bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accumulation of Laminin Monomers inDrosophilaGlia Leads to Glial Endoplasmic Reticulum Stress and Disrupted Larval Locomotion
Authors: Petley-Ragan Lindsay M. , Ardiel Evan L. , Rankin Catharine H. , Auld Vanessa J. 
Published: January 2016

The nervous system is surrounded by an extracellular matrix composed of large glycoproteins, including perlecan, collagens, and laminins. Glial cells in many organisms secrete laminin, a large heterotrimeric protein consisting of an α, β, and γ subunit. Prior studies have found that loss of laminin subunits from vertebrate Schwann cells causes loss of myelination and neuropathies, results attributed to loss of laminin-receptor signaling. We demonstrate that loss of the laminin γ subunit (LanB2) in the peripheral glia ofDrosophila melanogasterresults in the disruption of glial morphology due to disruption of laminin secretion. Specifically, knockdown of LanB2 in peripheral glia results in accumulation of the β subunit (LanB1), leading to distended endoplasmic reticulum (ER), ER stress, and glial swelling. The physiological consequences of disruption of laminin secretion in glia included decreased larval locomotion and ultimately lethality. Loss of the γ subunit from wrapping glia resulted in a disruption in the glial ensheathment of axons but surprisingly did not affect animal locomotion. We found that Tango1, a protein thought to exclusively mediate collagen secretion, is also important for laminin secretion in glia via a collagen-independent mechanism. However loss of secretion of the laminin trimer does not disrupt animal locomotion. Rather, it is the loss of one subunit that leads to deleterious consequences through the accumulation of the remaining subunits.SIGNIFICANCE STATEMENTThis research presents a new perspective on how mutations in the extracellular matrix protein laminin cause severe consequences in glial wrapping and function. Glial-specific loss of the β or γ laminin subunit disrupted glia morphology and led to ER expansion and stress due to retention of other subunits. The retention of the unpaired laminin subunit was key to the glial disruption as loss of Tango1 blocked secretion of the complete laminin trimer but did not lead to glial or locomotion defects. The effects were observed in the perineurial glia that envelope the peripheral and central nervous systems, providing evidence for the importance of this class of glia in supporting nervous system function.
Why Don't We Move Slower? The Value of Time in the Neural Control of Action
Authors: Berret Bastien , Jean Frédéric 
Published: January 2016

To want something now rather than later is a common attitude that reflects the brain's tendency to value the passage of time. Because the time taken to accomplish an action inevitably delays task achievement and reward acquisition, this idea was ported to neural movement control within the “cost of time” theory. This theory provides a normative framework to account for the underpinnings of movement time formation within the brain and the origin of a self-selected pace in human and animal motion. Then, how does the brain exactly value time in the control of action? To tackle this issue, we used an inverse optimal control approach and developed a general methodology allowing to squarely sample infinitesimal values of the time cost from experimental motion data. The cost of time underlying saccades was found to have a concave growth, thereby confirming previous results on hyperbolic reward discounting, yet without making any prior assumption about this hypothetical nature. For self-paced reaching, however, movement time was primarily valued according to a striking sigmoidal shape; its rate of change consistently presented a steep rise before a maximum was reached and a slower decay was observed. Theoretical properties of uniqueness and robustness of the inferred time cost were established for the class of problems under investigation, thus reinforcing the significance of the present findings. These results may offer a unique opportunity to uncover how the brain values the passage of time in healthy and pathological motor control and shed new light on the processes underlying action invigoration.SIGNIFICANCE STATEMENTMovement time is a fundamental characteristic of neural motor control, but the principles underlying its formation remain little known. This work addresses that question within the inverse optimal control framework where the challenge is to uncover what optimality criterion underlies a system's behavior. Here we rely on the “cost of time” theory that finds its roots into the brain's tendency to discount the actual value of future reward. It asserts that the time elapsed until action completion entails a cost, thereby making slow moves nonoptimal. By means of a thorough theoretical analysis, the present article shows how to sample the infinitesimal values of the time cost without prior assumption about its hypothetical nature and emphasizes its sigmoidal shape for reaching.
Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1
Authors: Heyward Frankie D. , Gilliam Daniel , Coleman Mark A. , Gavin Cristin F. , Wang Jing , Kaas Garrett , Trieu Richard , Lewis John , Moulden Jerome , Sweatt J. David 
Published: January 2016

Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specificSirt1knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus.SIGNIFICANCE STATEMENTPrevious studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, includingSirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic interventions for obesity-induced memory impairment.
Microsaccades Are Coupled to Heartbeat
Authors: Ohl Sven , Wohltat Christian , Kliegl Reinhold , Pollatos Olga , Engbert Ralf 
Published: January 2016

During visual fixation, the eye generates microsaccades and slower components of fixational eye movements that are part of the visual processing strategy in humans. Here, we show that ongoing heartbeat is coupled to temporal rate variations in the generation of microsaccades. Using coregistration of eye recording and ECG in humans, we tested the hypothesis that microsaccade onsets are coupled to the relative phase of the R-R intervals in heartbeats. We observed significantly more microsaccades during the early phase after the R peak in the ECG. This form of coupling between heartbeat and eye movements was substantiated by the additional finding of a coupling between heart phase and motion activity in slow fixational eye movements; i.e., retinal image slip caused by physiological drift. Our findings therefore demonstrate a coupling of the oculomotor system and ongoing heartbeat, which provides further evidence for bodily influences on visuomotor functioning.SIGNIFICANCE STATEMENTIn the present study, we show that microsaccades are coupled to heartbeat. Moreover, we revealed a strong modulation of slow eye movements around the R peak in the ECG. These results suggest that heartbeat as a basic physiological signal is related to statistical modulations of fixational eye movements, in particular, the generation of microsaccades. Therefore, our findings add a new perspective on the principles underlying the generation of fixational eye movements. Importantly, our study highlights the need to record eye movements when studying the influence of heartbeat in neuroscience to avoid misinterpretation of eye-movement-related artifacts as heart-evoked modulations of neural processing.
Age-Related Phasic Patterns of Mitochondrial Maintenance in AdultCaenorhabditis elegansNeurons
Authors: Morsci Natalia S. , Hall David H. , Driscoll Monica , Sheng Zu-Hang 
Published: January 2016

Aging is associated with cognitive decline and increasing risk of neurodegeneration. Perturbation of mitochondrial function, dynamics, and trafficking are implicated in the pathogenesis of several age-associated neurodegenerative diseases. Despite this fundamental importance, the critical understanding of how organismal aging affects lifetime neuronal mitochondrial maintenance remains unknown, particularly in a physiologically relevant context. To address this issue, we performed a comprehensivein vivoanalysis of age-associated changes in mitochondrial morphology, density, trafficking, and stress resistance in individualCaenorhabditis elegansneurons throughout adult life. Adult neurons display three distinct stages of increase, maintenance, and decrease in mitochondrial size and density during adulthood. Mitochondrial trafficking in the distal neuronal processes declines progressively with age starting from early adulthood. In contrast, long-liveddaf-2mutants exhibit delayed age-associated changes in mitochondrial morphology, constant mitochondrial density, and maintained trafficking rates during adulthood. Reduced mitochondrial load at late adulthood correlates with decreased mitochondrial resistance to oxidative stress. Revealing aging-associated changes in neuronal mitochondriain vivois an essential precedent that will allow future elucidation of the mechanistic causes of mitochondrial aging. Thus, our study establishes the critical foundation for the future analysis of cellular pathways and genetic and pharmacological factors regulating mitochondrial maintenance in aging- and disease-relevant conditions.SIGNIFICANCE STATEMENTUsingCaenorhabditis elegansas a model, we address long-standing questions: How does aging affect neuronal mitochondrial morphology, density, trafficking, and oxidative stress resistance? Are these age-related changes amenable to genetic manipulations that slow down the aging process? Our study illustrates that mitochondrial trafficking declines progressively from the first day of adulthood, whereas mitochondrial size, density, and resistance to oxidative stress undergo three distinct stages: increase in early adulthood, maintenance at high levels during mid-adulthood, and decline during late adulthood. Thus, our study characterizes mitochondrial aging profile at the level of a single neuron in its native environment and establishes the critical foundation for the future genetic and pharmacological dissection of factors that influence long-term mitochondrial maintenance in neurons.
Activation of PPARγ Ameliorates Spatial Cognitive Deficits through Restoring Expression of AMPA Receptors in Seipin Knock-Out Mice
Authors: Zhou Libin , Chen Tingting , Li Guoxi , Wu Chaoming , Wang Conghui , Li Lin , Sha Sha , Chen Lei , Liu George , Chen Ling 
Published: January 2016

A characteristic phenotype of congenital generalized lipodystrophy 2 (CGL2) that is caused by loss-of-function of seipin gene is mental retardation. Here, we show that seipin deficiency in hippocampal CA1 pyramidal cells caused the reduction of peroxisome proliferator-activated receptor gamma (PPARγ). Twelve-week-old systemicseipinknock-out mice and neuronalseipinknock-out (seipin-nKO) mice, but not adiposeseipinknock-out mice, exhibited spatial cognitive deficits as assessed by the Morris water maze and Y-maze, which were ameliorated by the treatment with the PPARγ agonist rosiglitazone (rosi). In addition,seipin-nKO mice showed the synaptic dysfunction and the impairment of NMDA receptor-dependent LTP in hippocampal CA1 regions. The density of AMPA-induced current (IAMPA) in CA1 pyramidal cells and GluR1/GluR2 expression were significantly reduced inseipin-nKO mice, whereas the NMDA-induced current (INMDA) and NR1/NR2 expression were not altered. Rosi treatment inseipin-nKO mice could correct the decrease in expression and activity of AMPA receptor (AMPAR) and was accompanied by recovered synaptic function and LTP induction. Furthermore, hippocampal ERK2 and CREB phosphorylation inseipin-nKO mice were reduced and this could be rescued by rosi treatment. Rosi treatment inseipin-nKO mice elevated BDNF concentration. The MEK inhibitor U0126 blocked rosi-restored AMPAR expression and LTP induction inseipin-nKO mice, but the Trk family inhibitor K252a did not. These findings indicate that the neuronal seipin deficiency selectively suppresses AMPAR expression through reducing ERK-CREB activities, leading to the impairment of LTP and spatial memory, which can be rescued by PPARγ activation.SIGNIFICANCE STATEMENTCongenital generalized lipodystrophy 2 (CGL2), caused by loss-of-function mutation of seipin gene, is characterized by mental retardation. By the generation of systemic or neuronalseipinknock-out mice, the present study providesin vivoevidence that neuronal seipin deficiency causes deficits in spatial memory and hippocampal LTP induction. Neuronal seipin deficiency selectively suppresses AMPA receptor expression, ERK-CREB phosphorylation with the decline of PPARγ. The PPARγ agonist rosiglitazone can ameliorate spatial cognitive deficits and rescue the LTP induction inseipinknock-out mice by restoring AMPA receptor expression and ERK-CREB activities.
AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons
Authors: Tuvikene Jürgen , Pruunsild Priit , Orav Ester , Esvald Eli-Eelika , Timmusk Tõnis 
Published: January 2016

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates both survival and differentiation of several neuronal populations in the nervous system during development, as well as synaptic plasticity in the adult brain. BDNF exerts its biological functions through its receptor TrkB. Although the regulation ofBDNFtranscription by neuronal activity has been widely studied, little is known about TrkB signaling-dependent expression ofBDNF. Using rat primary cortical neuron cultures, we show that theBDNFgene is a subject to an extensive autoregulatory loop, where TrkB signaling upregulates the expression of all majorBDNFtranscripts, mainly through activating MAPK pathways. Investigating the mechanisms behind this autoregulation, we found that AP-1 transcription factors, comprising Jun and Fos family members, participate in the induction ofBDNFexon I, III, and VI transcripts. AP-1 transcription factors directly upregulate the expression of exon I transcripts by binding two novel AP-1cis-elements in promoter I. Moreover, our results show that the effect of AP-1 proteins on the activity of ratBDNFpromoters III and VI is indirect, because AP-1 proteins were not detected to bind the respective promoter regions by chromatin immunoprecipitation (ChIP). Collectively, we describe an extensive positive feedback system inBDNFregulation, adding a new layer to the elaborate control ofBDNFgene expression.SIGNIFICANCE STATEMENTHere, we show for the first time that in rat primary cortical neurons the expression of all majorBDNFtranscripts (exon I, II, III, IV, VI, and IXa transcripts) is upregulated in response to TrkB signaling, and that AP-1 transcription factors participate in the induction of exon I, III, and VI transcripts. Moreover, we have described two novel functional AP-1cis-elements inBDNFpromoter I, responsible for the activation of the promoter in response to TrkB signaling. Our results indicate the existence of a positive feedback loop for obtaining sufficient BDNF levels necessary for various TrkB signaling-dependent physiological outcomes in neurons.
Equivalent Activities of Repulsive Axon Guidance Receptors
Authors: Long Hong , Yoshikawa Shingo , Thomas John B. 
Published: January 2016

Receptors on the growth cone at the leading edge of elongating axons play critical guidance roles by recognizing cues via their extracellular domains and transducing signals via their intracellular domains, resulting in changes in direction of growth. An important concept to have emerged in the axon guidance field is the importance of repulsion as a major guidance mechanism. Given the number and variety of different repulsive receptors, it is generally thought that there are likely to be qualitative differences in the signals they transduce. However, the nature of these possible differences is unknown. By creating chimeras using the extracellular and intracellular domains of three differentDrosophilarepulsive receptors, Unc5, Roundabout (Robo), and Derailed (Drl) and expressing them in defined cells within the embryonic nervous system, we examined the responses elicited by their intracellular domains systematically. Surprisingly, we found no qualitative differences in growth cone response or axon growth, suggesting that, despite their highly diverged sequences, each intracellular domain elicits repulsion via a common pathway. In terms of the signaling pathway(s) used by the repulsive receptors, mutations in the guanine nucleotide exchange factor Trio strongly enhance the repulsive activity of all three intracellular domains, suggesting that repulsion by Unc5, Robo, and Drl, and perhaps repulsion in general, involves Trio activity.SIGNIFICANCE STATEMENTA prevailing concept that has emerged in the axon guidance field is the importance of repulsion as a guidance mechanism for steering axons to their appropriate targets. Given the number and variety of different repulsive receptors, it is generally thought that there are differences in the signals that they transduce. However, this has never been tested directly. We have used the advanced genetics ofDrosophilato compare directly the outputs of different repulsive receptors. Surprisingly, we found no qualitative differences in receptor-mediated repulsion, suggesting that, despite their highly diverged domain structure, each receptor couples to a common repulsive pathway. We went on to show that this common pathway involves Trio, a guanine nucleotide exchange factor known to promote cytoskeletal remodeling.
Transcranial Stimulation of the Dorsolateral Prefrontal Cortex Prevents Stress-Induced Working Memory Deficits
Authors: Bogdanov Mario , Schwabe Lars 
Published: January 2016

Stress is known to impair working memory performance. This disruptive effect of stress on working memory has been linked to a decrease in the activity of the dorsolateral prefrontal cortex (dlPFC). In the present experiment, we tested whether transcranial direct current stimulation (tDCS) of the dlPFC can prevent stress-induced working memory impairments. We tested 120 healthy participants in a 2 d, sham-controlled, double-blind between-subjects design. Participants completed a test of their individual baseline working memory capacity on day 1. On day 2, participants were exposed to either a stressor or a control manipulation before they performed a visuospatial and a verbal working memory task. While participants completed the tasks, anodal, cathodal, or sham tDCS was applied over the right dlPFC. Stress impaired working memory performance in both tasks, albeit to a lesser extent in the verbal compared with the visuospatial working memory task. This stress-induced working memory impairment was prevented by anodal, but not sham or cathodal, stimulation of the dlPFC. Compared with sham or cathodal stimulation, anodal tDCS led to significantly better working memory performance in both tasks after stress. Our findings indicate a causal role of the dlPFC in working memory impairments after acute stress and point to anodal tDCS as a promising tool to reduce cognitive deficits related to working memory in stress-related mental disorders, such as depression, schizophrenia, or post-traumatic stress disorder.SIGNIFICANCE STATEMENTWorking memory deficits are prominent in stress-related mental disorders, such as depression, schizophrenia, or post-traumatic stress disorder. Similar working memory impairments have been observed in healthy individuals exposed to acute stress. So far, attempts to prevent such stress-induced working memory deficits focused mainly on pharmacological interventions. Here, we tested the idea that transcranial direct current stimulation of the dorsolateral prefrontal cortex (dlPFC), a critical neural substrate of working memory, may prevent working memory impairments after stress. Our results indicate that anodal stimulation of the dlPFC may indeed preserve working memory performance under stress, suggesting that the dlPFC plays a causal role in stress-induced working memory deficits and pointing to a potential new avenue to prevent stress-induced cognitive impairments.