex internal organs and a number of studies of epithelia have outlined a general view of tissue internalisation. Here we have used quantitative live imaging and mutant analysis to determine whether similar mechanisms are responsible for internalisation in a tissue that apparently does not have a typical epithelial organisation - the zebrafish neural plate. We found that although zebrafish embryos begin neurulation without a conventional epithelium, medially located neural plate cells adopt strategies typical of epithelia in order to constrict their dorsal surface membrane during cell internalisation. Furthermore, we show that Myosin-II activity is a significant driver of this transient cell remodeling which also depends on Cdh2 (N-cadherin). Abrogation of Cdh2 results in defective Myosin-II distribution, mislocalised internalisation events and defective neural plate morphogenesis. Our work suggests Cdh2 coordinates Myosin-II dependent internalisation of the zebrafish neural plate.
Exposure to Nanoscale Particulate Matter from Gestation to Adulthood Impairs Metabolic Homeostasis in Mice.
Feb 13, 2019   Scientific Reports
Woodward NC, Crow AL, Zhang Y, Epstein S, Hartiala J,   . . . . . .   , Finch CE, Bouret SG, Sioutas C, Morgan TE, Allayee H
Exposure to Nanoscale Particulate Matter from Gestation to Adulthood Impairs Metabolic Homeostasis in Mice.
Feb 13, 2019
Scientific Reports
Emerging evidence from epidemiological and animal studies suggests that exposure to traffic-related air pollutants and particulate matter less than 2.5 µm in diameter (PM2.5) contributes to development of obesity and related metabolic abnormalities. However, it is not known whether nanoscale particulate matter (nPM) with aerodynamic diameter ≤200 nm have similar adverse metabolic effects. The goal of the present study was to determine the effects of prenatal and early life exposure to nPM on metabolic homeostasis in mice. C57BL/6 J mice were exposed to nPM or filtered air from gestation until 17 weeks of age and characterized for metabolic and behavioral parameters. In male mice, nPM exposure increased food intake, body weight, fat mass, adiposity, and whole-body glucose intolerance (p < 0.05). Consistent with these effects, male mice exposed to nPM displayed alterations in the expression of metabolically-relevant neuropeptides in the hypothalamus and decreased expression of insulin receptor signaling genes in adipose (p < 0.05). There were no differences in exploratory behavior or motor function, fasting lipid levels, or the inflammatory profile of adipose tissue. Our results provide evidence that chronic nPM exposure from gestation to early adulthood in male mice promotes metabolic dysregulation in part through modulation of feeding behavior and in the absence of an obesogenic diet.
The Experience With Flow Diverters in the Treatment of Posterior Inferior Cerebellar Artery Aneurysms.
Feb 12, 2019   Operative Neurosurgery (Hagerstown, Md.)
Atallah E, Saad H, Li J, Kumar A, Tjoumakaris S, Chalouhi N, Hasan D, Zarzour H, Herial N, Gooch MR, Rosenwasser RH, Jabbour P
The Experience With Flow Diverters in the Treatment of Posterior Inferior Cerebellar Artery Aneurysms.
Feb 12, 2019
Operative Neurosurgery (Hagerstown, Md.)
BACKGROUND: The use of the pipeline embolization device (PED; Medtronic, Dublin, Ireland) in the posterior circulation has been limited and infrequently reported compared to other off-label utilizations. Posterior inferior cerebellar artery aneurysms (PICAA) constitute 1 of the least reported posterior circulation aneurysms treated with PED. No clinical studies have addressed the treatment of these aneurysms with flow diversion exclusively. OBJECTIVE: To appraise the feasibility and the safety of PED in the treatment of PICAAs. METHODS: Data on 12 consecutive patients, treated between 2011-2017 with PED for their PICAA, was retrospectively reviewed. To control confounding, we used multivariable logistic regression and propensity score conditioning. RESULTS: Of 534 patients, 12 (9/12, 75% males) were identified and constituted our study population. The average aneurysm size was 8.47 mm (SD = 2.6, 3.7-14). Patients were followed-up for an average of 10.3 months (SD = 11 mo). Two of 12 (16.7%) had a prior history of subarachnoid hemorrhage. Eight of 12 (67%) of the aneurysms were saccular, 3/12 (25%) were dolichoectatic, and 1/12 (8%) was a small blister aneurysm. Eleven of 12 (92%) aneurysms were treated with 1 PED; 2/12 (16.7%) patients received combined pipeline assisted coiling. All patients had a complete occlusion, regression, and resolution of their aneurysm(s). PED deployment was neither complicated with any hemorrhagic or clinically significant thromboembolic events nor with device migration in any of our patients. Three of 12 (25%) patients had a benign intrastent stenosis. No mortality, among our 12 patients, was noted throughout the follow-up period. CONCLUSION: PED, deployed by specialized experts, should be safe in treating PICAA. It can be contemplated as a novel alternative treatment of aneurysms located at the PICA-VA bifurcation or within the PICA.
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
Feb 16, 2019   Nature Communications
Friedman J, Smith DE, Issa MY, Stanley V, Wang R,   . . . . . .   , Kingsmore SF, Salomons GS, Zaki MS, Bernard G, Gleeson JG
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
Feb 16, 2019
Nature Communications
Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.
Development of frontoparietal connectivity predicts longitudinal symptom changes in young people with autism spectrum disorder.
Feb 16, 2019   Translational Psychiatry
Lin HY, Perry A, Cocchi L, Roberts JA, Tseng WI, Breakspear M, Gau SS
Development of frontoparietal connectivity predicts longitudinal symptom changes in young people with autism spectrum disorder.
Feb 16, 2019
Translational Psychiatry
Structural neuroimaging studies suggest altered brain maturation in autism spectrum disorder (ASD) compared with typically developing controls (TDC). However, the prognostic value of whole-brain structural connectivity analysis in ASD has not been established. Diffusion magnetic imaging data were acquired in 27 high-functioning young ASD participants (2 females) and 29 age-matched TDC (12 females; age 8-18 years) at baseline and again following 3-7 years. Whole-brain structural connectomes were reconstructed from these data and analyzed using a longitudinal statistical model. We identified distinct patterns of widespread brain connections that exhibited either significant increases or decreases in connectivity over time (p 
Neural variability limits adolescent skill learning.
Feb 13, 2019   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Caras ML, Sanes DH
Neural variability limits adolescent skill learning.
Feb 13, 2019
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Skill learning is fundamental to the acquisition of many complex behaviors that emerge during development. For example, years of practice give rise to perceptual improvements that contribute to mature speech and language skills. While fully honed learning skills might be thought to offer an advantage during the juvenile period, the ability to learn actually continues to develop through childhood and adolescence, suggesting that the neural mechanisms that support skill learning are slow to mature. To address this issue, we asked whether the rate and magnitude of perceptual learning varies as a function of age as male and female gerbils trained on an auditory task. Adolescents displayed a slower rate of perceptual learning as compared to their young and mature counterparts. We recorded auditory cortical neuron activity from a subset of adolescent and adult gerbils as they underwent perceptual training. While training enhanced the sensitivity of most adult units, the sensitivity of many adolescent units remained unchanged, or even declined across training days. Therefore, the average rate of cortical improvement was significantly slower in adolescents as compared to adults. Both smaller differences between sound-evoked response magnitudes and greater trial-to-trial response fluctuations contributed to the poorer sensitivity of individual adolescent neurons. Together, these findings suggest that elevated sensory neural variability limits adolescent skill learning.Significance Statement:The ability to learn new skills emerges gradually as children age. This prolonged development, often lasting well into adolescence, suggests that children, teens, and adults may rely on distinct neural strategies to improve their sensory and motor capabilities. Here, we found that practice-based improvement on a sound detection task is slower in adolescent gerbils than in younger or older animals. Neural recordings made during training revealed that practice enhanced the sound sensitivity of adult cortical neurons, but had a weaker effect in adolescents. This latter finding was partially explained by the fact that adolescent neural responses were more variable than in adults. Our results suggest that one mechanistic basis of adult-like skill learning is a reduction in neural response variability.
Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex.
Feb 13, 2019   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Datta D, Yang ST, Galvin V, Solder J, Luo F, Morozov YM, Arellano J, Duque A, Rakic P, Arnsten A, Wang M
Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex.
Feb 13, 2019
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Noradrenergic (NE) α1-adrenoceptors (α1-AR) contribute to arousal mechanisms, and play an important role in therapeutic medications, e.g. for treating Post-Traumatic Stress Disorder (PTSD). However, little is known about how α1-AR stimulation influences neuronal firing in the dorsolateral prefrontal cortex (dlPFC), a newly evolved region that is dysfunctional in PTSD and other mental illnesses. The current study examined the effects of α1-AR manipulation on neuronal firing in dlPFC of rhesus monkeys performing a visuospatial working memory task, focusing on the "Delay cells" that maintain spatially-tuned information across the delay period. Iontophoresis of the α1-AR antagonist, HEAT, had mixed effects, reducing firing in a majority of neurons, but having nonsignificant excitatory effects or no effect in remaining Delay cells. These data suggest that endogenous NE has excitatory effects in some Delay cells under basal conditions. In contrast, the α1-AR agonists phenylephrine and cirazoline suppressed Delay cell firing, and this was blocked by co-administration of HEAT. These results indicate an inverted-U dose response for α1-AR actions, with mixed excitatory actions under basal conditions, and suppressed firing with high levels of α1-AR stimulation, e.g. with stress exposure. Immunoelectron microscopy revealed α1-AR expression both pre-synaptically in axons and axon terminals, and post-synaptically in spines and dendrites, as well as in astrocytes. It is possible that α1-AR excitatory effects arise from pre-synaptic excitation of glutamate release, while post-synaptic actions suppress firing through calcium-PKC opening of potassium channels on spines. The latter may predominate under stressful conditions, leading to loss of dlPFC regulation during uncontrollable stress.SIGNIFICANCE STATEMENTNoradrenergic stimulation of α1-AR is implicated in Post-Traumatic Stress Disorder (PTSD) and other mental disorders that involve dysfunction of the prefrontal cortex, a brain region that provides top-down control. However, the location and contribution of α1-AR to prefrontal cortical physiology in primates has received little attention. This study found that α1-ARs are located near prefrontal synapses, and that α1-AR stimulation has mixed effects under basal conditions. However, high levels of α1-AR stimulation, as occur with stress, suppress neuronal firing. These findings help to explain why we lose top-down control under conditions of uncontrollable stress when there are high levels of NE release in brain, and why blocking α1-AR e.g. with prazosin, may be helpful in the treatment of PTSD.
Prelimbic Cortical Neurons Track Preferred Reward Value and Reflect Impulsive Choice During Delay Discounting Behavior.
Feb 13, 2019   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Sackett DA, Moschak TM, Carelli RM
Prelimbic Cortical Neurons Track Preferred Reward Value and Reflect Impulsive Choice During Delay Discounting Behavior.
Feb 13, 2019
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
In delay discounting, individuals discount the value of a reward based on the delay to its receipt. The prelimbic cortex (PrL) is heavily interconnected with several brain regions implicated in delay discounting, but the specific contributions of the PrL to delay discounting are unknown. Here, we used multineuron electrophysiological recording methods in Long Evans male (n=10) and female (n=9) rats to characterize the firing dynamics of PrL neurons during discrete cue and lever press events in a delay discounting task. Rats' initial preference for the large reward decreased as delays for that outcome increased across blocks, reflecting classic discounting behavior. Electrophysiological recordings revealed that subgroups of neurons exhibited phasic responses to cue presentations and lever presses. These phasic neurons were found to respond to either large/delay, small/immediate, or both trial types, and the percentage of these neurons shifted across blocks as the expected value of the reward changed. Critically, this shift was only seen during trials in which animals could choose their preferred option (Free Choice trials) and not during trials where animals could choose only one option (Forced Choice trials). Further, this shift was dependent on rats' inherent impulsivity, as high impulsive rats demonstrated a greater percentage of small/immediate-responsive neurons as the task progressed. Collectively, these findings suggest a unique role for the PrL in encoding reward value during delay discounting that is influenced by individual differences in impulsivity.SIGNIFICANCE STATEMENTIn delay discounting, individuals discount the value of a reward based on the delay to its receipt. Here, we used electrophysiology to investigate the role of the prelimbic cortex (PrL) in this process. We found that subsets of neurons shifted activity as a function of the changing expected delay and reward magnitude, but this shift was only evident during trials in which animals could choose their preferred option. Further, this dynamic neural activity depended on rats' inherent impulsivity, with impulsive rats exhibiting a stronger neural shift towards the immediate reward as the task progressed. These findings suggest a role for the PrL in encoding reward value during delay discounting that is influenced by goal-directed context and individual differences in impulsivity.
Perturbation of macaque supplementary motor area produces context-independent changes in the probability of movement initiation.
Feb 13, 2019   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Zimnik AJ, Lara AH, Churchland MM
Perturbation of macaque supplementary motor area produces context-independent changes in the probability of movement initiation.
Feb 13, 2019
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
The contribution of the supplementary motor area (SMA) to movement initiation remains unclear. SMA exhibits pre-movement activity across a variety of contexts, including externally cued and self-initiated movements. Yet SMA lesions impair initiation primarily for self-initiated movements. Does SMA influence initiation across contexts or does it play a more specialized role, perhaps contributing only when initiation is less dependent on external cues? To address this question, we perturbed SMA activity via microstimulation at variable times before movement onset. Experiments employed two adult male rhesus monkeys trained on a reaching task. We employed three contexts that differed regarding how tightly movement initiation was linked to external cues. Movement kinematics were not altered by microstimulation. Instead, microstimulation induced a variety of changes in the timing of movement initiation, with different effects dominating for different contexts. Despite their diversity, these changes could be explained by a simple model where microstimulation has a stereotyped impact on the probability of initiation. Surprisingly, a unified model accounted for effects across all three contexts, regardless of whether initiation was determined more by external cues versus internal considerations. All effects were present for stimulation both contralateral and ipsilateral to the moving arm. Thus, the probability of initiating a pending movement is altered by perturbation of SMA activity. However, changes in initiation probability are independent of the balance of internal and external factors that establish the baseline initiation probability.SIGNIFICANCE STATEMENTThe role of the supplementary motor area (SMA) in initiating movement remains unclear. Lesion experiments suggest that SMA makes a critical contribution only for self-initiated movements. Yet SMA is active before movements made under a range of contexts, suggesting a less-specialized role in movement initiation. Here, we use microstimulation to probe the role of SMA across a range of behavioral contexts that vary in the degree to which movement onset is influenced by external cues. We demonstrate that microstimulation produces a temporally stereotyped change in the probability of initiation that is independent of context. These results argue that SMA participates in the computations that lead to movement initiation and does so across a variety of contexts.
Gαs-coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells.
Feb 13, 2019   The Journal Of Experimental Medicine
Dimitrov S, Lange T, Gouttefangeas C, Jensen ATR, Szczepanski M, Lehnnolz J, Soekadar S, Rammensee HG, Born J, Besedovsky L
Gαs-coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells.
Feb 13, 2019
The Journal Of Experimental Medicine
Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)-mediated activation of β2-integrins. Gαs-coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of peptide major histocompatibility complex molecules (pMHC) and of ICAM-1-the ligand of β2-integrins-we show that the Gαs-coupled receptor agonists isoproterenol, epinephrine, norepinephrine, prostaglandin (PG) E2, PGD2, and adenosine strongly inhibit integrin activation on human CMV- and EBV-specific CD8+ T cells in a dose-dependent manner. In contrast, sleep, a natural condition of low levels of Gαs-coupled receptor agonists, up-regulates integrin activation compared with nocturnal wakefulness, a mechanism possibly underlying some of the immune-supportive effects of sleep. The findings are also relevant for several pathologies associated with increased levels of Gαs-coupled receptor agonists (e.g., tumor growth, malaria, hypoxia, stress, and sleep disturbances).
Quasi-periodic patterns contribute to functional connectivity in the brain.
Feb 12, 2019   NeuroImage
Abbas A, Belloy M, Kashyap A, Billings J, Nezafati M, Schumacher E, Keilholz S
Quasi-periodic patterns contribute to functional connectivity in the brain.
Feb 12, 2019
NeuroImage
Functional connectivity is widely used to study the coordination of activity between brain regions over time. Functional connectivity in the default mode and task positive networks is particularly important for normal brain function. However, the processes that give rise to functional connectivity in the brain are not fully understood. It has been postulated that low-frequency neural activity plays a key role in establishing the functional architecture of the brain. Quasi-periodic patterns (QPPs) are a reliably observable form of low-frequency neural activity that involve the default mode and task positive networks. Here, QPPs from resting-state and working memory task-performing individuals were acquired. The spatiotemporal pattern, strength, and frequency of the QPPs between the two groups were compared and the contribution of QPPs to functional connectivity in the brain was measured. In task-performing individuals, the spatiotemporal pattern of the QPP changes, particularly in task-relevant regions, and the QPP tends to occur with greater strength and frequency. Differences in the QPPs between the two groups could partially account for the variance in functional connectivity between resting-state and task-performing individuals. The QPPs contribute strongly to connectivity in the default mode and task positive networks and to the strength of anti-correlation seen between the two networks. Many of the connections affected by QPPs are also disrupted during several neurological disorders. These findings contribute to understanding the dynamic neural processes that give rise to functional connectivity in the brain and how they may be disrupted during disease.
Mapping tissue pH in an experimental model of acute stroke - Determination of graded regional tissue pH changes with non-invasive quantitative amide proton transfer MRI.
Feb 12, 2019   NeuroImage
Wang E, Wu Y, Cheung JS, Igarashi T, Wu L, Zhang X, Sun PZ
Mapping tissue pH in an experimental model of acute stroke - Determination of graded regional tissue pH changes with non-invasive quantitative amide proton transfer MRI.
Feb 12, 2019
NeuroImage
pH-weighted amide proton transfer (APT) MRI is sensitive to tissue pH change during acute ischemia, complementing conventional perfusion and diffusion stroke imaging. However, the currently used pH-weighted magnetization transfer (MT) ratio asymmetry (MTRasym) analysis is of limited pH specificity. To overcome this, MT and relaxation normalized APT (MRAPT) analysis has been developed that to homogenizes the background signal, thus providing highly pH conspicuous measurement. Our study aimed to calibrate MRAPT MRI toward absolute tissue pH mapping and determine regional pH changes during acute stroke. Using middle cerebral artery occlusion (MCAO) rats, we performed lactate MR spectroscopy and multi-parametric MRI. MRAPT MRI was calibrated against a region of interest (ROI)-based pH spectroscopy measurement (R2 = 0.70, P < 0.001), showing noticeably higher correlation coefficient than the simplistic MTRasym index. Capitalizing on this, we mapped brain tissue pH and semi-automatically segmented pH lesion, in addition to routine perfusion and diffusion lesions. Tissue pH from regions of the contralateral normal, perfusion/diffusion mismatch and diffusion lesion was found to be 7.03 ± 0.04, 6.84 ± 0.10, 6.52 ± 0.19, respectively. Most importantly, we delineated the heterogeneous perfusion/diffusion lesion mismatch into perfusion/pH and pH/diffusion lesion mismatches, with their pH being 7.01 ± 0.04 and 6.71 ± 0.12, respectively (P < 0.05). To summarize, our study calibrated pH-sensitive MRAPT MRI toward absolute tissue pH mapping, semi-automatically segmented and determined graded tissue pH changes in ischemic tissue and demonstrated its feasibility for refined demarcation of heterogeneous metabolic disruption following acute stroke.
Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson's disease patients.
Feb 12, 2019   Neurobiology Of Disease
Meidahl AC, Moll CKE, van Wijk B, Gulberti A, Tinkhauser G, Westphal M, Engel AK, Hamel W, Brown P, Sharott A
Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson's disease patients.
Feb 12, 2019
Neurobiology Of Disease
Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities, inter spike intervals and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Furthermore, inter spike interval frequencies peaked in the same frequencies for which PAC was observed. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinson's disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS. SIGNIFICANCE STATEMENT: Identifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinson's Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies.
Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?
Feb 13, 2019   Metabolic Brain Disease
Morris G, Maes M, Berk M, Puri BK
Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?
Feb 13, 2019
Metabolic Brain Disease
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.

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