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Journal of Neuroscience
Journal Prestige (SJR): 4.466
Citation Impact (citeScore): 6
Number of Followers: 303  
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ISSN (Print) 0270-6474 - ISSN (Online) 1529-2401
Published by Society for Neuroscience Homepage  [2 journals]
  • This Week in The Journal
    • Pages: 7451 - 7451
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.twij.39.38.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Peer Review Week: Quality in Peer Review
    • Authors: Picciotto M.
      Pages: 7452 - 7452
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.1987-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of
           Fragile X Syndrome
    • Authors: Gray, E. E; Murphy, J. G, Liu, Y, Trang, I, Tabor, G. T, Lin, L, Hoffman, D. A.
      Pages: 7453 - 7464
      Abstract: Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses. The absence of FMRP leads to neuronal and circuit-level hyperexcitability that is thought to arise from the aberrant expression and activity of voltage-gated ion channels, although the identification and characterization of these ion channels have been limited. Here, we show that FMRP binds the mRNA of the R-type voltage-gated calcium channel Cav2.3 in mouse brain synaptoneurosomes and represses Cav2.3 translation under basal conditions. Consequently, in hippocampal neurons from male and female FMRP KO mice, we find enhanced Cav2.3 protein expression by western blotting and abnormally large R currents in whole-cell voltage-clamp recordings. In agreement with previous studies showing that FMRP couples Group I metabotropic glutamate receptor (GpI mGluR) signaling to protein translation, we find that GpI mGluR stimulation results in increased Cav2.3 translation and R current in hippocampal neurons which is disrupted in FMRP KO mice. Thus, FMRP serves as a key translational regulator of Cav2.3 expression under basal conditions and in response to GpI mGluR stimulation. Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies.SIGNIFICANCE STATEMENT Patients with fragile X syndrome (FXS) exhibit signs of neuronal and circuit hyperexcitability, including anxiety and hyperactive behavior, attention deficit disorder, and seizures. FXS is caused by the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein, and the neuronal hyperexcitability observed in the absence of FMRP likely results from its ability to regulate the expression and activity of voltage-gated ion channels. Here we find that FMRP serves as a key translational regulator of the voltage-gated calcium channel Cav2.3 under basal conditions and following activity. Cav2.3 impacts cellular excitability and calcium signaling, and the alterations in channel translation and expression observed in the absence of FMRP could contribute to the neuronal hyperactivity that underlies FXS.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.1443-17.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Rgma-Induced Neo1 Proteolysis Promotes Neural Tube Morphogenesis
    • Authors: Brown, S; Jayachandran, P, Negesse, M, Olmo, V, Vital, E, Brewster, R.
      Pages: 7465 - 7484
      Abstract: Neuroepithelial cell (NEC) elongation is one of several key cell behaviors that mediate the tissue-level morphogenetic movements that shape the neural tube (NT), the precursor of the brain and spinal cord. However, the upstream signals that promote NEC elongation have been difficult to tease apart from those regulating apico-basal polarity and hingepoint formation, due to their confounding interdependence. The Repulsive Guidance Molecule a (Rgma)/Neogenin 1 (Neo1) signaling pathway plays a conserved role in NT formation (neurulation) and is reported to regulate both NEC elongation and apico-basal polarity, through signal transduction events that have not been identified. We examine here the role of Rgma/Neo1 signaling in zebrafish (sex unknown), an organism that does not use hingepoints to shape its hindbrain, thereby enabling a direct assessment of the role of this pathway in NEC elongation. We confirm that Rgma/Neo1 signaling is required for microtubule-mediated NEC elongation, and demonstrate via cell transplantation that Neo1 functions cell autonomously to promote elongation. However, in contrast to previous findings, our data do not support a role for this pathway in establishing apical junctional complexes. Last, we provide evidence that Rgma promotes Neo1 glycosylation and intramembrane proteolysis, resulting in the production of a transient, nuclear intracellular fragment (NeoICD). Partial rescue of Neo1a and Rgma knockdown embryos by overexpressing neoICD suggests that this proteolytic cleavage is essential for neurulation. Based on these observations, we propose that RGMA-induced NEO1 proteolysis orchestrates NT morphogenesis by promoting NEC elongation independently of the establishment of apical junctional complexes.SIGNIFICANCE STATEMENT The neural tube, the CNS precursor, is shaped during neurulation. Neural tube defects occur frequently, yet underlying genetic risk factors are poorly understood. Neuroepithelial cell (NEC) elongation is essential for proper completion of neurulation. Thus, connecting NEC elongation with the molecular pathways that control this process is expected to reveal novel neural tube defect risk factors and increase our understanding of NT development. Effectors of cell elongation include microtubules and microtubule-associated proteins; however, upstream regulators remain controversial due to the confounding interdependence of cell elongation and establishment of apico-basal polarity. Here, we reveal that Rgma-Neo1 signaling controls NEC elongation independently of the establishment of apical junctional complexes and identify Rgma-induced Neo1 proteolytic cleavage as a key upstream signaling event.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.3262-18.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Leveraging Nonhuman Primate Multisensory Neurons and Circuits in Assessing
           Consciousness Theory
    • Authors: Noel, J.-P; Ishizawa, Y, Patel, S. R, Eskandar, E. N, Wallace, M. T.
      Pages: 7485 - 7500
      Abstract: Both the global neuronal workspace (GNW) and integrated information theory (IIT) posit that highly complex and interconnected networks engender perceptual awareness. GNW specifies that activity recruiting frontoparietal networks will elicit a subjective experience, whereas IIT is more concerned with the functional architecture of networks than with activity within it. Here, we argue that according to IIT mathematics, circuits converging on integrative versus convergent yet non-integrative neurons should support a greater degree of consciousness. We test this hypothesis by analyzing a dataset of neuronal responses collected simultaneously from primary somatosensory cortex (S1) and ventral premotor cortex (vPM) in nonhuman primates presented with auditory, tactile, and audio-tactile stimuli as they are progressively anesthetized with propofol. We first describe the multisensory (audio-tactile) characteristics of S1 and vPM neurons (mean and dispersion tendencies, as well as noise-correlations), and functionally label these neurons as convergent or integrative according to their spiking responses. Then, we characterize how these different pools of neurons behave as a function of consciousness. At odds with the IIT mathematics, results suggest that convergent neurons more readily exhibit properties of consciousness (neural complexity and noise correlation) and are more impacted during the loss of consciousness than integrative neurons. Last, we provide support for the GNW by showing that neural ignition (i.e., same trial coactivation of S1 and vPM) was more frequent in conscious than unconscious states. Overall, we contrast GNW and IIT within the same single-unit activity dataset, and support the GNW.SIGNIFICANCE STATEMENT A number of prominent theories of consciousness exist, and a number of these share strong commonalities, such as the central role they ascribe to integration. Despite the important and far reaching consequences developing a better understanding of consciousness promises to bring, for instance in diagnosing disorders of consciousness (e.g., coma, vegetative-state, locked-in syndrome), these theories are seldom tested via invasive techniques (with high signal-to-noise ratios), and never directly confronted within a single dataset. Here, we first derive concrete and testable predictions from the global neuronal workspace and integrated information theory of consciousness. Then, we put these to the test by functionally labeling specific neurons as either convergent or integrative nodes, and examining the response of these neurons during anesthetic-induced loss of consciousness.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0934-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Morphological Cell Types Projecting from V1 Layer 4B to V2 Thick and Thin
    • Authors: Yarch, J; Larsen, H, Chen, M, Angelucci, A.
      Pages: 7501 - 7512
      Abstract: In macaque visual cortex, different cytochrome oxidase stripes of area V2 receive segregated projections from layers (L)2/3 and 4B of the primary visual cortex (V1), and project to dorsal or ventral stream extrastriate areas. Parallel V1-to-V2 pathways suggest functionally specialized circuits, but it is unknown whether these circuits arise from distinct cell types. V1 L4B includes two morphological types of excitatory projection neurons: pyramids, which carry mixed magnocellular (M) and parvocellular (P) information to downstream areas, and spiny stellates, which carry only M information. Previous studies have shown that, overall, V2 receives ~80% of its L4B inputs from pyramids, thus receiving mixed M and P signals. However, it is unknown how pyramids and stellates distribute their outputs to the different V2 stripes, and whether different stripes receive inputs from morphologically distinct neuron types. Using viral-mediated labeling of V2-projecting L4B neurons in male macaques, we show that thick stripes receive a greater contribution of L4B inputs from M-dominated spiny stellates compared with thin stripes. Both stripe types, however, receive a much larger contribution from spiny stellates than previously shown for V2 overall, indicating that a larger amount of M information than previously thought flows into both the dorsal and ventral streams via the V2 thick and thin stripes, respectively. Moreover, we identify four types of V2-projecting L4B cells differing in size and complexity. Three such cell types project to both thin and thick stripes, but one type, the giant spiny-stellate neuron, resembling L4B neurons projecting to motion-sensitive area MT, was only found to project to thick stripes.SIGNIFICANCE STATEMENT Area V1 partitions visual information into functionally specialized parallel pathways which terminate into distinct stripes of area V2. We asked whether V1 inputs to different V2 stripes arise from morphologically different cell types. V1 layer (L)4B has two cell types: pyramids, which carry both magnocellular (M) and parvocellular (P) visual signals, and spiny stellates, which carry only M signals. We find that V2 thick stripes, which project to areas processing object motion, receive a larger fraction of L4B input from M-dominated stellates compared with thin stripes, which project to areas processing object attributes. We also identify four morphological types of V2-projecting L4B neurons, suggestive of four functionally specialized cell types.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.1096-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • GPRIN3 Controls Neuronal Excitability, Morphology, and Striatal-Dependent
           Behaviors in the Indirect Pathway of the Striatum
    • Authors: Karadurmus, D; Rial, D, De Backer, J.-F, Communi, D, de Kerchove d'Exaerde, A, Schiffmann, S. N.
      Pages: 7513 - 7528
      Abstract: The regulation of the striatum by the GPCR signaling through neuromodulators is essential for its physiology and physiopathology, so it is necessary to know all the compounds of these pathways. In this study, we identified a new important partner of the dopaminergic pathway: GPRIN3 (a member of the GPRIN family). GPRIN3 is highly expressed in the striatum but with undefined function. Cell sorting of medium spiny neurons (MSNs) in indirect MSNs and direct MSNs indicated the presence of the GPRIN3 gene in both populations with a preferential expression in indirect MSNs. This led us to generate GPRIN3 KO mice by CRISPR/Cas9 and test male animals to access possible alterations in morphological, electrophysiological, and behavioral parameters following its absence. 3D reconstruction analysis of MSNs revealed increased neuronal arborization in GPRIN3 KO and modified passive and active electrophysiological properties. These cellular alterations were coupled with increased motivation and cocaine-induced hyperlocomotion. Additionally, using a specific indirect MSN knockdown, we showed a preferential role for GPRIN3 in indirect MSNs related to the D2R signaling. Together, these results show that GPRIN3 is a mediator of D2R function in the striatum playing a major role in striatal physiology.SIGNIFICANCE STATEMENT The striatum is the main input of the basal ganglia processing information from different brain regions through the combined actions of direct pathway neurons and indirect pathway neurons. Both neuronal populations are defined by the expression of dopamine D1R or D2R GPCRs, respectively. How these neurons signal to the respective G-protein is still debatable. Here we identified GPRIN3 as a putative selective controller of D2R function in the striatum playing a critical role in striatal-associated behaviors and cellular functions. This study represents the identification of a new target to tackle striatal dysfunction associated with the D2R, such as schizophrenia, Parkinson's disease, and drug addiction.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.2454-18.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Transplanted Cells Are Essential for the Induction But Not the Expression
           of Cortical Plasticity
    • Authors: Hoseini, M. S; Rakela, B, Flores-Ramirez, Q, Hasenstaub, A. R, Alvarez-Buylla, A, Stryker, M. P.
      Pages: 7529 - 7538
      Abstract: Transplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived eye. We transplanted MGE neurons expressing either archaerhodopsin or channelrhodopsin into the visual cortex of both male and female mice, closed one eyelid for 4–5 d, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed or enhanced optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.SIGNIFICANCE STATEMENT Interneuron transplantation into mouse V1 creates a window of heightened plasticity that is quantitatively and qualitatively similar to the normal critical period; that is, short-term occlusion of either eye markedly changes ocular dominance (OD). The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the OD shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the OD shift.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.1430-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Temporal Coding of Reward Value in Monkey Ventral Striatal Tonically
           Active Neurons
    • Authors: Falcone, R; Weintraub, D. B, Setogawa, T, Wittig, J. H, Chen, G, Richmond, B. J.
      Pages: 7539 - 7550
      Abstract: The rostromedioventral striatum is critical for behavior dependent on evaluating rewards. We asked what contribution tonically active neurons (TANs), the putative striatal cholinergic interneurons, make in coding reward value in this part of the striatum. Two female monkeys were given the option to accept or reject an offered reward in each trial, the value of which was signaled by a visual cue. Forty-five percent of the TANs use temporally modulated activity to encode information about discounted value. These responses were significantly better represented using principal component analysis than by just counting spikes. The temporal coding is straightforward: the spikes are distributed according to a sinusoidal envelope of activity that changes gain, ranging from positive to negative according to discounted value. Our results show that the information about the relative value of an offered reward is temporally encoded in neural spike trains of TANs. This temporal coding may allow well tuned, coordinated behavior to emerge.SIGNIFICANCE STATEMENT Ever since the discovery that neurons use trains of pulses to transmit information, it seemed self-evident that information would be encoded into the pattern of the spikes. However, there is not much evidence that spike patterns encode cognitive information. We find that a set of interneurons, the tonically active neurons (TANs) in monkeys' striatum, use temporal patterns of response to encode information about the discounted value of offered rewards. The code seems straightforward: a sinusoidal envelope that changes gain according to the discounted value of the offer, describes the rate of spiking across time. This temporal modulation may provide a means to synchronize these interneurons and the activity of other neural elements including principal output neurons.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0869-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Dopamine D2L Receptor Deficiency Causes Stress Vulnerability through
           5-HT1A Receptor Dysfunction in Serotonergic Neurons
    • Authors: Shioda, N; Imai, Y, Yabuki, Y, Sugimoto, W, Yamaguchi, K, Wang, Y, Hikida, T, Sasaoka, T, Mieda, M, Fukunaga, K.
      Pages: 7551 - 7563
      Abstract: Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0079-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Semantic Context Enhances the Early Auditory Encoding of Natural Speech
    • Authors: Broderick, M. P; Anderson, A. J, Lalor, E. C.
      Pages: 7564 - 7575
      Abstract: Speech perception involves the integration of sensory input with expectations based on the context of that speech. Much debate surrounds the issue of whether or not prior knowledge feeds back to affect early auditory encoding in the lower levels of the speech processing hierarchy, or whether perception can be best explained as a purely feedforward process. Although there has been compelling evidence on both sides of this debate, experiments involving naturalistic speech stimuli to address these questions have been lacking. Here, we use a recently introduced method for quantifying the semantic context of speech and relate it to a commonly used method for indexing low-level auditory encoding of speech. The relationship between these measures is taken to be an indication of how semantic context leading up to a word influences how its low-level acoustic and phonetic features are processed. We record EEG from human participants (both male and female) listening to continuous natural speech and find that the early cortical tracking of a word's speech envelope is enhanced by its semantic similarity to its sentential context. Using a forward modeling approach, we find that prediction accuracy of the EEG signal also shows the same effect. Furthermore, this effect shows distinct temporal patterns of correlation depending on the type of speech input representation (acoustic or phonological) used for the model, implicating a top-down propagation of information through the processing hierarchy. These results suggest a mechanism that links top-down prior information with the early cortical entrainment of words in natural, continuous speech.SIGNIFICANCE STATEMENT During natural speech comprehension, we use semantic context when processing information about new incoming words. However, precisely how the neural processing of bottom-up sensory information is affected by top-down context-based predictions remains controversial. We address this discussion using a novel approach that indexes a word's similarity to context and how well a word's acoustic and phonetic features are processed by the brain at the time of its utterance. We relate these two measures and show that lower-level auditory tracking of speech improves for words that are more related to their preceding context. These results suggest a mechanism that links top-down prior information with bottom-up sensory processing in the context of natural, narrative speech listening.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0584-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to
           Chronic Social Defeat Stress
    • Authors: Zhang, T. R; Larosa, A, Di Raddo, M.-E, Wong, V, Wong, A. S, Wong, T. P.
      Pages: 7576 - 7590
      Abstract: The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor. Compared with resilient and nonstressed control mice, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e., engram cells) in both the dorsal and ventral hippocampal CA1 regions. The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD and optogenetic approaches to activate and inactivate social defeat-related CA1 engram cells enhanced and suppressed social avoidance, respectively. Increased engram cells in susceptible mice could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-related, but not neutral stimuli-related, CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. The susceptibility to chronic social defeat stress is regulated by hippocampal CA1 engrams for negative memory. Hippocampal negative memory engrams may underlie the vulnerability and expression of cognitive symptoms in depression.SIGNIFICANCE STATEMENT We provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams has been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.1958-18.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Probing the Neural Mechanisms for Distractor Filtering and Their
           History-Contingent Modulation by Means of TMS
    • Authors: Lega, C; Ferrante, O, Marini, F, Santandrea, E, Cattaneo, L, Chelazzi, L.
      Pages: 7591 - 7603
      Abstract: In visual search, the presence of a salient, yet task-irrelevant, distractor in the stimulus array interferes with target selection and slows down performance. Neuroimaging data point to a key role of the frontoparietal dorsal attention network in dealing with visual distractors; however, the respective roles of different nodes within the network and their hemispheric specialization are still unresolved. Here, we used transcranial magnetic stimulation (TMS) to evaluate the causal role of two key regions of the dorsal attention network in resisting attentional capture by a salient singleton distractor: the frontal eye field (FEF) and the cortex within the intraparietal sulcus (IPS). The task of the participants (male/female human volunteers) was to discriminate the pointing direction of a target arrow while ignoring a task-irrelevant salient distractor. Immediately after stimulus onset, triple-pulse 10 Hz TMS was delivered either to IPS or FEF on either side of the brain. Results indicated that TMS over the right FEF significantly reduced the behavioral cost engendered by the salient distractor relative to left FEF stimulation. No such effect was obtained with stimulation of IPS on either side of brain. Interestingly, this FEF-dependent reduction in distractor interference interacted with the contingent trial history, being maximal when no distractor was present on the previous trial relative to when there was one. Our results provide direct causal evidence that the right FEF houses key mechanisms for distractor filtering, pointing to a pivotal role of the frontal cortex of the right hemisphere in limiting interference from an irrelevant but attention-grabbing stimulus.SIGNIFICANCE STATEMENT Visually conspicuous stimuli attract our attention automatically and interfere with performance by diverting resources away from the main task. Here, we applied transcranial magnetic stimulation over four frontoparietal cortex locations (frontal eye field and intraparietal sulcus in each hemisphere) to identify regions of the dorsal attention network that help limit interference from task-irrelevant, salient distractors. Results indicate that the right FEF participates in distractor-filtering mechanisms that are recruited when a distracting stimulus is encountered. Moreover, right FEF implements adjustments in distraction-filtering mechanisms following recent encounters with distractors. Together, these findings indicate a different hemispheric contribution of the left versus right dorsal frontal cortex to distraction filtering. This study expands our understanding of how our brains select relevant targets in the face of task-irrelevant, salient distractors.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.2740-18.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Altered Synaptic Drive onto Birthdated Dentate Granule Cells in
           Experimental Temporal Lobe Epilepsy
    • Authors: Althaus, A. L; Moore, S. J, Zhang, H, Du, X, Murphy, G. G, Parent, J. M.
      Pages: 7604 - 7614
      Abstract: Dysregulated adult hippocampal neurogenesis occurs in many temporal lobe epilepsy (TLE) models. Most dentate granule cells (DGCs) generated in response to an epileptic insult develop features that promote increased excitability, including ectopic location, persistent hilar basal dendrites (HBDs), and mossy fiber sprouting. However, some appear to integrate normally and even exhibit reduced excitability compared to other DGCs. To examine the relationship between DGC birthdate, morphology, and network integration in a model of TLE, we retrovirally birthdated either early-born [EB; postnatal day (P)7] or adult-born (AB; P60) DGCs. Male rats underwent pilocarpine-induced status epilepticus (SE) or sham treatment at P56. Three to six months after SE or sham treatment, we used whole-cell patch-clamp and fluorescence microscopy to record spontaneous excitatory and inhibitory currents from birthdated DGCs. We found that both AB and EB populations of DGCs recorded from epileptic rats received increased excitatory input compared with age-matched controls. Interestingly, when AB populations were separated into normally integrated (normotopic) and aberrant (ectopic or HBD-containing) subpopulations, only the aberrant populations exhibited a relative increase in excitatory input (amplitude, frequency, and charge transfer). The ratio of excitatory-to-inhibitory input was most dramatically upregulated for ectopically localized DGCs. These data provide definitive physiological evidence that aberrant integration of post-SE, AB DGCs contributes to increased synaptic drive and support the idea that ectopic DGCs serve as putative hub cells to promote seizures.SIGNIFICANCE STATEMENT Adult dentate granule cell (DGC) neurogenesis is altered in rodent models of temporal lobe epilepsy (TLE). Some of the new neurons show abnormal morphology and integration, but whether adult-generated DGCs contribute to the development of epilepsy is controversial. We examined the synaptic inputs of age-defined populations of DGCs using electrophysiological recordings and fluorescent retroviral reporter birthdating. DGCs generated neonatally were compared with those generated in adulthood, and adult-born (AB) neurons with normal versus aberrant morphology or integration were examined. We found that AB, ectopically located DGCs exhibit the most pro-excitatory physiological changes, implicating this population in seizure generation or progression.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0654-18.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Increased Expression of Fibronectin Leucine-Rich Transmembrane Protein 3
           in the Dorsal Root Ganglion Induces Neuropathic Pain in Rats
    • Authors: Yamada, M; Fujita, Y, Hayano, Y, Hayakawa, H, Baba, K, Mochizuki, H, Yamashita, T.
      Pages: 7615 - 7627
      Abstract: Neuropathic pain is a chronic condition that occurs frequently after nerve injury and induces hypersensitivity or allodynia characterized by aberrant neuronal excitability in the spinal cord dorsal horn. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) is a modulator of neurite outgrowth, axon pathfinding, and cell adhesion, which is upregulated in the dorsal horn following peripheral nerve injury. However, the function of FLRT3 in adults remains unknown. Therefore, we aimed to investigate the involvement of spinal FLRT3 in neuropathic pain using rodent models. In the dorsal horns of male rats, FLRT3 protein levels increased at day 4 after peripheral nerve injury. In the DRG, FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated Flrt3 transcription in the DRG but not in the spinal cord. Intrathecal administration of FLRT3 protein to naive rats induced mechanical allodynia and GluN2B phosphorylation in the spinal cord. DRG-specific FLRT3 overexpression using adeno-associated virus also produced mechanical allodynia. Conversely, a function-blocking FLRT3 antibody attenuated mechanical allodynia after partial sciatic nerve ligation. Therefore, FLRT3 derived from injured DRG neurons increases dorsal horn excitability and induces mechanical allodynia.SIGNIFICANCE STATEMENT Neuropathic pain occurs frequently after nerve injury and is associated with abnormal neuronal excitability in the spinal cord. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) regulates neurite outgrowth and cell adhesion. Here, nerve injury increased FLRT3 protein levels in the spinal cord dorsal root, despite the fact that Flrt3 transcripts were only induced in the DRG. FLRT3 protein injection into the rat spinal cord induced mechanical hypersensitivity, as did virus-mediated FLRT3 overexpression in DRG. Conversely, FLRT3 inhibition with antibodies attenuated mechanically induced pain after nerve damage. These findings suggest that FLRT3 is produced by injured DRG neurons and increases neuronal excitability in the dorsal horn, leading to pain sensitization. Neuropathic pain induction is a novel function of FLRT3.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0295-19.2019
      Issue No: Vol. 39, No. 38 (2019)
  • Female Sex and Brain-Selective Estrogen Benefit {alpha}-Synuclein
           Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice
    • Authors: Rajsombath, M. M; Nam, A. Y, Ericsson, M, Nuber, S.
      Pages: 7628 - 7640
      Abstract: Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on α-synuclein (αS) homeostasis and related PD neuropathology remain unknown. Here, we used an αS tetramer-abrogating mouse model of PD (3K) that amplifies the familial E46K PD mutation to investigate the effects of female sex and brain-selective estrogen treatment on αS tetramerization and solubility, formation of vesicle-rich αS+ aggregates, dopaminergic and cortical fiber integrity, and associated motor deficits. In male 3K mice, the motor phenotype became apparent at ~10 weeks and increased to age 6 months, paralleled by PD-like neuropathology, whereas 3K females showed a significant delay in onset. At 6 months, this beneficial phenotypic effect in 3K females was associated with a higher αS tetramer-to-monomer ratio and less decrease in dopaminergic and cortical fiber length and quantity. Brain-selective estrogen treatment in symptomatic 3K mice significantly increased the tetramer-to-monomer ratio, turnover by autophagy of aggregate-prone monomers, and neurite complexity of surviving DAergic and cortical neurons, in parallel with benefits in motor performance. Our findings support an upstream role for αS tetramer loss in PD phenotypes and a role for estrogen in mitigating PD-like neuropathology in vivo. Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women.SIGNIFICANCE STATEMENT The mechanisms responsible for the male-to-female preponderance in Parkinson's disease (PD) are not well understood yet important for treatment efficacy. We previously showed that abrogating native α-synuclein (αS) tetramers produces a close PD model, including dopaminergic and cortical fiber loss and a progressive motor disorder responsive to l-DOPA. Here, we analyzed sex and use 10b-17β-dihydroxyestra-1,4-dien-3-one treatment of symptomatic 3K males, and demonstrate that the beneficial effects of female sex on PD-like neuropathology can be reinstated by elevating estrogen in the male brain. The study provides evidence that 17β-estradiol restores the tetramer-to-monomer ratio by autophagy turnover of excess αS monomers, vesicle and fiber integrity in brain regions critically involved in motor behavior. These data provide the basis for understanding sex differences in αS homeostasis and the development of therapeutic approaches to treating men and postmenopausal women with PD.
      PubDate: 2019-09-18T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0313-19.2019
      Issue No: Vol. 39, No. 38 (2019)
School of Mathematical and Computer Sciences
Heriot-Watt University
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