Article added to library!
x
Pubchase is a service of protocols.io - free, open access, crowdsourced protocols repository. Explore protocols.
Sign in
Reset password
or connect with
Facebook
By signing in you are agreeing to our
Terms Of Service and Privacy Policy
Neurobiology
Oscillating PDF in termini of circadian pacemaker neurons and synchronous molecular clocks in downstream neurons are not sufficient for sustenance of activity rhythms in constant darkness
May 30, 2017   PloS One
Prakash P, Nambiar A, Sheeba V
Oscillating PDF in termini of circadian pacemaker neurons and synchronous molecular clocks in downstream neurons are not sufficient for sustenance of activity rhythms in constant darkness
May 30, 2017
PloS One
In Drosophila, neuropeptide Pigment Dispersing Factor (PDF) is expressed in small and large ventral Lateral Neurons (sLNv and lLNv), among which sLNv are critical for activity rhythms in constant darkness. Studies show that this is mediated by rhythmic accumulation and likely secretion of PDF from sLNv dorsal projections, which in turn synchronises molecular oscillations in downstream circadian neurons. Using targeted expression of a neurodegenerative protein Huntingtin in LNv, we evoke a selective loss of neuropeptide PDF and clock protein PERIOD from sLNv soma. However, PDF is not lost from sLNv dorsal projections and lLNv. These flies are behaviourally arrhythmic in constant darkness despite persistence of PDF oscillations in sLNv dorsal projections and synchronous PERIOD oscillations in downstream circadian neurons. We find that PDF oscillations in sLNv dorsal projections are not sufficient for sustenance of activity rhythms in constant darkness and this is suggestive of an additional component that is possibly dependent on sLNv molecular clock and PDF in sLNv soma. Additionally, despite loss of PERIOD in sLNv, their activity rhythms entrain to light/dark cycles indicating that sLNv molecular clocks are not necessary for entrainment. Under constant light, these flies lack PDF from both soma and dorsal projections of sLNv, and when subjected to light/dark cycles, show morning and evening anticipation and accurately phased morning and evening peaks. Thus, under light/dark cycles, PDF in sLNv is not necessary for morning anticipation.
Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
May 25, 2017   PloS One
Nuvolone M, Paolucci M, Sorce S, Kana V, Moos R, Matozaki T, Aguzzi A
Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
May 25, 2017
PloS One
Prion diseases are neurodegenerative conditions caused by misfolding of the prion protein, leading to conspicuous neuronal loss and intense microgliosis. Recent experimental evidence point towards a protective role of microglia against prion-induced neurodegeneration, possibly through elimination of prion-containing apoptotic bodies. The molecular mechanisms by which microglia recognize and eliminate apoptotic cells in the context of prion diseases are poorly defined. Here we investigated the possible involvement of signal regulatory protein α (SIRPα), a key modulator of host cell phagocytosis; SIRPα is encoded by the Sirpa gene that is genetically linked to the prion gene Prnp. We found that Sirpa transcripts are highly enriched in microglia cells within the brain. However, Sirpa mRNA levels were essentially unaltered during the course of experimental prion disease despite upregulation of other microglia-enriched transcripts. To study the involvement of SIRPα in prion pathogenesis in vivo, mice expressing a truncated SIRPα protein unable to inhibit phagocytosis were inoculated with rodent-adapted scrapie prions of the 22L strain. Homozygous and heterozygous Sirpa mutants and wild-type mice experienced similar incubation times after inoculation with either of two doses of 22L prions. Moreover, the extent of neuronal loss, microgliosis and abnormal prion protein accumulation was not significantly affected by Sirpa genotypes. Collectively, these data indicate that SIRPα-mediated phagocytosis is not a major determinant in prion disease pathogenesis. It will be important to search for additional candidates mediating prion phagocytosis, as this mechanism may represent an important target of antiprion therapies.
Molecular dynamics analysis of the aggregation propensity of polyglutamine segments
May 25, 2017   PloS One
Wen J, Scoles DR, Facelli JC
Molecular dynamics analysis of the aggregation propensity of polyglutamine segments
May 25, 2017
PloS One
Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases. This study finds a predominance in long-distance interactions between residues far apart in polyQ sequences with longer polyQ segments, that leads to significant conformational differences. This study also indicates that large loops, comprised of parallel β-structures, appear in long polyQ tracts and present new aggregation building blocks with aggregation driven by long-distance intra-polyQ interactions. Finally, consistent with previous observations using coarse-grain simulations, this study demonstrates that there is a gain in the aggregation propensity with increased polyQ length, and that this gain is correlated with decreasing ability of solvent-polyQ interaction. These results suggest the modulation of solvent-polyQ interactions as a possible therapeutic strategy for treating polyQ diseases.
Quantitative magnetic resonance imaging of brain atrophy in a mouse model of Niemann-Pick type C disease
May 25, 2017   PloS One
Totenhagen JW, Bernstein A, Yoshimaru ES, Erickson RP, Trouard TP
Quantitative magnetic resonance imaging of brain atrophy in a mouse model of Niemann-Pick type C disease
May 25, 2017
PloS One
In vivo magnetic resonance imaging (MRI) was used to investigate regional and global brain atrophy in the neurodegenerative Niemann Pick Type C1 (NPC1) disease mouse model. Imaging experiments were conducted with the most commonly studied mouse model of NPC1 disease at early and late disease states. High-resolution in vivo images were acquired at early and late stages of the disease and analyzed with atlas-based registration to obtain measurements of twenty brain region volumes. A two-way ANOVA analysis indicated eighteen of these regions were different due to genotype and thirteen showed a significant interaction with age and genotype. The ability to measure in vivo neurodegeneration evidenced by brain atrophy adds to the ability to monitor disease progression and treatment response in the mouse model.
Influence of catch up growth on spatial learning and memory in a mouse model of intrauterine growth restriction
May 25, 2017   PloS One
Duran Fernandez-Feijoo C, Carrasco Carrasco C, Villalmazo Francisco N, Cebrià Romero J, Fernández Lorenzo JR, Jiménez-Chillaron JC, Camprubí Camprubí M
Influence of catch up growth on spatial learning and memory in a mouse model of intrauterine growth restriction
May 25, 2017
PloS One
Intrauterine growth restriction (IUGR) and rapid postnatal weight gain or catch up growth (CUG) increase the susceptibility to metabolic syndrome during adult life. Longitudinal studies have also revealed a high incidence of learning difficulties in children with IUGR. The aim of the present study was to investigate the effect of nutrition and CUG on learning memory in an IUGR animal model. We hypothesized that synaptic protein expression and transcription, an essential mechanism for memory consolidation, might be affected by intrauterine undernutrition. IUGR was induced by 50% maternal caloric undernutrition throughout late gestation. During the suckling period, dams were either fed ad libitum or food restricted. The pups were divided into: Normal prenatal diet-Normal postnatal diet (NN), Restricted prenatal diet- Normal postnatal diet + catch up growth (RN+), Normal prenatal diet-Restricted postnatal diet (NR) and Restricted prenatal diet-Restricted postnatal diet (RR). At 4 weeks of age, memory was assessed via a water maze test. To evaluate synaptic function, 2 specific synaptic proteins (postsynaptic density-95 [PSD95], synaptophysin) as well as insulin receptors (IR) were tested by Western Blot and quantitative polymerase chain reaction (qPCR). Brain-derived neurotrophic factor and serum insulin levels were also studied. The RN+ group presented a learning curve similar to the NN animals. The RR animals without CUG showed learning disabilities. PSD95 was lower in the RR group than in the NN and RN+ mice. In contrast, synaptophysin was similar in all groups. IR showed an inverse expression pattern to that of the PSD95. In conclusion, perinatal nutrition plays an important role in learning. CUG after a period of prenatal malnutrition seems to improve learning skills. The functional alterations observed might be related to lower PSD95 activity and a possible dysfunction in the hormone regulation of synaptic plasticity.
A link between thrifty phenotype and maternal care across two generations of intercrossed mice
May 25, 2017   PloS One
Sauce B, Goes CP, Forti I, O do Monte BG, Watanabe IM, Cunha J, Peripato AC
A link between thrifty phenotype and maternal care across two generations of intercrossed mice
May 25, 2017
PloS One
Maternal effects are causal influences from mother to offspring beyond genetic information, and have lifelong consequences for multiple traits. Previously, we reported that mice whose mothers did not nurse properly had low birth weight followed by rapid fat accumulation and disturbed development of some organs. That pattern resembles metabolic syndromes known collectively as the thrifty phenotype, which is believed to be an adaptation to a stressful environment which prepares offspring for reduced nutrient supply. The potential link between maternal care, stress reactivity, and the thrifty phenotype, however, has been poorly explored in the human and animal literature: only a couple of studies even mention (much less, test) these concepts under a cohesive framework. Here, we explored this link using mice of the parental inbred strains SM/J and LG/J-who differ dramatically in their maternal care-and the intercrossed generations F1 and F2. We measured individual differences in 15 phenotypes and used structural equation modeling to test our hypotheses. We found a remarkable relationship between thrifty phenotype and lower quality of maternal behaviors, including nest building, pup retrieval, grooming/licking, and nursing. To our knowledge, this is the first study to show, in any mammal, a clear connection between the natural variation in thrifty phenotype and maternal care. Both traits in the mother also had a substantial effect on survival rate in the F3 offspring. To our surprise, however, stress reactivity seemed to play no role in our models. Furthermore, the strain of maternal grandmother, but not of paternal grandmother, affected the variation of maternal care in F2 mice, and this effect was mediated by thrifty phenotype in F2. Since F1 animals were all genetically identical, this finding suggests that maternal effects pass down both maternal care and thrifty phenotype in these mice across generations via epigenetic transmission.
Feasibility study of TSPO quantification with [18F]FEPPA using population-based input function
May 25, 2017   PloS One
Mabrouk R, Strafella AP, Knezevic D, Ghadery C, Mizrahi R, Gharehgazlou A, Koshimori Y, Houle S, Rusjan P
Feasibility study of TSPO quantification with [18F]FEPPA using population-based input function
May 25, 2017
PloS One
The input function (IF) is a core element in the quantification of Translocator protein 18 kDa with positron emission tomography (PET), as no suitable reference region with negligible binding has been identified. Arterial blood sampling is indeed needed to create the IF (ASIF). In the present manuscript we study individualization of a population based input function (PBIF) with a single arterial manual sample to estimate total distribution volume (VT) for [18F]FEPPA and to replicate previously published clinical studies in which the ASIF was used. The data of 3 previous [18F]FEPPA studies (39 of healthy controls (HC), 16 patients with Parkinson's disease (PD) and 18 with Alzheimer's disease (AD)) was reanalyzed with the new approach. PBIF was used with the Logan graphical analysis (GA) neglecting the vascular contribution to estimate VT. Time of linearization of the GA was determined with the maximum error criteria. The optimal calibration of the PBIF was determined based on the area under the curve (AUC) of the IF and the agreement range of VT between methods. The shape of the IF between groups was studied while taking into account genotyping of the polymorphism (rs6971). PBIF scaled with a single value of activity due to unmetabolized radioligand in arterial plasma, calculated as the average of a sample taken at 60 min and a sample taken at 90 min post-injection, yielded a good interval of agreement between methods and optimized the area under the curve of IF. In HC, gray matter VTs estimated by PBIF highly correlated with those using the standard method (r2 = 0.82, p = 0.0001). Bland-Altman plots revealed PBIF slightly underestimates (~1 mL/cm3) VT calculated by ASIF (including a vascular contribution). It was verified that the AUC of the ASIF were independent of genotype and disease (HC, PD, and AD). Previous clinical results were replicated using PBIF but with lower statistical power. A single arterial blood sample taken 75 minute post-injection contains enough information to individualize the IF in the groups of subjects studied; however, the higher variability produced requires an increase in sample size to reach the same effect size.
A neural circuit architecture for angular integration in Drosophila
May 24, 2017   Nature Add nature.com free-link Cancel
Green J, Adachi A, Shah KK, Hirokawa JD, Magani PS, Maimon G
A neural circuit architecture for angular integration in Drosophila
May 24, 2017
Nature
Many animals keep track of their angular heading over time while navigating through their environment. However, a neural-circuit architecture for computing heading has not been experimentally defined in any species. Here we describe a set of clockwise- and anticlockwise-shifting neurons in the Drosophila central complex whose wiring and physiology provide a means to rotate an angular heading estimate based on the fly's angular velocity. We show that each class of shifting neurons exists in two subtypes, with spatiotemporal activity profiles that suggest different roles for each subtype at the start and end of tethered-walking turns. Shifting neurons are required for the heading system to properly track the fly's heading in the dark, and stimulation of these neurons induces predictable shifts in the heading signal. The central features of this biological circuit are analogous to those of computational models proposed for head-direction cells in rodents and may shed light on how neural systems, in general, perform integration.
ROS regulation of axonal mitochondrial transport is mediated by Ca2+ and JNK in Drosophila
May 25, 2017   PloS One
Liao PC, Tandarich LC, Hollenbeck PJ
ROS regulation of axonal mitochondrial transport is mediated by Ca2+ and JNK in Drosophila
May 25, 2017
PloS One
Mitochondria perform critical functions including aerobic ATP production and calcium (Ca2+) homeostasis, but are also a major source of reactive oxygen species (ROS) production. To maintain cellular function and survival in neurons, mitochondria are transported along axons, and accumulate in regions with high demand for their functions. Oxidative stress and abnormal mitochondrial axonal transport are associated with neurodegenerative disorders. However, we know little about the connection between these two. Using the Drosophila third instar larval nervous system as the in vivo model, we found that ROS inhibited mitochondrial axonal transport more specifically, primarily due to reduced flux and velocity, but did not affect transport of other organelles. To understand the mechanisms underlying these effects, we examined Ca2+ levels and the JNK (c-Jun N-terminal Kinase) pathway, which have been shown to regulate mitochondrial transport and general fast axonal transport, respectively. We found that elevated ROS increased Ca2+ levels, and that experimental reduction of Ca2+ to physiological levels rescued ROS-induced defects in mitochondrial transport in primary neuron cell cultures. In addition, in vivo activation of the JNK pathway reduced mitochondrial flux and velocities, while JNK knockdown partially rescued ROS-induced defects in the anterograde direction. We conclude that ROS have the capacity to regulate mitochondrial traffic, and that Ca2+ and JNK signaling play roles in mediating these effects. In addition to transport defects, ROS produces imbalances in mitochondrial fission-fusion and metabolic state, indicating that mitochondrial transport, fission-fusion steady state, and metabolic state are closely interrelated in the response to ROS.
Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia
May 25, 2017   PloS One
Akhtar RS, Xie SX, Chen YJ, Rick J, Gross RG, Nasrallah IM, Van Deerlin VM, Trojanowski JQ, Chen-Plotkin AS, Hurtig HI, Siderowf AD, Dubroff JG, Weintraub D
Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia
May 25, 2017
PloS One
Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-β accumulation to these problems is unclear. We hypothesized that amyloid-β PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-β plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients. We assessed 61 non-demented Parkinson disease patients with detailed cognitive assessments and 18F-florbetapir PET brain imaging. Scans were interpreted qualitatively (positive or negative) by two independent nuclear medicine physicians blinded to clinical data, and quantitatively by a novel volume-weighted method. The presence of mild cognitive impairment was determined through an expert consensus process using Level 1 criteria from the Movement Disorder Society. Nineteen participants (31.2%) were diagnosed with mild cognitive impairment and the remainder had normal cognition. Qualitative 18F-florbetapir PET imaging was positive in 15 participants (24.6%). Increasing age and presence of an APOE ε4 allele were associated with higher composite 18F-florbetapir binding. In multivariable models, an abnormal 18F-florbetapir scan by expert rating was not associated with a diagnosis of mild cognitive impairment. However, 18F-florbetapir retention values in the posterior cingulate gyrus inversely correlated with verbal memory performance. Retention values in the frontal cortex, precuneus, and anterior cingulate gyrus retention values inversely correlated with naming performance. Regional cortical amyloid-β amyloid, as measured by 18F-florbetapir PET, may be a biomarker of specific cognitive deficits in non-demented Parkinson disease patients.
N-acetylaspartylglutamate Inhibits Heroin Self-Administration and Heroin-Seeking Behaviors Induced by Cue or Priming in Rats
May 23, 2017   Neuroscience Bulletin
Zhu H, Lai M, Chen W, Mei D, Zhang F, Liu H, Zhou W
N-acetylaspartylglutamate Inhibits Heroin Self-Administration and Heroin-Seeking Behaviors Induced by Cue or Priming in Rats
May 23, 2017
Neuroscience Bulletin
Activation of presynaptic group II metabotropic glutamate receptors (mGluR2/3) inhibits drug reward and drug-seeking behavior, but the role of N-acetylaspartylglutamate (NAAG), an agonist of endogenous mGluR2/3, in heroin reward and heroin-seeking behavior remained unclear. Here, we aimed to explore the effects of exogenous NAAG on heroin self-administration and heroin-seeking behavior. First, rats were trained to self-administer heroin under a fixed ratio 1 (FR1) schedule for 10 days, then received NAAG (50 or 100 μg/10 μL in each nostril) in the absence or presence of LY341495 (1 mg/kg, i.p.), an antagonist of mGluR2/3, on day 11 and the effects of NAAG on heroin self-administration under FR1 were recorded for 3 consecutive days. Motivation was assessed in heroin self-administration under a progressive ratio schedule on day 11 in another 5 groups with the same doses of NAAG. Additional rats were withdrawn for 14 days after 14 days of heroin self-administration, then received the same pharmacological pretreatment and were tested for heroin-seeking behaviors induced by heroin priming or cues. The results showed that intranasal administration of NAAG significantly decreased intravenous heroin self-administration on day 12, but not on day 11. Pretreatment with LY341495 prior to testing on day 12 prevented the inhibitory effect of NAAG on heroin reinforcement. The break-point for reward motivation was significantly reduced by NAAG. Moreover, NAAG also significantly inhibited the heroin-seeking behaviors induced by heroin priming or cues and these were restored by pretreatment with LY341495. These results demonstrated that NAAG, via activation of presynaptic mGluR2/3, attenuated the heroin reinforcement, heroin motivational value, and heroin-seeking behavior, suggesting that it may be used as an adjunct treatment for heroin addiction.
Mechanisms of Orientation Selectivity in the Primary Visual Cortex
May 23, 2017   Annual Review Of Vision Science
Priebe NJ
Mechanisms of Orientation Selectivity in the Primary Visual Cortex
May 23, 2017
Annual Review Of Vision Science
The mechanisms underlying the emergence of orientation selectivity in the visual cortex have been, and continue to be, the subjects of intense scrutiny. Orientation selectivity reflects a dramatic change in the representation of the visual world: Whereas afferent thalamic neurons are generally orientation insensitive, neurons in the primary visual cortex (V1) are extremely sensitive to stimulus orientation. This profound change in the receptive field structure along the visual pathway has positioned V1 as a model system for studying the circuitry that underlies neural computations across the neocortex. The neocortex is characterized anatomically by the relative uniformity of its circuitry despite its role in processing distinct signals from region to region. A combination of physiological, anatomical, and theoretical studies has shed some light on the circuitry components necessary for generating orientation selectivity in V1. This targeted effort has led to critical insights, as well as controversies, concerning how neural circuits in the neocortex perform computations.
Exogenous expression of Drp1 plays neuroprotective roles in the Alzheimer's disease in the Aβ42 transgenic Drosophila model
May 22, 2017   PloS One
Lv F, Yang X, Cui C, Su C
Exogenous expression of Drp1 plays neuroprotective roles in the Alzheimer's disease in the Aβ42 transgenic Drosophila model
May 22, 2017
PloS One
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Recent studies have shown that mitochondrial dysfunction is a causative factor of AD. Drp1 (Dynamin-related protein 1), a regulator of mitochondrial fission, shows neuroprotective effects on Parkinson's disease. In this study, we investigate the effect and mechanism of Drp1 on Aβ42 transgenic Drosophila. Elav-gal4/UAS>Aβ42 transgenic Drosophila model was constructed using Elav-gal4 promoter. The effects of Drp1 on the lifespan, motor ability and neuronal degeneration of the transgenic Drosophila were explored by over-expressing Drp1 in the Aβ42 transgenic Drosophila. ATP levels in the brain tissues of Aβ42 transgenic Drosophila were detected using high performance liquid chromatography (HPLC). Exogenous expression of Drp1 promoted crawling ability, reduced the levels of ATP in Drosophila brain and suppressed the neuronal degeneration. The protective effect of Drp1 on the Aβ42 transgenic Drosophila was achieved by protecting the mitochondrial function, suggesting that Drp1 may be a potential therapeutic strategies for AD.
Characterization of TauC3 antibody and demonstration of its potential to block tau propagation
May 22, 2017   PloS One
Nicholls SB, DeVos SL, Commins C, Nobuhara C, Bennett RE, Corjuc DL, Maury E, Eftekharzadeh B, Akingbade O, Fan Z, Roe AD, Takeda S, Wegmann S, Hyman BT
Characterization of TauC3 antibody and demonstration of its potential to block tau propagation
May 22, 2017
PloS One
The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer's disease (AD), which is thought to be caused by the propagation of "seeding" competent soluble misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.
No relevant association of kinematic gait parameters with Health-related Quality of Life in Parkinson's disease
May 22, 2017   PloS One
Bettecken K, Bernhard F, Sartor J, Hobert MA, Hofmann M, Gladow T, van Uem JMT, Liepelt-Scarfone I, Maetzler W
No relevant association of kinematic gait parameters with Health-related Quality of Life in Parkinson's disease
May 22, 2017
PloS One
Health-related Quality of Life (HrQoL) is probably the most important outcome parameter for the evaluation and management of chronic diseases. As this parameter is subjective and prone to bias, there is an urgent need to identify objective surrogate markers. Gait velocity has been shown to be associated with HrQoL in numerous chronic diseases, such as Parkinson's disease (PD). With the development and wide availability of simple-to-use wearable sensors and sophisticated gait algorithms, kinematic gait parameters may soon be implemented in clinical routine management. However, the association of such kinematic gait parameters with HrQoL in PD has not been assessed to date. Kinematic gait parameters from a 20-meter walk from 43 PD patients were extracted using a validated wearable sensor system. They were compared with the Visual Analogue Scale of the Euro-Qol-5D (EQ-5D VAS) by performing a multiple regression analysis, with the International Classification of Functioning, Disability and Health (ICF) model as a framework. Use of assistive gait equipment, but no kinematic gait parameter, was significantly associated with HrQoL. The widely accepted concept of a positive association between gait velocity and HrQoL may, at least in PD, be driven by relatively independent parameters, such as assistive gait equipment.
Reduced expression of Foxp1 as a contributing factor in Huntington's disease
May 27, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Louis Sam Titus ASC, Yusuff T, Cassar M, Thomas E, Kretzschmar D, D'Mello SR
Reduced expression of Foxp1 as a contributing factor in Huntington's disease
May 27, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine expansion in the huntington protein (htt). The neuropathological hallmark of HD is the loss of neurons in the striatum and, to a lesser extent, in the cortex. Foxp1 is a member of the Forkhead family of transcription factors expressed selectively in the striatum and the cortex. In the brain, three major Foxp1 isoforms are expressed - isoform-A (∼90 kDa), isoform-D (∼70 kDa) and isoform-C (∼50 kDa). We find that expression of Foxp1 isoforms A and D is selectively reduced in the striatum and cortex of R6/2 HD mice as well as in the striatum of HD patients. Furthermore, expression of mutant htt in neurons results in the downregulation of Foxp1 Elevating expression of isoform A or D protects cortical neurons from death caused by the expression of mutant htt On the other hand, knockdown of Foxp1 promotes death in otherwise healthy neurons. Neuroprotection by Foxp1 is likely to be mediated by the transcriptional stimulation of the cell cycle inhibitory protein, p21Waf1/Cip1. Consistently, Foxp1 activates transcription of the p21Waf1/Cip1 gene promoter and overexpression of Foxp1 in neurons results in the elevation of p21 expression. Moreover, knocking down of p21Waf1/Cip1 blocks the ability of Foxp1 to protect neurons from mut-Htt-induced neurotoxicity. We propose that the selective vulnerability of neurons of the striatum and cortex in HD is related to the loss of expression of Foxp1, a protein that is highly expressed in these neurons and required for their survival.SIGNIFICANCE STATEMENTAlthough the mutant huntingtin gene is expressed widely, neurons of the striatum and cortex are selectively affected in Huntington's disease (HD). Our results suggest that this selectivity is due to the reduced expression of Foxp1, a protein expressed selectively in striatal and cortical neurons which plays a neuroprotective role in these cells. We show that protection by Foxp1 involves stimulation of the p21Waf1/Cip1(Cdkn1a) gene. Although three major Foxp1 isoforms (A, C and D) are expressed in the brain, only isoform-A has been studied in the nervous system. We show that isoform-D is also expressed selectively, neuroprotective and downregulated in HD mice and patients. Our results suggest that Foxp1 might be an attractive therapeutic target for HD. Copyright © 2017 the authors.
Dentate gyrus contributes to retrieval as well as encoding: Evidence from context fear conditioning, recall, and extinction
May 26, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Bernier BE, Lacagnina AF, Ayoub A, Shue F, Zemelman BV, Krasne FB, Drew MR
Dentate gyrus contributes to retrieval as well as encoding: Evidence from context fear conditioning, recall, and extinction
May 26, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON, a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear.SIGNIFICANCE STATEMENTDespite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether DG's role relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a longstanding question about the role of DG in memory and provide insight into how disorders affecting DG, including aging, stress and depression, influence cognitive processes. Copyright © 2017 the authors.
Unbiased Proteomics of Early Lewy Body Formation Model Implicates Active Microtubule Affinity-Regulating Kinases (MARKs) in Synucleinopathies
May 19, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Henderson MX, Chung CH, Riddle DM, Zhang B, Gathagan RJ, Seeholzer SH, Trojanowski JQ, Lee VMY
Unbiased Proteomics of Early Lewy Body Formation Model Implicates Active Microtubule Affinity-Regulating Kinases (MARKs) in Synucleinopathies
May 19, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Parkinson's disease (PD) patients progressively accumulate intracytoplasmic inclusions formed by misfolded α-synuclein known as Lewy bodies (LBs). LBs also contain other proteins that may or may not be relevant in the disease process. To identify proteins involved early in LB formation, we performed proteomic analysis of insoluble proteins in a primary neuron culture model of α-synuclein pathology. We identified proteins previously found in authentic LBs in PD as well as several novel proteins, including the microtubule affinity-regulating kinase 1 (MARK1), one of the most enriched proteins in this model of LB formation. Activated MARK proteins (MARKs) accumulated in LB-like inclusions in this cell-based model as well as in a mouse model of LB disease and in LBs of postmortem synucleinopathy brains. Inhibition of MARKs dramatically exacerbated α-synuclein pathology. These findings implicate MARKs early in synucleinopathy pathogenesis and as potential therapeutic drug targets.SIGNIFICANCE STATEMENT Neurodegenerative diseases are diagnosed definitively only in postmortem brains by the presence of key misfolded and aggregated disease proteins, but cellular processes leading to accumulation of these proteins have not been well elucidated. Parkinson's disease (PD) patients accumulate misfolded α-synuclein in LBs, the diagnostic signatures of PD. Here, unbiased mass spectrometry was used to identify the microtubule affinity-regulating kinase family (MARKs) as activated and insoluble in a neuronal culture PD model. Aberrant activation of MARKs was also found in a PD mouse model and in postmortem PD brains. Further, inhibition of MARKs led to increased pathological α-synuclein burden. We conclude that MARKs play a role in PD pathogenesis. Copyright © 2017 the authors 0270-6474/17/375870-15$15.00/0.
Voluntary Control of Epileptiform Spike-Wave Discharges in Awake Rats
May 19, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Taylor JA, Rodgers KM, Bercum FM, Booth CJ, Dudek FE, Barth DS
Voluntary Control of Epileptiform Spike-Wave Discharges in Awake Rats
May 19, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Genetically inherited absence epilepsy in humans is typically characterized by brief (seconds) spontaneous seizures, which involve spike-wave discharges (SWDs) in the EEG and interruption of consciousness and ongoing behavior. Genetic (inbred) models of this disorder in rats have been used to examine mechanisms, comorbidities, and antiabsence drugs. SWDs have also been proposed as models of complex partial seizures (CPSs) following traumatic brain injury (post-traumatic epilepsy). However, the ictal characteristics of these rat models, including SWDs and associated immobility, are also prevalent in healthy outbred laboratory rats. We therefore hypothesized that SWDs are not always associated with classically defined absence seizures or CPSs. To test this hypothesis, we used operant conditioning in male rats to determine whether outbred strains, Sprague Dawley and Long-Evans, and/or the inbred WAG/Rij strain (a rat model of heritable human absence epilepsy) could exercise voluntary control over these epileptiform events. We discovered that both inbred and outbred rats could shorten the duration of SWDs to obtain a reward. These results indicate that SWD and associated immobility in rats may not reflect the obvious cognitive/behavioral interruption classically associated with absence seizures or CPSs in humans. One interpretation of these results is that human absence seizures and perhaps CPSs could permit a far greater degree of cognitive capacity than often assumed and might be brought under voluntary control in some cases. However, these results also suggest that SWDs and associated immobility may be nonepileptic in healthy outbred rats and reflect instead voluntary rodent behavior unrelated to genetic manipulation or to brain trauma.SIGNIFICANCE STATEMENT Our evidence that inbred and outbred rats learn to control the duration of spike-wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior. Copyright © 2017 the authors 0270-6474/17/375861-09$15.00/0.
Mnemonic Encoding and Cortical Organization in Parietal and Prefrontal Cortices
May 25, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Masse NY, Hodnefield JM, Freedman DJ
Mnemonic Encoding and Cortical Organization in Parietal and Prefrontal Cortices
May 25, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Persistent activity within the frontoparietal network is consistently observed during tasks that require working memory. However, the neural circuit mechanisms underlying persistent neuronal encoding within this network remain unresolved. Here, we ask how neural circuits support persistent activity by examining population recordings from posterior parietal (PPC) and prefrontal (PFC) cortices in two male monkeys that performed spatial and motion direction-based tasks that required working memory. While spatially selective persistent activity was observed in both areas, robust selective persistent activity for motion direction was only observed in PFC. Crucially, we find that this difference between mnemonic encoding in PPC and PFC is associated with the presence of functional clustering: PPC and PFC neurons up to ∼700 μm apart preferred similar spatial locations, and PFC neurons up to ∼700 μm apart preferred similar motion directions. In contrast, motion-direction tuning similarity between nearby PPC neurons was much weaker and decayed rapidly beyond ∼200 μm. We also observed a similar association between persistent activity and functional clustering in trained recurrent neural network models embedded with a columnar topology. These results suggest that functional clustering facilitates mnemonic encoding of sensory information.SIGNIFICANCE STATEMENT Working memory refers to our ability to temporarily store and manipulate information. Numerous studies have observed that, during working memory, neurons in higher cortical areas, such as the parietal and prefrontal cortices, mnemonically encode the remembered stimulus. However, several recent studies have failed to observe mnemonic encoding during working memory, raising the question as to why mnemonic encoding is observed during some, but not all, conditions. In this study, we show that mnemonic encoding occurs when a cortical area is organized such that nearby neurons preferentially respond to the same stimulus. This result provides plausible neuronal conditions that allow for mnemonic encoding, and gives us further understanding of the brain's mechanisms that support working memory. Copyright © 2017 the authors 0270-6474/17/376098-15$15.00/0.
Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity
May 24, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Aydemir TB, Kim MH, Kim J, Colon-Perez LM, Banan G, Mareci TH, Febo M, Cousins RJ
Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity
May 24, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.SIGNIFICANCE STATEMENT Manganese is an essential micronutrient. When acquired in excess, manganese accumulates in tissues of the CNS and is associated with neurodegenerative disease, particularly Parkinson-like syndrome and dystonia. Some members of the ZIP metal transporter family transport manganese. Using mutant mice deficient in the ZIP14 metal transporter, we have discovered that ZIP14 is essential for manganese elimination via the gastrointestinal tract, and a lack of ZIP14 results in manganese accumulation in critical tissues such as the brain, as measured by MRI, and produces signatures of brain injury and impaired motor function. Humans with altered ZIP14 function would lack this gatekeeper function of ZIP14 and therefore would be prone to manganese-related neurological diseases. Copyright © 2017 the authors 0270-6474/17/375996-11$15.00/0.
Molecular heterogeneity at the network level: high-dimensional testing, clustering and a TCGA case study
May 23, 2017   Bioinformatics (Oxford, England)
Städler N, Dondelinger F, Hill SM, Akbani R, Lu Y, Mills GB, Mukherjee S
Molecular heterogeneity at the network level: high-dimensional testing, clustering and a TCGA case study
May 23, 2017
Bioinformatics (Oxford, England)
Molecular pathways and networks play a key role in basic and disease biology. An emerging notion is that networks encoding patterns of molecular interplay may themselves differ between contexts, such as cell type, tissue or disease (sub)type. However, while statistical testing of differences in mean expression levels has been extensively studied, testing of network differences remains challenging. Furthermore, since network differences could provide important and biologically interpretable information to identify molecular subgroups, there is a need to consider the unsupervised task of learning subgroups and networks that define them. This is a nontrivial clustering problem, with neither subgroups nor subgroup-specific networks known at the outset. We leverage recent ideas from high-dimensional statistics for testing and clustering in the network biology setting. The methods we describe can be applied directly to most continuous molecular measurements and networks do not need to be specified beforehand. We illustrate the ideas and methods in a case study using protein data from the Cancer Genome Atlas (TCGA). This provides evidence that patterns of interplay between signalling proteins differ significantly between cancer types. Furthermore, we show how the proposed approaches can be used to learn subtypes and the molecular networks that define them. As the Bioconductor package nethet . staedler.n@gmail.com , sach.mukherjee@dzne.de.
Perirhinal firing patterns are sustained across large spatial segments of the task environment
May 26, 2017   Nature Communications
Bos JJ, Vinck M, van Mourik-Donga LA, Jackson JC, Witter MP, Pennartz CMA
Perirhinal firing patterns are sustained across large spatial segments of the task environment
May 26, 2017
Nature Communications
Spatial navigation and memory depend on the neural coding of an organism's location. Fine-grained coding of location is thought to depend on the hippocampus. Likewise, animals benefit from knowledge parsing their environment into larger spatial segments, which are relevant for task performance. Here we investigate how such knowledge may be coded, and whether this occurs in structures in the temporal lobe, supplying cortical inputs to the hippocampus. We found that neurons in the perirhinal cortex of rats generate sustained firing patterns that discriminate large segments of the task environment. This contrasted to transient firing in hippocampus and sensory neocortex. These spatially extended patterns were not explained by task variables or temporally discrete sensory stimuli. Previously it has been suggested that the perirhinal cortex is part of a pathway processing object, but not spatial information. Our results indicate a greater complexity of neural coding than captured by this dichotomy.
A canonical neural mechanism for behavioral variability
May 22, 2017   Nature Communications
Darshan R, Wood WE, Peters S, Leblois A, Hansel D
A canonical neural mechanism for behavioral variability
May 22, 2017
Nature Communications
The ability to generate variable movements is essential for learning and adjusting complex behaviours. This variability has been linked to the temporal irregularity of neuronal activity in the central nervous system. However, how neuronal irregularity actually translates into behavioural variability is unclear. Here we combine modelling, electrophysiological and behavioural studies to address this issue. We demonstrate that a model circuit comprising topographically organized and strongly recurrent neural networks can autonomously generate irregular motor behaviours. Simultaneous recordings of neurons in singing finches reveal that neural correlations increase across the circuit driving song variability, in agreement with the model predictions. Analysing behavioural data, we find remarkable similarities in the babbling statistics of 5-6-month-old human infants and juveniles from three songbird species and show that our model naturally accounts for these 'universal' statistics.
Endogenous opioids regulate social threat learning in humans
May 25, 2017   Nature Communications
Haaker J, Yi J, Petrovic P, Olsson A
Endogenous opioids regulate social threat learning in humans
May 25, 2017
Nature Communications
Many fearful expectations are shaped by observation of aversive outcomes to others. Yet, the neurochemistry regulating social learning is unknown. Previous research has shown that during direct (Pavlovian) threat learning, information about personally experienced outcomes is regulated by the release of endogenous opioids, and activity within the amygdala and periaqueductal gray (PAG). Here we report that blockade of this opioidergic circuit enhances social threat learning through observation in humans involving activity within the amygdala, midline thalamus and the PAG. In particular, anticipatory responses to learned threat cues (CS) were associated with temporal dynamics in the PAG, coding the observed aversive outcomes to other (observational US). In addition, pharmacological challenge of the opioid receptor function is classified by distinct brain activity patterns during the expression of conditioned threats. Our results reveal an opioidergic circuit that codes the observed aversive outcomes to others into threat responses and long-term memory in the observer.

The link you entered does not seem to be valid

Please make sure the link points to nature.com contains a valid shared_access_token

Downloading PDF to your library...

Uploading PDF...

PDF uploading

Delete tag: