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Neuroscience
Atypical functional connectivity in adolescents and adults with persistent and remitted ADHD during a cognitive control task.
Apr 17, 2019   Translational Psychiatry
Michelini G, Jurgiel J, Bakolis I, Cheung CHM, Asherson P, Loo SK, Kuntsi J, Mohammad-Rezazadeh I
Atypical functional connectivity in adolescents and adults with persistent and remitted ADHD during a cognitive control task.
Apr 17, 2019
Translational Psychiatry
We previously provided initial evidence for cognitive and event-related potential markers of persistence/remission of attention-deficit/hyperactivity disorder (ADHD) from childhood to adolescence and adulthood. Here, using a novel brain-network connectivity approach, we aimed to examine whether task-based functional connectivity reflects a marker of ADHD remission or an enduring deficit unrelated to ADHD outcome. High-density EEG was recorded in a follow-up of 110 adolescents and young adults with childhood ADHD (87 persisters, 23 remitters) and 169 typically developing individuals during an arrow-flanker task, eliciting cognitive control. Functional connectivity was quantified with network-based graph-theory metrics before incongruent (high-conflict) target onset (pre-stimulus), during target processing (post-stimulus) and in the degree of change between pre-stimulus/post-stimulus. ADHD outcome was examined with parent-reported symptoms and impairment using both a categorical (DSM-IV) and a dimensional approach. Graph-theory measures converged in indicating that, compared to controls, ADHD persisters showed increased connectivity in pre-stimulus theta, alpha, and beta and in post-stimulus beta (all p 
Putting objects in their place.
Apr 13, 2019   Nature Reviews. Neuroscience
Lewis S
Putting objects in their place.
Apr 13, 2019
Nature Reviews. Neuroscience
Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction.
Apr 13, 2019   Brain, Behavior, And Immunity
Chen C, Gao R, Li M, Wang Q, Chen H,   . . . . . .   , Li Q, Yu H, Yang J, Zhu T, Liu J
Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction.
Apr 13, 2019
Brain, Behavior, And Immunity
Postoperative cognitive dysfunction (POCD) is considered a severe complication after surgery among elderly patients. Toll-like receptor 3 (TLR3) has recently been reported to play an important role in hippocampus-dependent working memory. However, the role of TLR3 in the development of POCD remains unclear. In the current study, we hypothesized that increased extracellular RNAs (exRNAs) during anesthesia and surgical operation, especially double stranded RNAs (dsRNAs), would activate TLR3 signaling pathways and mediate POCD. Using a mouse model of POCD, 20-22 months wild-type (WT) mice were undergoing unilateral nephrectomy and increased TLR3 expression levels and co-localization with neuronal and microglial cells were found in the surgery group compared with the sham group. Compared with WT mice, TLR3 knockout (KO, -/-) mice had improved hippocampus-dependent memory and attenuated production of inflammatory cytokines and apoptosis. Increased exRNAs and/or co-localization with TLR3 were found in both in vitro and in vivo models. Of note, TLR3/dsRNA complex inhibitor administration reduced hippocampal dsRNA level and TLR3 expression, attenuated hippocampal inflammatory cytokines production and apoptosis, and thus improved hippocampus-dependent memory. Our results indicate that exRNAs, especially dsRNAs, present under stressful conditions may trigger TLR3 activation and initiate the downstream inflammatory and apoptotic signaling, and play a substantial role in the development of POCD.
Cerebral transcriptome analysis reveals age-dependent progression of neuroinflammation in P301S mutant tau transgenic male mice.
Apr 16, 2019   Brain, Behavior, And Immunity
Kim J, Selvaraji S, Kang SW, Lee WT, Chen CL, Choi H, Koo EH, Jo DG, Leong Lim K, Lim YA, Arumugam TV
Cerebral transcriptome analysis reveals age-dependent progression of neuroinflammation in P301S mutant tau transgenic male mice.
Apr 16, 2019
Brain, Behavior, And Immunity
Aggregation of the microtubule-associated protein, tau, can lead to neurofibrillary tangle formation in neurons and glia which is the hallmark of tauopathy. The cellular damage induced by the formation of neurofibrillary tangles leads to neuroinflammation and consecutive neuronal death. However, detailed observation of transcriptomic changes under tauopathy together with the comparison of age-dependent progression of neuroinflammatory gene expressions mediated by tau overexpression is required. Employing RNA sequencing on PS19 transgenic mice that overexpress human mutant tau harboring the P301S mutation, we have examined the effects of age-dependent tau overexpression on transcriptomic changes of immune and inflammatory responses in the cerebral cortex. Compared to age-matched wild type control, P301S transgenic mice exhibit significant transcriptomic alterations. We have observed age-dependent neuroinflammatory gene expression changes in both wild type and P301S transgenic mice where tau overexpression further promoted the expression of neuroinflammatory genes in 10-month old P301S transgenic mice. Moreover, functional gene network analyses (gene ontology and pathway enrichment) and prospective target protein interactions predicted the potential involvement of multiple immune and inflammatory pathways that may contribute to tau-mediated neuronal pathology. Our current study on P301S transgenic mice model revealed for the first time, the differences of gene expression patterns in both early and late stage of tau pathology in cerebral cortex. Our analyses also revealed that tau overexpression alone induces multiple inflammatory and immune transcriptomic changes and may provide a roadmap to elucidate the targets of anti-inflammatory therapeutic strategy focused on tau pathology and related neurodegenerative diseases.
Influence of poly(I:C) variability on thermoregulation, immune responses and pregnancy outcomes in mouse models of maternal immune activation.
Apr 16, 2019   Brain, Behavior, And Immunity
Mueller FS, Richetto J, Hayes LN, Zambon A, Pollak DD, Sawa A, Meyer U, Weber-Stadlbauer U
Influence of poly(I:C) variability on thermoregulation, immune responses and pregnancy outcomes in mouse models of maternal immune activation.
Apr 16, 2019
Brain, Behavior, And Immunity
Maternal immune activation (MIA) models that are based on administration of the viral mimetic, poly(I:C), are widely used as experimental tools to study neuronal and behavioral dysfunctions in relation to immune-mediated neurodevelopmental disorders and mental illnesses. Evidence from investigations in non-pregnant rodents suggests that different poly(I:C) products can vary in terms of their immunogenicity, even if they are obtained from the same vendor. The present study aimed at extending these findings to pregnant mice, while also controlling various poly(I:C) products for potential contamination with lipopolysaccharide (LPS). We found significant variability between different batches of poly(I:C) potassium salt obtained from the same vendor (Sigma-Aldrich) in terms of the relative amount of dsRNA fragments in the high molecular weight range (1000-6000 nucleotides long) and with regards to their effects on maternal thermoregulation and immune responses in maternal plasma, placenta and fetal brain. Batches of poly(I:C) potassium salt containing larger amounts of high molecular weight fragments induced more extensive effects on thermoregulation and immune responses compared to batches with minimal amounts of high molecular weight fragments. Consistent with these findings, poly(I:C) enriched for high molecular weight dsRNA (HMW) caused larger maternal and placental immune responses compared to low molecular weight (LMW) poly(I:C). These variable effects were unrelated to possible LPS contamination. Finally, we found marked variability between different batches of the poly(I:C) potassium salt in terms of their effects on spontaneous abortion rates. This batch-to-batch variability was confirmed by three independent research groups using distinct poly(I:C) administration protocols in mice. Taken together, the present data confirm that different poly(I:C) products can induce varying immune responses and can differentially affect maternal physiology and pregnancy outcomes. It is therefore pivotal that researchers working with poly(I:C)-based MIA models ascertain and consider the precise molecular composition and immunogenicity of the product in use. We recommend the establishment of reference databases that combine phenotype data with empirically acquired quality information, which can aid the design, implementation and interpretation of poly(I:C)-based MIA models.
Retinal Defects in Mice Lacking the Autism-Associated Gene Engrailed-2.
Apr 13, 2019   Neuroscience
Zhang X, Piano I, Messina A, D'Antongiovanni V, Crò F, Provenzano G, Bozzi Y, Gargini C, Casarosa S
Retinal Defects in Mice Lacking the Autism-Associated Gene Engrailed-2.
Apr 13, 2019
Neuroscience
Defective cortical processing of visual stimuli and altered retinal function have been described in autism spectrum disorder (ASD) patients. In keeping with these findings, anatomical and functional defects have been found in the visual cortex and retina of mice bearing mutations for ASD-associated genes. Here we sought to investigate the anatomy and function of the adult retina of Engrailed 2 knockout (En2-/-) mice, a model for ASD. Our results showed that En2 is expressed in all three nuclear layers of the adult retina. When compared to age-matched En2+/+ controls, En2-/- adult retinas showed a significant decrease in the number of calbindin+ horizontal cells, and a significant increase in calbindin+ amacrine/ganglion cells. The total number of ganglion cells was not altered in the adult En2-/- retina, as shown by Brn3a+ cell counts. In addition, En2-/- adult mice showed a significant reduction of photoreceptor (rhodopsin) and bipolar cell (Pcp2, PKCα) markers. Functional defects were also present in the retina of En2 mutants, as indicated by electroretinogram recordings showing a significant reduction in both a-wave and b-wave amplitude in En2-/- mice as compared to controls. These data show for the first time that anatomical and functional defects are present in the retina of the En2 ASD mouse model.
Endogenous GLP-1 in lateral septum promotes satiety and suppresses motivation for food in mice.
Apr 13, 2019   Physiology & Behavior
Terrill SJ, Holt MK, Maske CB, Abrams N, Reimann F, Trapp S, Williams DL
Endogenous GLP-1 in lateral septum promotes satiety and suppresses motivation for food in mice.
Apr 13, 2019
Physiology & Behavior
Glucagon-like peptide 1 receptors (GLP-1R) are expressed in the lateral septum (LS) of rats and mice, and we have published that endogenous LS GLP-1 affects feeding and motivation for food in rats. Here we asked if these effects are also observed in mice. In separate dose-response studies using male C57Bl6J mice, intra-LS GLP-1 or the GLP-1R antagonist Exendin 9 (Ex9) was delivered shortly before dark onset, at doses subthreshold for effect when injected intracerebroventricularly (icv). Intra-LS GLP-1 significantly suppressed chow intake early in the dark phase and tended to reduce overnight intake. However, blockade of LS GLP-1R with Ex9 had no effect on ad libitum dark onset chow intake. We then asked if LS GLP-1R blockade blunts nutrient preload-induced intake suppression. Mice were trained to consume Ensure immediately before dark onset, which suppressed subsequent chow intake, and intra-LS Ex9 attenuated that preload-induced intake suppression. We also found that restraint stress robustly activates hindbrain GLP-1-producing neurons, and that LS GLP-1R blockade attenuates 30-min restraint stress-induced hypophagia in mice. Furthermore, we have reported that in the rat, GLP-1R in the dorsal subregion of the LS (dLS) affect motivation for food. We examined this in food-restricted mice responding for sucrose pellets on a progressive ratio (PR) schedule. Intra-dLS GLP-1R stimulation significantly suppressed, and Ex9 significantly increased, operant responding, and the Ex9 effect remained after mice returned to ad libitum conditions. Similarly, we found that stimulation of dLS GLP-1 suppressed licking for sucrose and conversely, Ex9 increased licking under ad libitum feeding conditions. Together, our data suggest that endogenous activation of LS GLP-1R plays a role in feeding in mice under some but not all conditions, and that these receptors strongly influence motivation for food.
The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments.
Apr 13, 2019   Neuropharmacology
Löscher W
The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments.
Apr 13, 2019
Neuropharmacology
A variety of acute brain insults can induce epileptogenesis, a complex process that results in acquired epilepsy. Despite advances in understanding mechanisms of epileptogenesis, there is currently no approved treatment that prevents the development or progression of epilepsy in patients at risk. The current concept of epileptogenesis assumes a window of opportunity following acute brain insults that allows intervention with preventive treatment. Recent results suggest that injury-induced epileptogenesis can be a much more rapid process than previously thought, suggesting that the 'therapeutic window' may only be open for a brief period, as in stroke therapy. However, experimental data also suggest a second, possibly delayed process ("secondary epileptogenesis") that influences the progression and refractoriness of the epileptic state over time, allowing interfering with this process even after onset of epilepsy. In this review, both methodological issues in preclinical drug development and novel targets for antiepileptogenesis will be discussed. Several promising drugs that either prevent epilepsy (antiepileptogenesis) or slow epilepsy progression and alleviate cognitive or behavioral comorbidities of epilepsy (disease modification) have been described in recent years, using diverse animal models of acquired epilepsy. Promising agents include TrkB inhibitors, losartan, statins, isoflurane, anti-inflammatory and anti-oxidative drugs, the SV2A modulator levetiracetam, and epigenetic interventions. Research on translational target validity and on prognostic biomarkers that can be used to stratify patients (or experimental animals) at high risk of developing epilepsy will hopefully soon lead to proof-of-concept clinical trials with the most promising drugs, which will be essential to make prevention of epilepsy a reality.
Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury.
Apr 15, 2019   Clinical Chemistry And Laboratory Medicine
Minta K, Cullen NC, Nimer FA, Thelin EP, Piehl F, Clarin M, Tullberg M, Jeppsson A, Portelius E, Zetterberg H, Blennow K, Andreasson U
Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury.
Apr 15, 2019
Clinical Chemistry And Laboratory Medicine
Background Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI). The aims of this study were to investigate if matrix proteins in CSF and serum are associated with functional outcome following traumatic brain injury, if their concentrations change over time and to compare their levels between brain injured patients to controls. Methods In total, 42 traumatic brain injury patients, nine healthy controls and a contrast group consisting of 38 idiopathic normal pressure hydrocephalus patients were included. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the concentrations of proteins. Results Increased concentrations of brevican, tenascin-C and tenascin-R in CSF correlated with unfavourable outcome, with stronger outcome prediction ability compared to other biomarkers of brain tissue injury. CSF brevican, tenascin-R and serum neurocan gradually decreased with time (p = 0.04, p = 0.008, p = 0.005, respectively), while serum tenascin-C (p = 0.01) increased. CSF concentrations of brevican, neurocan and tenascin-R (only in time point 3) after TBI were lower than in the idiopathic normal pressure hydrocephalus group (p 
Age-Related Differences in Motivational Integration and Cognitive Control.
Apr 13, 2019   Cognitive, Affective & Behavioral Neuroscience
Yee DM, Adams S, Beck A, Braver TS
Age-Related Differences in Motivational Integration and Cognitive Control.
Apr 13, 2019
Cognitive, Affective & Behavioral Neuroscience
Motivational incentives play an influential role in value-based decision-making and cognitive control. A compelling hypothesis in the literature suggests that the motivational value of diverse incentives are integrated in the brain into a common currency value signal that influences decision-making and behavior. To investigate whether motivational integration processes change during healthy aging, we tested older (N = 44) and younger (N = 54) adults in an innovative incentive integration task paradigm that establishes dissociable and additive effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. The results reveal that motivational incentives improve cognitive task performance in both older and younger adults, providing novel evidence demonstrating that age-related cognitive control deficits can be ameliorated with sufficient incentive motivation. Additional analyses revealed clear age-related differences in motivational integration. Younger adult task performance was modulated by both monetary and liquid incentives, whereas monetary reward effects were more gradual in older adults and more strongly impacted by trial-by-trial performance feedback. A surprising discovery was that older adults shifted attention from liquid valence toward monetary reward throughout task performance, but younger adults shifted attention from monetary reward toward integrating both monetary reward and liquid valence by the end of the task, suggesting differential strategic utilization of incentives. These data suggest that older adults may have impairments in incentive integration and employ different motivational strategies to improve cognitive task performance. The findings suggest potential candidate neural mechanisms that may serve as the locus of age-related change, providing targets for future cognitive neuroscience investigations.
Decreased miR-325-5p Contributes to Visceral Hypersensitivity Through Post-transcriptional Upregulation of CCL2 in Rat Dorsal Root Ganglia.
Apr 13, 2019   Neuroscience Bulletin
Wu R, Zhang PA, Liu X, Zhou Y, Xu M, Jiang X, Yan J, Xu GY
Decreased miR-325-5p Contributes to Visceral Hypersensitivity Through Post-transcriptional Upregulation of CCL2 in Rat Dorsal Root Ganglia.
Apr 13, 2019
Neuroscience Bulletin
Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chronic pain conditions. However, the role of miRNA-325-5p in chronic visceral pain remains unknown. The present study was designed to determine the roles and mechanism of miRNA-325-5p in a rat model of chronic visceral pain. This model was induced by neonatal colonic inflammation (NCI). In adulthood, NCI led to a significant reduction in the expression of miRNA-325-5p in colon-related dorsal root ganglia (DRGs), starting to decrease at the age of 4 weeks and being maintained to 8 weeks. Intrathecal administration of miRNA-325-5p agomir significantly enhanced the colorectal distention (CRD) threshold in a time-dependent manner. NCI also markedly increased the expression of CCL2 (C-C motif chemokine ligand 2) in colon-related DRGs at the mRNA and protein levels relative to age-matched control rats. The expression of CXCL12, IL33, SFRS7, and LGI1 was not significantly altered in NCI rats. CCL2 was co-expressed in NeuN-positive DRG neurons but not in glutamine synthetase-positive glial cells. Furthermore, CCL2 was mainly expressed in isolectin B4-binding- and calcitonin gene-related peptide-positive DRG neurons but in few NF-200-positive cells. More importantly, CCL2 was expressed in miR-325-5p-positive DRG neurons. Intrathecal injection of miRNA-325-5p agomir remarkably reduced the upregulation of CCL2 in NCI rats. Administration of Bindarit, an inhibitor of CCL2, markedly raised the CRD threshold in NCI rats in a dose- and time-dependent manner. These data suggest that NCI suppresses miRNA-325-5p expression and enhances CCL2 expression, thus contributing to visceral hypersensitivity in adult rats.
Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling.
Apr 13, 2019   Neuromolecular Medicine
Zhu WW, Ning M, Peng YZ, Tang YY, Kang X, Zhan KB, Zou W, Zhang P, Tang XQ
Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling.
Apr 13, 2019
Neuromolecular Medicine
It has been previously demonstrated that hydrogen sulfide (H2S) prevents formaldehyde (FA)-induced neurotoxicity. However, the exact mechanisms underlying this protection remain to be fully elucidated. Neuronal senescence is involved in FA-induced neurotoxicity. Leptin signaling has anti-aging function. The present work was to investigate the protection of H2S against FA-induced neuronal senescence and the mediatory role of leptin signaling. FA-exposed HT-22 cells were used as the vitro model of FA-induced neuronal senescence. The senescence-associated β-galactosidase (SA-β-Gal) positive cell was detected by β-galactosidase staining. The expressions of P16INK4a, P21CIP1, leptin, and lepRb (leptin receptor) were measured by western blot. The proliferation, viability, and apoptosis of cells were evaluated by Trypan blue exclusion assay, Cell Counting Kit-8 (CCK-8) assay, and Flow cytometry analysis, respectively. We found that H2S suppressed FA-induced senescence, as evidenced by the decrease in SA-β-Gal positive cells, the downregulations of P16INK4a and P21CIP1, as well as decrease in cell growth arrest, in HT-22 cells. Also, H2S upregulated the expressions of leptin and lepRb in FA-exposed HT-22 cells. Furthermore, leptin tA (a specific inhibitor of the leptin) abolished the protective effects of H2S on FA-induced senescence and neurotoxicity (as evidenced by the increase in cell viability and the decrease in cell apoptosis) in HT-22 cells. These results indicated that H2S prevents FA-induced neuronal senescence via upregulation of leptin signaling. Our findings offer a novel insight into the mechanisms underlying the protection of H2S against FA-induced neurotoxicity. FA upregulates the expressions of P16INK4a and P21CIP1 via inhibiting leptin signaling, which in turn induces senescence in HT-22 cells; H2S downregulates the expressions of P16INK4a and P21CIP1 via reversing FA-downregulated leptin signaling, which in turn prevents FA-induced senescence in HT-22 cells.
New for old.
Apr 13, 2019   Nature Reviews. Neuroscience
Lewis S
New for old.
Apr 13, 2019
Nature Reviews. Neuroscience
Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.
Apr 17, 2019   Translational Psychiatry
Bauman MD, Lesh TA, Rowland DJ, Schumann CM, Smucny J, Kukis DL, Cherry SR, McAllister AK, Carter CS
Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation.
Apr 17, 2019
Translational Psychiatry
Women exposed to a variety of viral and bacterial infections during pregnancy have an increased risk of giving birth to a child with autism, schizophrenia or other neurodevelopmental disorders. Preclinical maternal immune activation (MIA) models are powerful translational tools to investigate mechanisms underlying epidemiological links between infection during pregnancy and offspring neurodevelopmental disorders. Our previous studies documenting the emergence of aberrant behavior in rhesus monkey offspring born to MIA-treated dams extends the rodent MIA model into a species more closely related to humans. Here we present novel neuroimaging data from these animals to further explore the translational potential of the nonhuman primate MIA model. Nine male MIA-treated offspring and 4 controls from our original cohort underwent in vivo positron emission tomography (PET) scanning at approximately 3.5-years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum, which are consistently elevated in individuals with schizophrenia. Analysis of [18F]FMT signal in the striatum of these nonhuman primates showed that MIA animals had significantly higher [18F]FMT index of influx compared to control animals. In spite of the modest sample size, this group difference reflects a large effect size (Cohen's d = 0.998). Nonhuman primates born to MIA-treated dams exhibited increased striatal dopamine in late adolescence-a hallmark molecular biomarker of schizophrenia. These results validate the MIA model in a species more closely related to humans and open up new avenues for understanding the neurodevelopmental biology of schizophrenia and other neurodevelopmental disorders associated with prenatal immune challenge.
Targeting senescence.
Apr 13, 2019   Nature Reviews. Neuroscience
Lewis S
Targeting senescence.
Apr 13, 2019
Nature Reviews. Neuroscience
Where to eat?
Apr 13, 2019   Nature Reviews. Neuroscience
Lewis S
Where to eat?
Apr 13, 2019
Nature Reviews. Neuroscience
MiR-218: a molecular switch and potential biomarker of susceptibility to stress.
Apr 16, 2019   Molecular Psychiatry
Torres-Berrío A, Nouel D, Cuesta S, Parise EM, Restrepo-Lozano JM, Larochelle P, Nestler EJ, Flores C
MiR-218: a molecular switch and potential biomarker of susceptibility to stress.
Apr 16, 2019
Molecular Psychiatry
Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in blood, as compared with control or resilient groups. We show further that upregulation and downregulation of miR-218 levels specifically in the mPFC correlate with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility vs. resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.
Chronic sleep fragmentation enhances habenula cholinergic neural activity.
Apr 13, 2019   Molecular Psychiatry
Ge F, Mu P, Guo R, Cai L, Liu Z, Dong Y, Huang YH
Chronic sleep fragmentation enhances habenula cholinergic neural activity.
Apr 13, 2019
Molecular Psychiatry
Sleep is essential to emotional health. Sleep disturbance, particularly REM sleep disturbance, profoundly impacts emotion regulation, but the underlying neural mechanisms remain elusive. Here we show that chronic REM sleep disturbance, achieved in mice by chronic sleep fragmentation (SF), enhanced neural activity in the medial habenula (mHb), a brain region increasingly implicated in negative affect. Specifically, after a 5-day SF procedure that selectively fragmented REM sleep, cholinergic output neurons (ChNs) in the mHb exhibited increased spontaneous firing rate and enhanced firing regularity in brain slices. The SF-induced firing changes remained intact upon inhibition of glutamate, GABA, acetylcholine, and histamine receptors, suggesting cell-autonomous mechanisms independent of synaptic transmissions. Moreover, the SF-induced hyperactivity was not because of enhanced intrinsic membrane excitability, but was accompanied by depolarized resting membrane potential in mHb ChNs. Furthermore, inhibition of TASK-3 (KCNK9) channels, a subtype of two-pore domain K+ channels, mimicked the SF effects by increasing the firing rate and regularity, as well as depolarizing the resting membrane potential in mHb ChNs in control-sleep mice. These effects of TASK-3 inhibition were absent in SF mice, suggesting reduced TASK-3 activity following SF. By contrast, inhibition of small-conductance Ca2+-activated K+ (SK) channels did not produce similar effects. Thus, SF compromised TASK-3 function in mHb ChNs, which likely led to depolarized resting membrane potential and increased spontaneous firing. These results not only demonstrate that selective REM sleep disturbance leads to hyperactivity of mHb ChNs, but also identify a key molecular substrate through which REM sleep disturbance may alter affect regulation.
Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.
Apr 16, 2019   Molecular Psychiatry
Arber C, Toombs J, Lovejoy C, Ryan NS, Paterson RW,   . . . . . .   , Hardy J, Lashley T, Fox NC, Zetterberg H, Wray S
Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.
Apr 16, 2019
Molecular Psychiatry
Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.
Developmental differences in the expression of ABC transporters at rat brain barrier interfaces following chronic exposure to diallyl sulfide.
Apr 13, 2019   Scientific Reports
Koehn LM, Dziegielewska KM, Møllgård K, Saudrais E, Strazielle N, Ghersi-Egea JF, Saunders NR, Habgood MD
Developmental differences in the expression of ABC transporters at rat brain barrier interfaces following chronic exposure to diallyl sulfide.
Apr 13, 2019
Scientific Reports
Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s-transferase (GST) were measured in livers, brain cortices (blood-brain-barrier) and choroid plexuses (blood-cerebrospinal fluid, CSF, barrier) during postnatal rat development. Controls were compared to animals chronically injected (4 days, 200 mg/kg/day) with known abcb1a inducer diallyl sulfide (DAS). Results reveal both tissue- and age-dependent regulation. In liver abcb1a and abcc3 were up-regulated at all ages. In cortex abcb1a/b, abcg2 and abcc4/abcc5 were up-regulated in adults only, while in choroid plexus abcb1a and abcc2 were up-regulated only at P14. DAS treatment increased GST activity in livers, but not in cortex or choroid plexuses. Immunocytochemistry of ABC transporters at the CSF-brain interface showed that PGP and BCRP predominated in neuroepithelium while MRP2/4/5 were prominent in adult ependyma. These results indicate an age-related capacity of brain barriers to dynamically regulate their defence mechanisms when chronically challenged by xenobiotic compounds.
Intergeneric hybrids inform reproductive isolating barriers in the Antarctic icefish radiation.
Apr 13, 2019   Scientific Reports
Desvignes T, Le François NR, Goetz LC, Smith SS, Shusdock KA, Parker SK, Postlethwait JH, Detrich HW
Intergeneric hybrids inform reproductive isolating barriers in the Antarctic icefish radiation.
Apr 13, 2019
Scientific Reports
Interspecific hybridization or barriers to hybridization may have contributed to the diversification of Antarctic icefishes (Channichthyidae), but data supporting these hypotheses is scarce. To understand the potential for hybridization and to investigate reproductive isolating mechanisms among icefish species, we performed in vitro fertilization experiments using eggs from a female blackfin icefish Chaenocephalus aceratus and sperm from a male of another genera, the ocellated icefish Chionodraco rastrospinosus. Sequencing of genomic and mitochondrial DNA confirmed the intergeneric hybrid nature of resulting embryos which successfully developed and hatched as active larvae at about four and a half months during the Antarctic winter. This result demonstrates the compatibility of gametes of these two species and the viability of resulting zygotes and larvae. Due to logistic constraints and the slow developmental rate of icefishes, we could not test for long-term hybrid viability, fertility, fitness, or hybrid breakdown. Analysis of our fishing records and available literature, however, suggests that the strongest barriers to hybridization among parapatric icefish species are likely to be behavioral and characterized by assortative mating and species-specific courtship and nesting behaviors. This conclusion suggests that, in long-lived fish species with late sexual maturity and high energetic investment in reproduction like icefishes, pre-mating barriers are energetically more efficient than post-mating barriers to prevent hybridization.
The serial blocking effect: a testbed for the neural mechanisms of temporal-difference learning.
Apr 13, 2019   Scientific Reports
Mahmud A, Petrov P, Esber GR, Iordanova MD
The serial blocking effect: a testbed for the neural mechanisms of temporal-difference learning.
Apr 13, 2019
Scientific Reports
Temporal-difference (TD) learning models afford the neuroscientist a theory-driven roadmap in the quest for the neural mechanisms of reinforcement learning. The application of these models to understanding the role of phasic midbrain dopaminergic responses in reward prediction learning constitutes one of the greatest success stories in behavioural and cognitive neuroscience. Critically, the classic learning paradigms associated with TD are poorly suited to cast light on its neural implementation, thus hampering progress. Here, we present a serial blocking paradigm in rodents that overcomes these limitations and allows for the simultaneous investigation of two cardinal TD tenets; namely, that learning depends on the computation of a prediction error, and that reinforcing value, whether intrinsic or acquired, propagates back to the onset of the earliest reliable predictor. The implications of this paradigm for the neural exploration of TD mechanisms are highlighted.
Altered steady state and activity-dependent de novo protein expression in fragile X syndrome.
Apr 17, 2019   Nature Communications
Bowling H, Bhattacharya A, Zhang G, Alam D, Lebowitz JZ,   . . . . . .   , Sharp K, Kirshenbaum K, Berry-Kravis E, Neubert TA, Klann E
Altered steady state and activity-dependent de novo protein expression in fragile X syndrome.
Apr 17, 2019
Nature Communications
Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.
Human noise blindness drives suboptimal cognitive inference.
Apr 17, 2019   Nature Communications
Herce Castañón S, Moran R, Ding J, Egner T, Bang D, Summerfield C
Human noise blindness drives suboptimal cognitive inference.
Apr 17, 2019
Nature Communications
Humans typically make near-optimal sensorimotor judgements but show systematic biases when making more cognitive judgements. Here we test the hypothesis that, while humans are sensitive to the noise present during early sensory encoding, the "optimality gap" arises because they are blind to noise introduced by later cognitive integration of variable or discordant pieces of information. In six psychophysical experiments, human observers judged the average orientation of an array of contrast gratings. We varied the stimulus contrast (encoding noise) and orientation variability (integration noise) of the array. Participants adapted near-optimally to changes in encoding noise, but, under increased integration noise, displayed a range of suboptimal behaviours: they ignored stimulus base rates, reported excessive confidence in their choices, and refrained from opting out of objectively difficult trials. These overconfident behaviours were captured by a Bayesian model blind to integration noise. Our study provides a computationally grounded explanation of human suboptimal cognitive inference.
Stress and the medial temporal lobe at rest: Functional connectivity is associated with both memory and cortisol.
Apr 17, 2019   Psychoneuroendocrinology
Shields GS, McCullough AM, Ritchey M, Ranganath C, Yonelinas AP
Stress and the medial temporal lobe at rest: Functional connectivity is associated with both memory and cortisol.
Apr 17, 2019
Psychoneuroendocrinology
When acute stress is experienced immediately after memory encoding (i.e., post-encoding stress) it can significantly impact subsequent memory for that event. For example, recent work has suggested that post-encoding stress occurring in a different context from encoding impairs memory. However, the neural processes underlying these effects are poorly understood. We aimed to expand this understanding by conducting an analysis of resting functional connectivity in the period following post-encoding stress that occurred in a different context than encoding, using seed regions in the medial temporal lobes known for their roles in memory. In the current study of 44 males randomized to stress (n = 23) or control (n = 21) groups, we found that stress increased cortisol, impaired recollection of neutral materials, and altered functional connectivity with medial temporal lobe regions. Although stress did not significantly alter hippocampus-amygdala functional connectivity, relative to participants in the control group, participants in the post-encoding stress group showed lower functional connectivity between the hippocampus and a region with a peak in the superior temporal gyrus. Across participants in both groups, functional connectivity between these regions was related to greater increases in cortisol, and it was also inversely related to recollection of neutral materials. In contrast, the stress group showed greater parahippocampal cortex functional connectivity with a region in the left middle temporal gyrus than the control group. Moreover, greater functional connectivity between the parahippocampal cortex and the observed cluster in the middle temporal gyrus was associated with greater cortisol changes from pre- to post-manipulation, but was not related to differences in memory. The results show that post-encoding stress can alter the resting-state functional connectivity between the medial temporal lobe and neocortex, which may help explain how stress impacts memory.

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