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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: 5629 - 5629
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.twij.39.29.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • An Integrative and Mechanistic Model of Impaired Belief Updating in
           Schizophrenia
    • Authors: Ghane, M; Sparer, T.
      Pages: 5630 - 5633
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.0002-19.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation
           Mediate Structural and Behavioral Adaptations During Withdrawal From
           Cocaine Self-Administration
    • Authors: Calipari, E. S; Godino, A, Salery, M, Damez-Werno, D. M, Cahill, M. E, Werner, C. T, Gancarz, A. M, Peck, E. G, Jlayer, Z, Rabkin, J, Landry, J. A, Smith, A. C. W, Defilippi, P, Kenny, P. J, Hurd, Y. L, Neve, R. L, Dietz, D. M, Nestler, E. J.
      Pages: 5634 - 5646
      Abstract: Addictive behaviors, including relapse, are thought to depend in part on long-lasting drug-induced adaptations in dendritic spine signaling and morphology in the nucleus accumbens (NAc). While the influence of activity-dependent actin remodeling in these phenomena has been studied extensively, the role of microtubules and associated proteins remains poorly understood. We report that pharmacological inhibition of microtubule polymerization in the NAc inhibited locomotor sensitization to cocaine and contextual reward learning. We then investigated the roles of microtubule end-binding protein 3 (EB3) and SRC kinase in the neuronal and behavioral responses to volitionally administered cocaine. In synaptoneurosomal fractions from the NAc of self-administering male rats, the phosphorylation of SRC at an activating site was induced after 1 d of withdrawal, while EB3 levels were increased only after 30 d of withdrawal. Blocking SRC phosphorylation during early withdrawal by virally overexpressing SRCIN1, a negative regulator of SRC activity known to interact with EB3, abolished the incubation of cocaine craving in both male and female rats. Conversely, mimicking the EB3 increase observed after prolonged withdrawal increased the motivation to consume cocaine in male rats. In mice, the overexpression of either EB3 or SRCIN1 increased dendritic spine density and altered the spine morphology of NAc medium spiny neurons. Finally, a cocaine challenge after prolonged withdrawal recapitulated most of the synaptic protein expression profiles observed at early withdrawal. These findings suggest that microtubule-associated signaling proteins such as EB3 cooperate with actin remodeling pathways, notably SRC kinase activity, to establish and maintain long-lasting cellular and behavioral alterations following cocaine self-administration.SIGNIFICANCE STATEMENT Drug-induced morphological restructuring of dendritic spines of nucleus accumbens neurons is thought to be one of the cellular substrates of long-lasting drug-associated memories. The molecular basis of these persistent changes has remained incompletely understood. Here we implicate for the first time microtubule function in this process, together with key players such as microtubule-bound protein EB3 and synaptic SRC phosphorylation. We propose that microtubule and actin remodeling cooperate during withdrawal to maintain the plastic structural changes initially established by cocaine self-administration. This work opens new translational avenues for further characterization of microtubule-associated regulatory molecules as putative drug targets to tackle relapse to drug taking.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.0024-19.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Striatal Cholinergic Interneurons Are a Novel Target of Corticotropin
           Releasing Factor
    • Authors: Lemos, J. C; Shin, J. H, Alvarez, V. A.
      Pages: 5647 - 5661
      Abstract: Cholinergic interneurons (CINs) are critical regulators of striatal network activity and output. Changes in CIN activity are thought to encode salient changes in the environment and stimulus–response–outcome associations. Here we report that the stress-associated neuropeptide corticotropin releasing factor (CRF) produces a profound and reliable increase in the spontaneous firing of CINs in both dorsal striatum and nucleus accumbens (NAc) through activation of CRF type 1 receptors, production of cAMP and reduction in spike accommodation in male mice. The increase of CIN firing by CRF results in the activation muscarinic acetylcholine receptors type 5, which mediate potentiation of dopamine transmission in the striatum. This study provides critical mechanistic insight into how CRF modulates striatal activity and dopamine transmission in the NAc to likely account for CRF facilitation of appetitive behaviors.SIGNIFICANCE STATEMENT Although the presence of CRF receptors in the dorsal and ventral striatum has been acknowledged, the cellular identity and the functional consequences of receptor activation is unknown. Here we report that striatal cholinergic interneurons express CRF-R1 receptors and are acutely activated by the neuropeptide CRF that is released in response to salient environmental stimuli. Cholinergic interneurons make
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.0479-19.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • C. elegans Tensin Promotes Axon Regeneration by Linking the Met-like SVH-2
           and Integrin Signaling Pathways
    • Authors: Hisamoto, N; Shimizu, T, Asai, K, Sakai, Y, Pastuhov, S. I, Hanafusa, H, Matsumoto, K.
      Pages: 5662 - 5672
      Abstract: Axon regeneration is a conserved mechanism induced by axon injury that initiates a neuronal response leading to regrowth of the axon. In Caenorhabditis elegans, the initiation of axon regeneration is regulated by the JNK MAP kinase (MAPK) pathway. We have previously identified a number of genes affecting the JNK pathway using an RNAi-based screen. Analysis of these genes, called the svh genes, has shed new light on the regulation of axon regeneration, revealing the involvement of a signaling cascade consisting of a growth factor SVH-1 and its receptor, the tyrosine kinase SVH-2. Here, we characterize the svh-6/tns-1 gene, which is a homolog of mammalian tensin, and show that it is a positive regulator of axon regeneration in motor neurons. We demonstrate that TNS-1 interacts with tyrosine-autophosphorylated SVH-2 and the integrin β subunit PAT-3 via its SH2 and PTB domains, respectively, to promote axon regeneration. These results suggest that TNS-1 acts as an adaptor to link the SVH-2 and integrin signaling pathways.SIGNIFICANCE STATEMENT The Caenorhabditis elegans JNK MAPK pathway regulates the initiation of axon regeneration. Previously, we showed that a signaling cascade consisting of the HGF-like growth factor SVH-1 and its Met-like receptor tyrosine kinase SVH-2 promotes axon regeneration through activation of the JNK pathway. In this study, we show that the C. elegans tensin, TNS-1, is required for efficient regeneration after axon injury. Phosphorylation of SVH-2 on tyrosine mediates its interaction with the SH2 domain of TNS-1 to positively regulate axon regeneration. Furthermore, TNS-1 interacts via its PTB domain with the integrin β subunit PAT-3. These results suggest that TNS-1 plays a critical role in the regulation of axon regeneration by linking the SVH-2 and integrin signaling pathways.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2059-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Spiking Noise and Information Density of Neurons in Visual Area V2 of
           Infant Monkeys
    • Authors: Wang, Y; Zhang, B, Tao, X, Shen, G, Smith, E. L, Chino, Y. M.
      Pages: 5673 - 5684
      Abstract: Encoding of visual information requires precisely timed spiking activity in the network of cortical neurons; irregular spiking can interfere with information processing especially for low-contrast images. The vision of newborn infants is impoverished. An infant's contrast sensitivity is low and the ability to discriminate complex stimuli is poor. The neural mechanisms that limit the visual capacities of infants are a matter of debate. Here we asked whether noisy spiking and/or crude information processing in visual cortex limit infant vision. Since neurons beyond the primary visual cortex (V1) have rarely been studied in neonates or infants, we focused on the firing pattern of neurons in visual area V2, the earliest extrastriate visual area of both male and female macaque monkeys (Maccaca mulatta). For eight stimulus contrasts ranging from 0% to 80%, we analyzed spiking irregularity by calculating the square of the coefficient of variation (CV2) in interspike intervals, the trial-to-trial fluctuation in spiking (Fano factor), and the amount of information on contrast conveyed by each spiking (information density). While the contrast sensitivity of infant neurons was reduced as expected, spiking noise, both the magnitude of spiking irregularity and the trial-to-trial fluctuations, was much lower in the spike trains of infant V2 neurons compared with those of adults. However, information density for V2 neurons was significantly lower in infants. Our results suggest that poor contrast sensitivity combined with lower information density of extrastriate neurons, despite their lower spiking noise, may limit behaviorally determined contrast sensitivity soon after birth.SIGNIFICANCE STATEMENT Despite>50 years of investigations on the postnatal development of the primary visual cortex (V1), cortical mechanisms that may limit infant vision are still unclear. We investigated the quality and strength of neuronal firing in primate visual area V2 by analyzing contrast sensitivity, spiking variability, and the amount of information on contrast conveyed by each action potential (information density). Here we demonstrate that the firing rate, contrast sensitivity, and dynamic range of V2 neurons were depressed in infants compared with adults. Although spiking noise was less, information density was lower in infant V2. Impoverished neuronal drive and lower information density in extrastriate visual areas, despite lower spiking noise, largely explain the impoverished visual sensitivity of primates near birth.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2023-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry
    • Authors: Popova, D; Desai, N, Blendy, J. A, Pang, Z. P.
      Pages: 5685 - 5696
      Abstract: Mu-opioid receptors (MORs) are the primary site of action of opioid drugs, both licit and illicit. Susceptibility to opioid addiction is associated with variants in the gene encoding the MOR, OPRM1. Varying with ethnicity, ~25% of humans carry a single nucleotide polymorphism (SNP) in OPRM1 (A118G). This SNP produces a nonsynonymous amino acid substitution, replacing asparagine (N40) with aspartate (D40), and has been linked with an increased risk for drug addiction. While a murine model of human OPRM1 A118G (A112G in mouse) recapitulates most of the phenotypes reported in humans, the neuronal mechanisms underlying these phenotypes remain elusive. Here, we investigated the impact of A118G on opioid regulation of synaptic transmission in mesolimbic VTA dopaminergic neurons. Using electrophysiology, we showed that both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to the NAc medial shell were suppressed by the MOR agonists DAMGO and morphine, which caused a shift in the excitatory/inhibitory balance and an increased action potential firing rate. Mice carrying the 112G/G allele exhibited lower sensitivity to DAMGO and morphine compared with major allele carriers (112A/A). Paradoxically, DAMGO produced facilitatory effects on mEPSCs, which were mediated by presynaptic GABAB receptors. However, this was only prominent in homozygous major allele carriers, which could explain a stronger shift in action potential firing in 112A/A mice. This study provides a better understanding on the neurobiological mechanisms that may underlie risk of addiction development in carriers of the A118G SNP in OPRM1.SIGNIFICANCE STATEMENT The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the μ-opioid receptor (MOR), encoded by the OPRM1 gene, which is highly polymorphic in humans. Using a mouse model of the human OPRM1 A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABAB signaling coordinate in regulating mesolimbic dopamine neuronal firing via presynaptic regulation. The A118G SNP affects MOR-mediated suppression of GABA and glutamate release, showing weaker efficacy of synaptic regulation by MORs. These results may shed light on whether MOR SNPs need to be considered for devising effective therapeutic interventions.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2317-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • The Augmentation of Retinogeniculate Communication during Thalamic Burst
           Mode
    • Authors: Alitto, H; Rathbun, D. L, Vandeleest, J. J, Alexander, P. C, Usrey, W. M.
      Pages: 5697 - 5710
      Abstract: Retinal signals are transmitted to cortex via neurons in the lateral geniculate nucleus (LGN), where they are processed in burst or tonic response mode. Burst mode occurs when LGN neurons are sufficiently hyperpolarized for T-type Ca2+ channels to deinactivate, allowing them to open in response to depolarization, which can trigger a high-frequency sequence of Na+-based spikes (i.e., burst). In contrast, T-type channels are inactivated during tonic mode and do not contribute to spiking. Although burst mode is commonly associated with sleep and the disruption of retinogeniculate communication, bursts can also be triggered by visual stimulation, thereby transforming the retinal signals relayed to the cortex. To determine how burst mode affects retinogeniculate communication, we made recordings from monosynaptically connected retinal ganglion cells and LGN neurons in male/female cats during visual stimulation. Our results reveal a robust augmentation of retinal signals within the LGN during burst mode. Specifically, retinal spikes were more effective and often triggered multiple LGN spikes during periods likely to have increased T-type Ca2+ channel activity. Consistent with the biophysical properties of T-type Ca2+ channels, analysis revealed that effect magnitude was correlated with the duration of the preceding thalamic interspike interval and occurred even in the absence of classically defined bursts. Importantly, the augmentation of geniculate responses to retinal input was not associated with a degradation of visual signals. Together, these results indicate a graded nature of response mode and suggest that, under certain conditions, bursts facilitate the transmission of visual information to the cortex by amplifying retinal signals.SIGNIFICANCE STATEMENT The thalamus is the gateway for retinal information traveling to the cortex. The lateral geniculate nucleus, like all thalamic nuclei, has two classically defined categories of spikes—tonic and burst—that differ in their underlying cellular mechanisms. Here we compare retinogeniculate communication during burst and tonic response modes. Our results show that retinogeniculate communication is enhanced during burst mode and visually evoked thalamic bursts, thereby augmenting retinal signals transmitted to cortex. Further, our results demonstrate that the influence of burst mode on retinogeniculate communication is graded and can be measured even in the absence of classically defined thalamic bursts.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2320-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Oscillatory Properties of Functional Connections Between Sensory Areas
           Mediate Cross-Modal Illusory Perception
    • Authors: Cooke, J; Poch, C, Gillmeister, H, Costantini, M, Romei, V.
      Pages: 5711 - 5718
      Abstract: The presentation of simple auditory stimuli can significantly impact visual processing and even induce visual illusions, such as the auditory-induced double flash illusion (DFI). These cross-modal processes have been shown to be driven by occipital oscillatory activity within the alpha band. Whether this phenomenon is network specific or can be generalized to other sensory interactions remains unknown. The aim of the current study was to test whether cross-modal interactions between somatosensory-to-visual areas leading to the same (but tactile-induced) DFI share similar properties with the auditory DFI. We hypothesized that if the effects are mediated by the oscillatory properties of early visual areas per se, then the two versions of the illusion should be subtended by the same neurophysiological mechanism (i.e., the speed of the alpha frequency). Alternatively, if the oscillatory activity in visual areas predicting this phenomenon is dependent on the specific neural network involved, then it should reflect network-specific oscillatory properties. In line with the latter, results recorded in humans (both sexes) show a network-specific oscillatory profile linking the auditory DFI to occipital alpha oscillations, replicating previous findings, and tactile DFI to occipital beta oscillations, a rhythm typical of somatosensory processes. These frequency-specific effects are observed for visual (but not auditory or somatosensory) areas and account for auditory–visual connectivity in the alpha band and somatosensory–visual connectivity in the beta band. We conclude that task-dependent visual oscillations reflect network-specific oscillatory properties favoring optimal directional neural communication timing for sensory binding.SIGNIFICANCE STATEMENT We investigated the oscillatory correlates of the auditory- and tactile-induced double flash illusion (DFI), a phenomenon where two interleaved beeps (taps) set within 100 ms apart and paired with one visual flash induce the sensation of a second illusory flash. Results confirm previous evidence that the speed of individual occipital alpha oscillations predict the temporal window of the auditory-induced illusion. Importantly, they provide novel evidence that the tactile-induced DFI is instead mediated by the speed of individual occipital beta oscillations. These task-dependent occipital oscillations are shown to be mediated by the oscillatory properties of the neural network engaged in the task to favor optimal temporal integration between the senses.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.3184-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • How Does iReadMore Therapy Change the Reading Network of Patients with
           Central Alexia'
    • Authors: Kerry, S. J; Aguilar, O. M, Penny, W, Crinion, J. T, Leff, A. P, Woodhead, Z. V. J.
      Pages: 5719 - 5727
      Abstract: Central alexia (CA) is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). The roles of perilesional and ipsilesional tissue in recovery from poststroke aphasia are unclear. We investigated the impact of reading training (using iReadMore, a therapy app) on the connections within and between the right and left hemisphere of the reading network of patients with CA. In patients with pure alexia, iReadMore increased feedback from left inferior frontal gyrus (IFG) region to the left occipital (OCC) region. We aimed to identify whether iReadMore therapy was effective through a similar mechanism in patients with CA. Participants with chronic poststroke CA (n = 23) completed 35 h of iReadMore training over 4 weeks. Reading accuracy for trained and untrained words was assessed before and after therapy. The neural response to reading trained and untrained words in the left and right OCC, ventral occipitotemporal, and IFG regions was examined using event-related magnetoencephalography. The training-related modulation in effective connectivity between regions was modeled at the group level with dynamic causal modeling. iReadMore training improved participants' reading accuracy by an average of 8.4% (range, –2.77 to 31.66) while accuracy for untrained words was stable. Training increased regional sensitivity in bilateral frontal and occipital regions, and strengthened feedforward connections within the left hemisphere. Our data suggest that iReadMore training in these patients modulates lower-order visual representations, as opposed to higher-order, more abstract representations, to improve word-reading accuracy.SIGNIFICANCE STATEMENT This is the first study to conduct a network-level analysis of therapy effects in participants with poststroke central alexia. When patients trained with iReadMore (a multimodal, behavioral, mass practice, computer-based therapy), reading accuracy improved by an average 8.4% on trained items. A network analysis of the magnetoencephalography data associated with this improvement revealed an increase in regional sensitivity in bilateral frontal and occipital regions and strengthening of feedforward connections within the left hemisphere. This indicates that in patients with CA iReadMore engages lower-order, intact resources within the left hemisphere (posterior to their lesion locations) to improve word reading. This provides a foundation for future research to investigate reading network modulation in different CA subtypes, or for sentence-level therapy.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.1426-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Anterior Cingulate Cortex to Ventral Hippocampus Circuit Mediates
           Contextual Fear Generalization
    • Authors: Bian, X.-L; Qin, C, Cai, C.-Y, Zhou, Y, Tao, Y, Lin, Y.-H, Wu, H.-Y, Chang, L, Luo, C.-X, Zhu, D.-Y.
      Pages: 5728 - 5739
      Abstract: Contextual fear memory becomes less context-specific over time, a phenomenon referred to as contextual fear generalization. Overgeneralization of contextual fear memory is a core symptom of post-traumatic stress disorder (PTSD), but circuit mechanisms underlying the generalization remain unclear. We show here that neural projections from the anterior cingulate cortex (ACC) to ventral hippocampus (vHPC) mediate contextual fear generalization in male mice. Retrieval of contextual fear in a novel context at a remote time point activated cells in the ACC and vHPC, as indicated by significantly increased C-fos+ cells. Using chemogenetic or photogenetic manipulations, we observed that silencing the activity of ACC or vHPC neurons reduced contextual fear generalization at the remote time point, whereas stimulating the activity of ACC or vHPC neurons facilitated contextual fear generalization at a recent time point. We found that ACC neurons projected to the vHPC unidirectionally, and importantly, silencing the activity of projection fibers from the ACC to vHPC inhibited contextual fear generalization at the remote time point. Together, our findings reveal an ACC to vHPC circuit that controls expression of fear generalization and may offer new strategies to prevent or reverse contextual fear generalization in subjects with anxiety disorders, especially in PTSD.SIGNIFICANCE STATEMENT Overgeneralization of contextual fear memory is a cardinal feature of PTSD, but circuit mechanisms underlying it remain unclear. Our study indicates that neural projections from the anterior cingulate cortex to ventral hippocampus control the expression of contextual fear generalization. Thus, manipulating the circuit may prevent or reverse fear overgeneralization in subjects with PTSD.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2739-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Regional Striatal Cholinergic Involvement in Human Behavioral Flexibility
    • Authors: Bell, T; Lindner, M, Langdon, A, Mullins, P. G, Christakou, A.
      Pages: 5740 - 5749
      Abstract: Animal studies have shown that the striatal cholinergic system plays a role in behavioral flexibility but, until recently, this system could not be studied in humans due to a lack of appropriate noninvasive techniques. Using proton magnetic resonance spectroscopy, we recently showed that the concentration of dorsal striatal choline (an acetylcholine precursor) changes during reversal learning (a measure of behavioral flexibility) in humans. The aim of the present study was to examine whether regional average striatal choline was associated with reversal learning. A total of 22 participants (mean age = 25.2 years, range = 18–32 years, 13 female) reached learning criterion in a probabilistic learning task with a reversal component. We measured choline at rest in both the dorsal and ventral striatum using magnetic resonance spectroscopy. Task performance was described using a simple reinforcement learning model that dissociates the contributions of positive and negative prediction errors to learning. Average levels of choline in the dorsal striatum were associated with performance during reversal, but not during initial learning. Specifically, lower levels of choline in the dorsal striatum were associated with a lower number of perseverative trials. Moreover, choline levels explained interindividual variance in perseveration over and above that explained by learning from negative prediction errors. These findings suggest that the dorsal striatal cholinergic system plays an important role in behavioral flexibility, in line with evidence from the animal literature and our previous work in humans. Additionally, this work provides further support for the idea of measuring choline with magnetic resonance spectroscopy as a noninvasive way of studying human cholinergic neurochemistry.SIGNIFICANCE STATEMENT Behavioral flexibility is a crucial component of adaptation and survival. Evidence from the animal literature shows that the striatal cholinergic system is fundamental to reversal learning, a key paradigm for studying behavioral flexibility, but this system remains understudied in humans. Using proton magnetic resonance spectroscopy, we showed that choline levels at rest in the dorsal striatum are associated with performance specifically during reversal learning. These novel findings help to bridge the gap between animal and human studies by demonstrating the importance of cholinergic function in the dorsal striatum in human behavioral flexibility. Importantly, the methods described here cannot only be applied to furthering our understanding of healthy human neurochemistry, but also to extending our understanding of cholinergic disorders.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2110-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Neural Speech Tracking in the Theta and in the Delta Frequency Band
           Differentially Encode Clarity and Comprehension of Speech in Noise
    • Authors: Etard, O; Reichenbach, T.
      Pages: 5750 - 5759
      Abstract: Humans excel at understanding speech even in adverse conditions such as background noise. Speech processing may be aided by cortical activity in the delta and theta frequency bands, which have been found to track the speech envelope. However, the rhythm of non-speech sounds is tracked by cortical activity as well. It therefore remains unclear which aspects of neural speech tracking represent the processing of acoustic features, related to the clarity of speech, and which aspects reflect higher-level linguistic processing related to speech comprehension. Here we disambiguate the roles of cortical tracking for speech clarity and comprehension through recording EEG responses to native and foreign language in different levels of background noise, for which clarity and comprehension vary independently. We then use a both a decoding and an encoding approach to relate clarity and comprehension to the neural responses. We find that cortical tracking in the theta frequency band is mainly correlated to clarity, whereas the delta band contributes most to speech comprehension. Moreover, we uncover an early neural component in the delta band that informs on comprehension and that may reflect a predictive mechanism for language processing. Our results disentangle the functional contributions of cortical speech tracking in the delta and theta bands to speech processing. They also show that both speech clarity and comprehension can be accurately decoded from relatively short segments of EEG recordings, which may have applications in future mind-controlled auditory prosthesis.SIGNIFICANCE STATEMENT Speech is a highly complex signal whose processing requires analysis from lower-level acoustic features to higher-level linguistic information. Recent work has shown that neural activity in the delta and theta frequency bands track the rhythm of speech, but the role of this tracking for speech processing remains unclear. Here we disentangle the roles of cortical entrainment in different frequency bands and at different temporal lags for speech clarity, reflecting the acoustics of the signal, and speech comprehension, related to linguistic processing. We show that cortical speech tracking in the theta frequency band encodes mostly speech clarity, and thus acoustic aspects of the signal, whereas speech tracking in the delta band encodes the higher-level speech comprehension.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.1828-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Increased Lysosomal Exocytosis Induced by Lysosomal Ca2+ Channel Agonists
           Protects Human Dopaminergic Neurons from {alpha}-Synuclein Toxicity
    • Authors: Tsunemi, T; Perez-Rosello, T, Ishiguro, Y, Yoroisaka, A, Jeon, S, Hamada, K, Rammonhan, M, Wong, Y. C, Xie, Z, Akamatsu, W, Mazzulli, J. R, Surmeier, D. J, Hattori, N, Krainc, D.
      Pages: 5760 - 5772
      Abstract: The accumulation of misfolded proteins is a common pathological feature of many neurodegenerative disorders, including synucleinopathies such as Parkinson's disease (PD), which is characterized by the presence of α-synuclein (α-syn)-containing Lewy bodies. However, although recent studies have investigated α-syn accumulation and propagation in neurons, the molecular mechanisms underlying α-syn transmission have been largely unexplored. Here, we examined a monogenic form of synucleinopathy caused by loss-of-function mutations in lysosomal ATP13A2/PARK9. These studies revealed that lysosomal exocytosis regulates intracellular levels of α-syn in human neurons. Loss of PARK9 function in patient-derived dopaminergic neurons disrupted lysosomal Ca2+ homeostasis, reduced lysosomal Ca2+ storage, increased cytosolic Ca2+, and impaired lysosomal exocytosis. Importantly, this dysfunction in lysosomal exocytosis impaired α-syn secretion from both axons and soma, promoting α-syn accumulation. However, activation of the lysosomal Ca2+ channel transient receptor potential mucolipin 1 (TRPML1) was sufficient to upregulate lysosomal exocytosis, rescue defective α-syn secretion, and prevent α-syn accumulation. Together, these results suggest that intracellular α-syn levels are regulated by lysosomal exocytosis in human dopaminergic neurons and may represent a potential therapeutic target for PD and other synucleinopathies.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is the second most common neurodegenerative disease linked to the accumulation of α-synuclein (α-syn) in patient neurons. However, it is unclear what the mechanism might be. Here, we demonstrate a novel role for lysosomal exocytosis in clearing intracellular α-syn and show that impairment of this pathway by mutations in the PD-linked gene ATP13A2/PARK9 contributes to α-syn accumulation in human dopaminergic neurons. Importantly, upregulating lysosomal exocytosis by increasing lysosomal Ca2+ levels was sufficient to rescue defective α-syn secretion and accumulation in patient neurons. These studies identify lysosomal exocytosis as a potential therapeutic target in diseases characterized by the accumulation of α-syn, including PD.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.3085-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent
           Cortical Synaptic Plasticity and Pain Hypersensitivity
    • Authors: Li, H.-S; Su, X.-Y, Song, X.-L, Qi, X, Li, Y, Wang, R.-Q, Maximyuk, O, Krishtal, O, Wang, T, Fang, H, Liao, L, Cao, H, Zhang, Y.-Q, Zhu, M. X, Liu, M.-G, Xu, T.-L.
      Pages: 5773 - 5793
      Abstract: Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C -mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.0213-19.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a
           Mouse Model of Frontotemporal Dementia
    • Authors: Terreros-Roncal, J; Flor-Garcia, M, Moreno-Jimenez, E. P, Pallas-Bazarra, N, Rabano, A, Sah, N, van Praag, H, Giacomini, D, Schinder, A. F, Avila, J, Llorens-Martin, M.
      Pages: 5794 - 5815
      Abstract: Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, TauVLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female TauVLW mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn TauVLW DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of TauVLW mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1+ DGCs in TauVLW mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of TauVLW mice and FTD patients.SIGNIFICANCE STATEMENT We show, for the first time to our knowledge, that the population of dentate granule cells is disconnected from other regions of the brain in the neurodegenerative disease frontotemporal dementia (FTD). These alterations were observed in FTD patients and in a mouse model of this disease. Moreover, we tested the therapeutic potential of two strategies, environmental enrichment and chemoactivation, to stimulate the activity of these neurons in mice. We found that some of the alterations were reversed by these therapeutic interventions.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2724-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
  • A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a
           Role of Glycosphingolipids in Neuronal Polarity
    • Authors: Cui, M; Ying, R, Jiang, X, Li, G, Zhang, X, Zheng, J, Tam, K. Y, Liang, B, Shi, A, Göbel, V, Zhang, H.
      Pages: 5816 - 5834
      Abstract: Hereditary sensory and autonomic neuropathy Type 1 (HSAN1) is a rare autosomal dominantly inherited neuropathy, clinically characterized by a loss of distal peripheral sensory and motoneuronal function. Mutations in subunits of serine palmitoyltransferase (SPT) have been linked to the majority of HSAN1 cases. SPTs catalyze the condensation of l-serine with palmitoyl-CoA, the first committed and rate-limiting step in de novo sphingolipid biosynthesis. Despite extensive investigation, the molecular pathogenesis of HSAN1 remains controversial. Here, we established a Caenorhabditis elegans (C. elegans) model of HSAN1 by generating a sptl-1(c363g) mutation, encoding SPTL-1(C121W) and equivalent to human SPTLC1C133W, at the C. elegans genomic locus through CRISPR. The sptl-1(c363g) homozygous mutants exhibited the same larval lethality and epithelial polarity defect as observed in sptl-1(RNAi) animals, suggesting a loss-of-function effect of the SPTL-1(C121W) mutation. sptl-1(c363g)/+ heterozygous mutants displayed sensory dysfunction with concomitant neuronal morphology and axon-dendrite polarity defects, demonstrating that the C. elegans model recapitulates characteristics of the human disease. sptl-1(c363g)-derived neuronal defects were copied in animals with defective sphingolipid biosynthetic enzymes downstream of SPTL-1, including ceramide glucosyltransferases, suggesting that SPTLC1C133W contributes to the HSAN1 pathogenesis by limiting the production of complex sphingolipids, including glucosylceramide. Overexpression of SPTL-1(C121W) led to similar epithelial and neuronal defects and to reduced levels of complex sphingolipids, specifically glucosylceramide, consistent with a dominant-negative effect of SPTL-1(C121W) that is mediated by loss of this downstream product. Genetic interactions between SPTL-1(C121W) and components of directional trafficking in neurons suggest that the neuronal polarity phenotype could be caused by glycosphingolipid-dependent defects in polarized vesicular trafficking.SIGNIFICANCE STATEMENT The symptoms of inherited metabolic diseases are often attributed to the accumulation of toxic intermediates or byproducts, no matter whether the disease-causing enzyme participates in a biosynthetic or a degradation pathway. By showing that the phenotypes observed in a C. elegans model of HSAN1 disease could be caused by loss of a downstream product (glucosylceramide) rather than the accumulation of a toxic byproduct, our work provides new insights into the origins of the symptoms of inherited metabolic diseases while expanding the repertoire of sphingolipid functions, specifically, of glucosylceramides. These findings not only have their most immediate relevance for neuroprotective treatments for HSAN1, they may also have implications for a much broader range of neurologic conditions.
      PubDate: 2019-07-17T09:30:27-07:00
      DOI: 10.1523/JNEUROSCI.2541-18.2019
      Issue No: Vol. 39, No. 29 (2019)
       
 
 
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