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Journal Cover Journal of Neuroscience
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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
    • PubDate: 2018-01-10T09:06:25-08:00
      Issue No: Vol. 38, No. 2 (2018)
  • Cognitive Control, the Anterior Cingulate, and Nicotinic Receptors: A Case
           of Heterozygote Advantage
    • Authors: Smucny J.
      Pages: 257 - 259
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2775-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Does Auditory Cortex Code Temporal Information from Acoustic and Cochlear
           Implant Stimulation in a Similar Way'
    • Authors: Navntoft, C. A; Adenis, V.
      Pages: 260 - 262
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2774-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Behavioral, Modeling, and Electrophysiological Evidence for Supramodality
           in Human Metacognition
    • Authors: Faivre, N; Filevich, E, Solovey, G, Kühn, S, Blanke, O.
      Pages: 263 - 277
      Abstract: Human metacognition, or the capacity to introspect on one's own mental states, has been mostly characterized through confidence reports in visual tasks. A pressing question is to what extent results from visual studies generalize to other domains. Answering this question allows determining whether metacognition operates through shared, supramodal mechanisms or through idiosyncratic, modality-specific mechanisms. Here, we report three new lines of evidence for decisional and postdecisional mechanisms arguing for the supramodality of metacognition. First, metacognitive efficiency correlated among auditory, tactile, visual, and audiovisual tasks. Second, confidence in an audiovisual task was best modeled using supramodal formats based on integrated representations of auditory and visual signals. Third, confidence in correct responses involved similar electrophysiological markers for visual and audiovisual tasks that are associated with motor preparation preceding the perceptual judgment. We conclude that the supramodality of metacognition relies on supramodal confidence estimates and decisional signals that are shared across sensory modalities.SIGNIFICANCE STATEMENT Metacognitive monitoring is the capacity to access, report, and regulate one's own mental states. In perception, this allows rating our confidence in what we have seen, heard, or touched. Although metacognitive monitoring can operate on different cognitive domains, we ignore whether it involves a single supramodal mechanism common to multiple cognitive domains or modality-specific mechanisms idiosyncratic to each domain. Here, we bring evidence in favor of the supramodality hypothesis by showing that participants with high metacognitive performance in one modality are likely to perform well in other modalities. Based on computational modeling and electrophysiology, we propose that supramodality can be explained by the existence of supramodal confidence estimates and by the influence of decisional cues on confidence estimates.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.0322-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • The Role of Cysteine String Protein {alpha} Phosphorylation at Serine 10
           and 34 by Protein Kinase C{gamma} for Presynaptic Maintenance
    • Authors: Shirafuji, T; Ueyama, T, Adachi, N, Yoshino, K.-I, Sotomaru, Y, Uwada, J, Kaneoka, A, Ueda, T, Tanaka, S, Hide, I, Saito, N, Sakai, N.
      Pages: 278 - 290
      Abstract: Protein kinase C (PKC) knock-out (KO) animals exhibit symptoms of Parkinson's disease (PD), including dopaminergic neuronal loss in the substantia nigra. However, the PKC substrates responsible for the survival of dopaminergic neurons in vivo have not yet been elucidated. Previously, we found 10 potent substrates in the striatum of PKC-KO mice. Here, we focused on cysteine string protein α (CSPα), a protein from the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles. We found that in cultured cells, PKC phosphorylates CSPα at serine (Ser) 10 and Ser34. Additionally, apoptosis was found to have been enhanced by the overexpression of a phosphorylation-null mutant of CSPα, CSPα(S10A/S34A). Compared with wild-type (WT) CSPα, the CSPα(S10A/S34A) mutant had a weaker interaction with HSP70. However, in sharp contrast, a phosphomimetic CSPα(S10D/S34D) mutant, compared with WT CSPα, had a stronger interaction with HSP70. In addition, total levels of synaptosomal-associated protein (SNAP) 25, a main downstream target of the HSC70/HSP70 chaperone complex, were found to have decreased by the CSPα(S10A/S34A) mutant through increased ubiquitination of SNAP25 in PC12 cells. In the striatum of 2-year-old male PKC-KO mice, decreased phosphorylation levels of CSPα and decreased SNAP25 protein levels were observed. These findings indicate the phosphorylation of CSPα by PKC may protect the presynaptic terminal from neurodegeneration. The PKC–CSPα–HSC70/HSP70–SNAP25 axis, because of its role in protecting the presynaptic terminal, may provide a new therapeutic target for the treatment of PD.SIGNIFICANCE STATEMENT Cysteine string protein α (CSPα) is a protein belonging to the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles, which maintain the presynaptic terminal. However, the function of CSPα phosphorylation by protein kinase C (PKC) for neuronal cell survival remains unclear. The experiments presented here demonstrate that PKC phosphorylates CSPα at serine (Ser) 10 and Ser34. CSPα phosphorylation at Ser10 and Ser34 by PKC protects the presynaptic terminal by promoting HSP70 chaperone activity. This report suggests that CSPα phosphorylation, because of its role in modulating HSP70 chaperone activity, may be a target for the treatment of neurodegeneration.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1649-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • The Microtubule-Associated Protein Tau Mediates the Organization of
           Microtubules and Their Dynamic Exploration of Actin-Rich Lamellipodia and
           Filopodia of Cortical Growth Cones
    • Authors: Biswas, S; Kalil, K.
      Pages: 291 - 307
      Abstract: Proper organization and dynamics of the actin and microtubule (MT) cytoskeleton are essential for growth cone behaviors during axon growth and guidance. The MT-associated protein tau is known to mediate actin/MT interactions in cell-free systems but the role of tau in regulating cytoskeletal dynamics in living neurons is unknown. We used cultures of cortical neurons from postnatal day (P)0–P2 golden Syrian hamsters (Mesocricetus auratus) of either sex to study the role of tau in the organization and dynamics of the axonal growth cone cytoskeleton. Here, using super resolution microscopy of fixed growth cones, we found that tau colocalizes with MTs and actin filaments and is also located at the interface between actin filament bundles and dynamic MTs in filopodia, suggesting that tau links these two cytoskeletons. Live cell imaging in concert with shRNA tau knockdown revealed that reducing tau expression disrupts MT bundling in the growth cone central domain, misdirects trajectories of MTs in the transition region and prevents single dynamic MTs from extending into growth cone filopodia along actin filament bundles. Rescue experiments with human tau expression restored MT bundling, MT penetration into the growth cone periphery and close MT apposition to actin filaments in filopodia. Importantly, we found that tau knockdown reduced axon outgrowth and growth cone turning in Wnt5a gradients, likely due to disorganized MTs that failed to extend into the peripheral domain and enter filopodia. These results suggest an important role for tau in regulating cytoskeletal organization and dynamics during growth cone behaviors.SIGNIFICANCE STATEMENT Growth cones are the motile tips of growing axons whose guidance behaviors require interaction of the dynamic actin and microtubule cytoskeleton. Tau is a microtubule-associated protein that stabilizes microtubules in neurons and in cell-free systems regulates actin–microtubule interaction. Here, using super resolution microscopy, live-cell imaging, and tau knockdown, we show for the first time in living axonal growth cones that tau is important for microtubule bundling and microtubule exploration of the actin-rich growth cone periphery. Importantly tau knockdown reduced axon outgrowth and growth cone turning, due to disorganized microtubules that fail to enter filopodia and co-align with actin filaments. Understanding normal tau functions will be important for identifying mechanisms of tau in neurodegenerative diseases such as Alzheimer's.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2281-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • CD44 Signaling Mediates High Molecular Weight Hyaluronan-Induced
    • Authors: Ferrari, L. F; Khomula, E. V, Araldi, D, Levine, J. D.
      Pages: 308 - 321
      Abstract: We studied, in male Sprague Dawley rats, the role of the cognate hyaluronan receptor, CD44 signaling in the antihyperalgesia induced by high molecular weight hyaluronan (HMWH). Low molecular weight hyaluronan (LMWH) acts at both peptidergic and nonpeptidergic nociceptors to induce mechanical hyperalgesia that is prevented by intrathecal oligodeoxynucleotide antisense to CD44 mRNA, which also prevents hyperalgesia induced by a CD44 receptor agonist, A6. Ongoing LMWH and A6 hyperalgesia are reversed by HMWH. HMWH also reverses the hyperalgesia induced by diverse pronociceptive mediators, prostaglandin E2, epinephrine, TNFα, and interleukin-6, and the neuropathic pain induced by the cancer chemotherapy paclitaxel. Although CD44 antisense has no effect on the hyperalgesia induced by inflammatory mediators or paclitaxel, it eliminates the antihyperalgesic effect of HMWH. HMWH also reverses the hyperalgesia induced by activation of intracellular second messengers, PKA and PKC, indicating that HMWH-induced antihyperalgesia, although dependent on CD44, is mediated by an intracellular signaling pathway rather than as a competitive receptor antagonist. Sensitization of cultured small-diameter DRG neurons by prostaglandin E2 is also prevented and reversed by HMWH. These results demonstrate the central role of CD44 signaling in HMWH-induced antihyperalgesia, and establish it as a therapeutic target against inflammatory and neuropathic pain.SIGNIFICANCE STATEMENT We demonstrate that hyaluronan (HA) with different molecular weights produces opposing nociceptive effects. While low molecular weight HA increases sensitivity to mechanical stimulation, high molecular weight HA reduces sensitization, attenuating inflammatory and neuropathic hyperalgesia. Both pronociceptive and antinociceptive effects of HA are mediated by activation of signaling pathways downstream CD44, the cognate HA receptor, in nociceptors. These results contribute to our understanding of the role of the extracellular matrix in pain, and indicate CD44 as a potential therapeutic target to alleviate inflammatory and neuropathic pain.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2695-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors
           in the Rostral Ventromedial Medulla
    • Authors: Klinger-Gratz, P. P; Ralvenius, W. T, Neumann, E, Kato, A, Nyilas, R, Lele, Z, Katona, I, Zeilhofer, H. U.
      Pages: 322 - 334
      Abstract: Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action. Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB1 receptors by the acetaminophen metabolite and endocannabinoid reuptake inhibitor AM 404. However, the contribution of the cannabinoid system to antihyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB1 receptors have remained elusive. Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent antihyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their antihyperalgesic activity in CB1–/– mice, confirming the involvement of the cannabinoid system. Consistent with a mechanism downstream of proinflammatory prostaglandin formation, acetaminophen also reversed hyperalgesia induced by intrathecal prostaglandin E2. To distinguish between a peripheral/spinal and a supraspinal action, we administered acetaminophen and AM 404 to hoxB8-CB1–/– mice, which lack CB1 receptors from the peripheral nervous system and the spinal cord. These mice exhibited unchanged antihyperalgesia indicating a supraspinal site of action. Accordingly, local injection of the CB1 receptor antagonist rimonabant into the rostral ventromedial medulla blocked acetaminophen-induced antihyperalgesia, while local rostral ventromedial medulla injection of AM 404 reduced hyperalgesia in wild-type mice but not in CB1–/– mice. Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB1 receptors reside in the rostral ventromedial medulla.SIGNIFICANCE STATEMENT Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action, including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue-specific CB1 receptor-deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1945-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Tonotopic Variation of the T-Type Ca2+ Current in Avian Auditory
           Coincidence Detector Neurons
    • Authors: Fukaya, R; Yamada, R, Kuba, H.
      Pages: 335 - 346
      Abstract: Neurons in avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and are characterized by striking structural variations in dendrites and axon initial segment (AIS) according to their acoustic tuning [characteristic frequency (CF)]. T-type Ca2+ (CaT) channels regulate synaptic integration and firing behavior at these neuronal structures. However, whether or how CaT channels contribute to the signal processing in NL neurons is not known. In this study, we addressed this issue with whole-cell recording and two-photon Ca2+ imaging in brain slices of posthatch chicks of both sexes. We found that the CaT current was prominent in low-CF neurons, whereas it was almost absent in higher-CF neurons. In addition, a large Ca2+ transient occurred at the dendrites and the AIS of low-CF neurons, indicating a localization of CaT channels at these structures in the neurons. Because low-CF neurons have long dendrites, dendritic CaT channels may compensate for the attenuation of EPSPs at dendrites. Furthermore, the short distance of AIS from the soma may accelerate activation of axonal CaT current in the neurons and help EPSPs reach spike threshold. Indeed, the CaT current was activated by EPSPs and augmented the synaptic response and spike generation of the neurons. Notably, the CaT current was inactivated during repetitive inputs, and these augmenting effects predominated at the initial phase of synaptic activity. These results suggested that dendritic and axonal CaT channels increase the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation in low-CF NL neurons.SIGNIFICANCE STATEMENT Neurons in nucleus laminaris are binaural coincidence detectors for sound localization. We report that T-type Ca2+ (CaT) current was prominent at dendrites and the axonal trigger zone in neurons tuned to low-frequency sound. Because these neurons have long dendrites and a closer trigger zone compared with those tuned to higher-frequency sound, the CaT current augmented EPSPs at dendrites and accelerated spike triggers in the neurons, implying a strategic arrangement of the current within the nucleus. This effect was limited to the onset of repetitive inputs due to progressive inactivation of CaT current. The results suggested that the CaT current increases the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation of low-frequency sound.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2237-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • The Mouse Pulvinar Nucleus Links the Lateral Extrastriate Cortex,
           Striatum, and Amygdala
    • Authors: Zhou, N; Masterson, S. P, Damron, J. K, Guido, W, Bickford, M. E.
      Pages: 347 - 362
      Abstract: The pulvinar nucleus is a large thalamic structure involved in the integration of visual and motor signals. The pulvinar forms extensive connections with striate and extrastriate cortical areas, but the impact of these connections on cortical circuits has not previously been directly tested. Using a variety of anatomical, optogenetic, and in vitro physiological techniques in male and female mice, we show that pulvinocortical terminals are densely distributed in the extrastriate cortex where they form synaptic connections with spines and small-diameter dendrites. Optogenetic activation of these synapses in vitro evoked large excitatory postsynaptic responses in the majority of pyramidal cells, spiny stellate cells, and interneurons within the extrastriate cortex. However, specificity in pulvinar targeting was revealed when recordings were targeted to projection neuron subtypes. The neurons most responsive to pulvinar input were those that project to the striatum and amygdala (76% responsive) or V1 (55%), whereas neurons that project to the superior colliculus were rarely responsive (6%). Because the pulvinar also projects directly to the striatum and amygdala, these results establish the pulvinar nucleus as a hub linking the visual cortex with subcortical regions involved in the initiation and control of movement. We suggest that these circuits may be particularly important for coordinating body movements and visual perception.SIGNIFICANCE STATEMENT We found that the pulvinar nucleus can strongly influence extrastriate cortical circuits and exerts a particularly strong impact on the activity of extrastriate neurons that project to the striatum and amygdala. Our results suggest that the conventional hierarchical view of visual cortical processing may not apply to the mouse visual cortex. Instead, our results establish the pulvinar nucleus as a hub linking the visual cortex with subcortical regions involved in the initiation and control of movement, and predict that the execution of visually guided movements relies on this network.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1279-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via
           Caspase-Dependent Microtubule Destabilization
    • Authors: Khatri, N; Gilbert, J. P, Huo, Y, Sharaflari, R, Nee, M, Qiao, H, Man, H.-Y.
      Pages: 363 - 378
      Abstract: UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs). However, the underlying cellular and molecular neurobiology remains less clear. Here we report the role of ASD-related increased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cultured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites. This remodeling effect is mediated by the ubiquitination and degradation of XIAP (X-linked inhibitors of aptosis protein) by E6AP, which leads to activation of caspase-3 and cleavage of microtubules. In vivo, male and female Ube3A 2X ASD mice show decreased XIAP levels, increased caspase-3 activation, and elevated levels of tubulin cleavage. Consistently, dendritic branching and spine density are reduced in cortical neurons of Ube3A 2X ASD mice. In revealing an important role for Ube3A/E6AP in ASD-related developmental alteration in dendritic arborization and synapse formation, our findings provide new insights into the pathogenesis of Ube3A/E6AP-dependent ASD.SIGNIFICANCE STATEMENT Copy number variation of the UBE3A gene and aberrant overexpression of the gene product E6AP protein is a common cause of autism spectrum disorders (ASDs). During brain development, dendritic growth and remodeling play crucial roles in neuronal connectivity and information integration. We found that in primary neurons and in Ube3A transgenic autism mouse brain, overexpression of E6AP leads to significant loss of dendritic arborization. This effect is mediated by the ubiquitination of XIAP (X-linked inhibitor of aptosis protein) by E6AP, subsequent activation of caspases, and the eventual cleavage of microtubules, leading to local degeneration and retraction at the tips of dendritic branches. These findings demonstrate dysregulation in neuronal structural stability as a major cellular neuropathology in ASD.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1511-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • A Critical Role for Dopamine D5 Receptors in Pain Chronicity in Male Mice
    • Authors: Megat, S; Shiers, S, Moy, J. K, Barragan-Iglesias, P, Pradhan, G, Seal, R. P, Dussor, G, Price, T. J.
      Pages: 379 - 397
      Abstract: Dopaminergic modulation of spinal cord plasticity has long been recognized, but circuits affected by this system and the precise receptor subtypes involved in this modulation have not been defined. Dopaminergic modulation from the A11 nucleus of the hypothalamus contributes to plasticity in a model of chronic pain called hyperalgesic priming. Here we tested the hypothesis that the key receptor subtype mediating this effect is the D5 receptor (D5R). We find that a spinally directed lesion of dopaminergic neurons reverses hyperalgesic priming in both sexes and that a D1/D5 antagonist transiently inhibits neuropathic pain. We used mice lacking D5Rs (DRD5KO mice) to show that carrageenan, interleukin 6, as well as BDNF-induced hyperalgesia and priming are reduced specifically in male mice. These male DRD5KO mice also show reduced formalin pain responses and decreased heat pain. To characterize the subtypes of dorsal horn neurons engaged by dopamine signaling in the hyperalgesic priming model, we used c-fos labeling. We find that a mixed D1/D5 agonist given spinally to primed mice activates a subset of neurons in lamina III and IV of the dorsal horn that coexpress PAX2, a transcription factor for GABAergic interneurons. In line with this, we show that gabazine, a GABA-A receptor antagonist, is antihyperalgesic in primed mice exposed to spinal administration of a D1/D5 agonist. Therefore, the D5R, in males, and the D1R, in females, exert a powerful influence over spinal cord circuitry in pathological pain likely via modulation of deep dorsal horn GABAergic neurons.SIGNIFICANCE STATEMENT Pain is the most prominent reason why people seek medical attention, and chronic pain incidence worldwide has been estimated to be as high as 33%. This study provides new insight into how descending dopamine controls pathological pain states. Our work demonstrates that dopaminergic spinal projections are necessary for the maintenance of a chronic pain state in both sexes; however, D5 receptors seem to play a critical role in males whereas females rely more heavily on D1 receptors, an effect that could be explained by sexual dimorphisms in receptor expression levels. Collectively, our work provides new insights into how the dopaminergic system interacts with spinal circuits to promote pain plasticity.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2110-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Inverted Encoding Models of Human Population Response Conflate Noise and
           Neural Tuning Width
    • Authors: Liu, T; Cable, D, Gardner, J. L.
      Pages: 398 - 408
      Abstract: Channel-encoding models offer the ability to bridge different scales of neuronal measurement by interpreting population responses, typically measured with BOLD imaging in humans, as linear sums of groups of neurons (channels) tuned for visual stimulus properties. Inverting these models to form predicted channel responses from population measurements in humans seemingly offers the potential to infer neuronal tuning properties. Here, we test the ability to make inferences about neural tuning width from inverted encoding models. We examined contrast invariance of orientation selectivity in human V1 (both sexes) and found that inverting the encoding model resulted in channel response functions that became broader with lower contrast, thus apparently violating contrast invariance. Simulations showed that this broadening could be explained by contrast-invariant single-unit tuning with the measured decrease in response amplitude at lower contrast. The decrease in response lowers the signal-to-noise ratio of population responses that results in poorer population representation of orientation. Simulations further showed that increasing signal to noise makes channel response functions less sensitive to underlying neural tuning width, and in the limit of zero noise will reconstruct the channel function assumed by the model regardless of the bandwidth of single units. We conclude that our data are consistent with contrast-invariant orientation tuning in human V1. More generally, our results demonstrate that population selectivity measures obtained by encoding models can deviate substantially from the behavior of single units because they conflate neural tuning width and noise and are therefore better used to estimate the uncertainty of decoded stimulus properties.SIGNIFICANCE STATEMENT It is widely recognized that perceptual experience arises from large populations of neurons, rather than a few single units. Yet, much theory and experiment have examined links between single units and perception. Encoding models offer a way to bridge this gap by explicitly interpreting population activity as the aggregate response of many single neurons with known tuning properties. Here we use this approach to examine contrast-invariant orientation tuning of human V1. We show with experiment and modeling that due to lower signal to noise, contrast-invariant orientation tuning of single units manifests in population response functions that broaden at lower contrast, rather than remain contrast-invariant. These results highlight the need for explicit quantitative modeling when making a reverse inference from population response profiles to single-unit responses.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2453-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Dissociable Decoding of Spatial Attention and Working Memory from EEG
           Oscillations and Sustained Potentials
    • Authors: Bae, G.-Y; Luck, S. J.
      Pages: 409 - 422
      Abstract: In human scalp EEG recordings, both sustained potentials and alpha-band oscillations are present during the delay period of working memory tasks and may therefore reflect the representation of information in working memory. However, these signals may instead reflect support mechanisms rather than the actual contents of memory. In particular, alpha-band oscillations have been tightly tied to spatial attention and may not reflect location-independent memory representations per se. To determine how sustained and oscillating EEG signals are related to attention and working memory, we attempted to decode which of 16 orientations was being held in working memory by human observers (both women and men). We found that sustained EEG activity could be used to decode the remembered orientation of a stimulus, even when the orientation of the stimulus varied independently of its location. Alpha-band oscillations also carried clear information about the location of the stimulus, but they provided little or no information about orientation independently of location. Thus, sustained potentials contain information about the object properties being maintained in working memory, consistent with previous evidence of a tight link between these potentials and working memory capacity. In contrast, alpha-band oscillations primarily carry location information, consistent with their link to spatial attention.SIGNIFICANCE STATEMENT Working memory plays a key role in cognition, and working memory is impaired in several neurological and psychiatric disorders. Previous research has suggested that human scalp EEG recordings contain signals that reflect the neural representation of information in working memory. However, to conclude that a neural signal actually represents the object being remembered, it is necessary to show that the signal contains fine-grained information about that object. Here, we show that sustained voltages in human EEG recordings contain fine-grained information about the orientation of an object being held in memory, consistent with a memory storage signal.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2860-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Modulation of Ether-a-Go-Go Related Gene (ERG) Current Governs Intrinsic
           Persistent Activity in Rodent Neocortical Pyramidal Cells
    • Authors: Cui, E. D; Strowbridge, B. W.
      Pages: 423 - 440
      Abstract: While cholinergic receptor activation has long been known to dramatically enhance the excitability of cortical neurons, the cellular mechanisms responsible for this effect are not well understood. We used intracellular recordings in rat (both sexes) neocortical brain slices to assess the ionic mechanisms supporting persistent firing modes triggered by depolarizing stimuli following cholinergic receptor activation. We found multiple lines of evidence suggesting that a component of the underlying hyperexcitability associated with persistent firing reflects a reduction in the standing (leak) K+ current mediated by Ether-a-go-go-Related Gene (ERG) channels. Three chemically diverse ERG channel blockers (terfenadine, ErgToxin-1, and E-4031) abolished persistent firing and the underlying increase in input resistance in deep pyramidal cells in temporal and prefrontal association neocortex. Calcium accumulation during triggering stimuli appears to attenuate ERG currents, leading to membrane potential depolarization and increased input resistance, two critical elements generating persistent firing. Our results also suggest that ERG current normally governs cortical neuron responses to depolarizing stimuli by opposing prolonged discharges and by enhancing the poststimulus repolarization. The broad expression of ERG channels and the ability of ERG blocks to abolish persistent firing evoked by both synaptic and intracellular step stimuli suggest that modulation of ERG channels may underlie many forms of persistent activity observed in vivo.SIGNIFICANCE STATEMENT Persistent activity, where spiking continues beyond the triggering stimulus, is a common phenomenon observed in many types of neurons. Identifying the mechanism underlying this elementary process of memory is a step forward in understanding higher cognitive function including short-term memory. Our results suggest that a reduction in the currents normally mediated by Ether-a-go-go-Related Gene (ERG) K+ channels contributes to persistent firing in neocortical pyramidal cells. ERG currents have been previously studied primarily in the heart; relatively little is known about ERG function in the brain, although mutations in ERG channels have recently been linked to schizophrenia. The present study is among the first to describe its role in neocortex in relation to biophysical correlates of memory function.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1774-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues
           Sleep Disturbances Induced by Early-Life Obesity
    • Authors: Gazea, M; Patchev, A. V, Anderzhanova, E, Leidmaa, E, Pissioti, A, Flachskamm, C, Almeida, O. F. X, Kimura, M.
      Pages: 441 - 451
      Abstract: Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep–wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep–wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep–wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3–36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep–wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep.SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY3–36 can reverse this neurochemical imbalance and acutely restore sleep composition. These findings add insight into how innate behaviors such as feeding and sleep are integrated and suggest a novel mechanism through which diet-induced obesity during puberty imposes its long-lasting effects on sleep–wake behavior.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1333-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Disrupted Neuroglial Metabolic Coupling after Peripheral Surgery
    • Authors: Femenia, T; Gimenez-Cassina, A, Codeluppi, S, Fernandez-Zafra, T, Katsu-Jimenez, Y, Terrando, N, Eriksson, L. I, Gomez-Galan, M.
      Pages: 452 - 464
      Abstract: Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction.SIGNIFICANCE STATEMENT A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1797-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Brainstem Pain-Control Circuitry Connectivity in Chronic Neuropathic Pain
    • Authors: Mills, E. P; Di Pietro, F, Alshelh, Z, Peck, C. C, Murray, G. M, Vickers, E. R, Henderson, L. A.
      Pages: 465 - 473
      Abstract: Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top–down engagement of the circuitry alongside altered reward processing in pain conditions.SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain-modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain-modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative for the development of more efficacious therapies.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1647-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Zinc Inhibits TRPV1 to Alleviate Chemotherapy-Induced Neuropathic Pain
    • Authors: Luo, J; Bavencoffe, A, Yang, P, Feng, J, Yin, S, Qian, A, Yu, W, Liu, S, Gong, X, Cai, T, Walters, E. T, Dessauer, C. W, Hu, H.
      Pages: 474 - 483
      Abstract: Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1.SIGNIFICANCE STATEMENT The chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1816-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine
           Transporter Conformation
    • Authors: Siciliano, C. A; Saha, K, Calipari, E. S, Fordahl, S. C, Chen, R, Khoshbouei, H, Jones, S. R.
      Pages: 484 - 497
      Abstract: Cocaine abuse disrupts dopamine system function, and reduces cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criterion for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were twofold; we sought to (1) identify the molecular mechanisms by which cocaine exposure produces tolerance and (2) determine whether amphetamine-induced reductions in cocaine intake are connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats, we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed cocaine tolerance. Amphetamine treatment also reversed escalated cocaine intake and decreased motivation to obtain cocaine as measured in a behavioral economics task, thereby linking tolerance to multiple facets of cocaine use. Finally, using fluorescence resonance energy transfer imaging, we found that cocaine tolerance is associated with the formation of DAT-DAT complexes, and that amphetamine disperses these complexes. In addition to extending our basic understanding of DATs and their role in cocaine reinforcement, we serendipitously identified a novel therapeutic target: DAT oligomer complexes. We show that dispersion of oligomers is concomitant with reduced cocaine intake, and propose that pharmacotherapeutics aimed at these complexes may have potential for cocaine addiction treatment.SIGNIFICANCE STATEMENT Tolerance to cocaine's subjective effects is a cardinal symptom of cocaine addiction and a DSM-V criterion for substance abuse disorders. However, elucidating the molecular adaptions that produce tolerance and determining its behavioral impact have proven difficult. Using cocaine self-administration in rats, we link tolerance to cocaine effects at the dopamine transporter (DAT) with aberrant cocaine-taking behaviors. Further, tolerance was associated with multi-DAT complexes, which formed after cocaine exposure. Treatment with amphetamine deconstructed DAT complexes, reversed tolerance, and decreased cocaine seeking. These data describe the behavioral consequence of cocaine tolerance, provide a putative mechanism for its development, and suggest that compounds that disperse DAT complexes may be efficacious treatments for cocaine addiction.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.2604-17.2017
      Issue No: Vol. 38, No. 2 (2018)
  • Distinct Roles of Different Presynaptic and Postsynaptic NCAM Isoforms in
           Early Motoneuron-Myotube Interactions Required for Functional Synapse
    • Authors: Hata, K; Maeno-Hikichi, Y, Yumoto, N, Burden, S. J, Landmesser, L. T.
      Pages: 498 - 510
      Abstract: The neural cell adhesion molecule (NCAM) is expressed both presynaptically and postsynaptically during neuromuscular junction formation. Genetic deletion in mice of all three isoforms (180, 140, and 120 kDa), or just the 180 isoform, suggested that different isoforms played distinct roles in synaptic maturation. Here we characterized in mice of either sex the earliest adhesive contacts between the growth cones of motoneurons and myotubes and their subsequent maturation into functional synapses in cocultures of motoneurons and myotubes, which expressed their normal complement of NCAM isoforms, or were lacking all isoforms either presynaptically or postsynaptically. Growth cone contact with +/+ mouse myotubes resulted in immediate adhesive contacts and the rapid downregulation of growth cone motility. When contacting NCAM–/– myotubes, growth cones touched and retracted/collapsed multiple times and failed to form stable contacts, even after 10 h. Exogenous expression in myotubes of either the 180 or 140 isoform, but not the 120 kDa isoform, rescued the rapid formation of stable contacts, the accumulation of presynaptic and postsynaptic molecules, and functional transmission. When NCAM was absent only in motoneurons, growth cones did not retract upon myotube contact, but, since their motility was not downregulated, they grew off the ends of the myotubes, failing to form synapses. The agrin receptor Lrp4 was strongly downregulated in NCAM-negative myotubes, and motoneuron growth cones did not make stable contacts with Lrp4-negative myotubes. These studies have identified novel roles for presynaptic and postsynaptic NCAM in mediating early cell–cell interactions required for synapse formation.SIGNIFICANCE STATEMENT Although many molecular signals needed to form the functionally effective neuromuscular synapses required for normal movement have been described, the earliest signals that let motoneuron growth cones make stable adhesive contacts with myotubes and cease motility are not well understood. Using dynamic imaging of motoneuron–myotube cocultures, we show that NCAM is required on both the growth cone and myotube and that different NCAM isoforms mediate initial adhesion and the downregulation of growth cone motility. The agrin receptor Lrp4 was also essential for initial adhesive contacts and was downregulated on NCAM–/– myotubes. Our identification of novel roles for NCAM and Lrp4 and possible interactions between them in transforming motile growth cones into stable contacts opens interesting new avenues for exploration.
      PubDate: 2018-01-10T09:06:25-08:00
      DOI: 10.1523/JNEUROSCI.1014-17.2017
      Issue No: Vol. 38, No. 2 (2018)
School of Mathematical and Computer Sciences
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