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Journal of Neuroscience
Journal Prestige (SJR): 4.466
Citation Impact (citeScore): 6
Number of Followers: 291  
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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: 2977 - 2977
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.twij.39.16.2019
      Issue No: Vol. 39, No. 16 (2019)
  • A Domain-General Role for the Angular Gyrus in Retrieving Internal
           Representations of the External World
    • Authors: Ramanan, S; Bellana, B.
      Pages: 2978 - 2980
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.3231-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Presynaptic Diversity Revealed by Ca2+-Permeable AMPA Receptors at the
           Calyx of Held Synapse
    • Authors: Lujan, B; Dagostin, A, von Gersdorff, H.
      Pages: 2981 - 2994
      Abstract: GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs) play integral roles in synaptic plasticity and can mediate excitotoxic cellular signaling at glutamatergic synapses. However, the developmental profile of functional CP-AMPARs at the auditory brainstem remains poorly understood. Through a combination of electrophysiological and live-cell Ca2+ imaging from mice of either sex, we show that the synaptic release of glutamate from the calyx of Held nerve terminal activates CP-AMPARs in the principal cells of the medial nucleus of the trapezoid body in the brainstem. This leads to significant Ca2+ influx through these receptors before the onset of hearing at postnatal day 12 (P12). Using a selective open channel blocker of CP-AMPARs, IEM-1460, we estimate that ~80% of the AMPAR population are permeable to Ca2+ at immature P4–P5 synapses. However, after the onset of hearing, Ca2+ influx through these receptors was greatly reduced. We estimate that CP-AMPARs comprise approximately 40% and 33% of the AMPAR population at P18–P22 and P30–P34, respectively. By quantifying the rate of EPSC block by IEM-1460, we found an increased heterogeneity in glutamate release probability for adult-like calyces (P30–P34). Using tetraethylammonium (TEA), a presynaptic potassium channel blocker, we show that the apparent reduction of CP-AMPARs in more mature synapses is not a consequence of presynaptic action potential (AP) speeding. Finally, through postsynaptic AP recordings, we show that inhibition of CP-AMPARs reduces spike fidelity in juvenile synapses, but not in more mature synapses. We conclude that the expression of functional CP-AMPARs declines over early postnatal development in the calyx of Held synapse.SIGNIFICANCE STATEMENT The calyx of Held synapse is pivotal to the circuitry that computes sound localization. Postsynaptic Ca2+ influx via AMPARs may be critical for signaling the maturation of this brainstem synapse. The GluA4 subunit may dominate the AMPAR complex at mature synapses because of its fast gating kinetics and large unitary conductance. The expectation is that AMPARs dominated by GluA4 subunits should be highly Ca2+ permeable. However, we find that Ca2+-permeable AMPAR expression declines during postnatal development. Using the rate of EPSC block by IEM-1460, an open channel blocker of Ca2+-permeable AMPARs, we propose a novel method to determine glutamate release probability and uncover an increased heterogeneity in release probability for more mature calyces of Held nerve terminals.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2565-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Activity-Dependent Remodeling of Drosophila Olfactory Sensory Neuron Brain
           Innervation during an Early-Life Critical Period
    • Authors: Golovin, R. M; Vest, J, Vita, D. J, Broadie, K.
      Pages: 2995 - 3012
      Abstract: Critical periods are windows of development when the environment has a pronounced effect on brain circuitry. Models of neurodevelopmental disorders, including autism spectrum disorders, intellectual disabilities, and schizophrenia, are linked to disruption of critical period remodeling. Critical periods open with the onset of sensory experience; however, it remains unclear exactly how sensory input modifies brain circuits. Here, we examine olfactory sensory neuron (OSN) innervation of the Drosophila antennal lobe of both sexes as a genetic model of this question. We find that olfactory sensory experience during an early-use critical period drives loss of OSN innervation of antennal lobe glomeruli and subsequent axon retraction in a dose-dependent mechanism. This remodeling does not result from olfactory receptor loss or OSN degeneration, but rather from rapid synapse elimination and axon pruning in the target olfactory glomerulus. Removal of the odorant stimulus only during the critical period leads to OSN reinnervation, demonstrating that remodeling is transiently reversible. We find that this synaptic refinement requires the OSN-specific olfactory receptor and downstream activity. Conversely, blocking OSN synaptic output elevates glomeruli remodeling. We find that GABAergic neurotransmission has no detectable role, but that glutamatergic signaling via NMDA receptors is required for OSN synaptic refinement. Together, these results demonstrate that OSN inputs into the brain manifest robust, experience-dependent remodeling during an early-life critical period, which requires olfactory reception, OSN activity, and NMDA receptor signaling. This work reveals a pathway linking initial olfactory sensory experience to glutamatergic neurotransmission in the activity-dependent remodeling of brain neural circuitry in an early-use critical period.SIGNIFICANCE STATEMENT Neurodevelopmental disorders manifest symptoms at specific developmental milestones that suggest an intersection between early sensory experience and brain neural circuit remodeling. One classic example is Fragile X syndrome caused by loss of an RNA-binding translation regulator of activity-dependent synaptic refinement. As a model, Drosophila olfactory circuitry is well characterized, genetically tractable, and rapidly developing, and thus ideally suited to probe underlying mechanisms. Here, we find olfactory sensory neurons are dramatically remodeled by heightened sensory experience during an early-life critical period. We demonstrate removing the olfactory stimulus during the critical period can reverse the connectivity changes. We find that this remodeling requires neural activity and NMDA receptor-mediated glutamatergic transmission. This improved understanding may help us design treatments for neurodevelopmental disorders.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2223-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Regulation of Myelination by Exosome Associated Retinoic Acid Release from
           NG2-Positive Cells
    • Authors: Goncalves, M. B; Wu, Y, Clarke, E, Grist, J, Hobbs, C, Trigo, D, Jack, J, Corcoran, J. P. T.
      Pages: 3013 - 3027
      Abstract: In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron–glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR–calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin–Ca2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2922-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • A Comprehensive Quantitative Genetic Analysis of Cerebral Surface Area in
    • Authors: Schmitt, J. E; Neale, M. C, Clasen, L. S, Liu, S, Seidlitz, J, Pritikin, J. N, Chu, A, Wallace, G. L, Lee, N. R, Giedd, J. N, Raznahan, A.
      Pages: 3028 - 3040
      Abstract: The genetics of cortical arealization in youth is not well understood. In this study, we use a genetically informative sample of 677 typically developing children and adolescents (mean age 12.72 years), high-resolution MRI, and quantitative genetic methodology to address several fundamental questions on the genetics of cerebral surface area. We estimate that >85% of the phenotypic variance in total brain surface area in youth is attributable to additive genetic factors. We also observed pronounced regional variability in the genetic influences on surface area, with the most heritable areas seen in primary visual and visual association cortex. A shared global genetic factor strongly influenced large areas of the frontal and temporal cortex, mirroring regions that are the most evolutionarily novel in humans relative to other primates. In contrast to studies on older populations, we observed statistically significant genetic correlations between measures of surface area and cortical thickness (rG = 0.63), suggestive of overlapping genetic influences between these endophenotypes early in life. Finally, we identified strong and highly asymmetric genetically mediated associations between Full-Scale Intelligence Quotient and left perisylvian surface area, particularly receptive language centers. Our findings suggest that spatially complex and temporally dynamic genetic factors are influencing cerebral surface area in our species.SIGNIFICANCE STATEMENT Over evolution, the human cortex has undergone massive expansion. In humans, patterns of neurodevelopmental expansion mirror evolutionary changes. However, there is a sparsity of information on how genetics impacts surface area maturation. Here, we present a systematic analysis of the genetics of cerebral surface area in youth. We confirm prior research that implicates genetics as the dominant force influencing individual differences in global surface area. We also find evidence that evolutionarily novel brain regions share common genetics, that overlapping genetic factors influence both area and thickness in youth, and the presence of strong genetically mediated associations between intelligence and surface area in language centers. These findings further elucidate the complex role that genetics plays in brain development and function.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2248-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Rod Photoresponse Kinetics Limit Temporal Contrast Sensitivity in Mesopic
    • Authors: Umino, Y; Guo, Y, Chen, C.-K, Pasquale, R, Solessio, E.
      Pages: 3041 - 3056
      Abstract: The mammalian visual system operates over an extended range of ambient light levels by switching between rod and cone photoreceptors. Rod-driven vision is sluggish, highly sensitive, and operates in dim or scotopic lights, whereas cone-driven vision is brisk, less sensitive, and operates in bright or photopic lights. At intermediate or mesopic lights, vision transitions seamlessly from rod-driven to cone-driven, despite the profound differences in rod and cone response dynamics. The neural mechanisms underlying such a smooth handoff are not understood. Using an operant behavior assay, electrophysiological recordings, and mathematical modeling we examined the neural underpinnings of the mesopic visual transition in mice of either sex. We found that rods, but not cones, drive visual sensitivity to temporal light variations over much of the mesopic range. Surprisingly, speeding up rod photoresponse recovery kinetics in transgenic mice improved visual sensitivity to slow temporal variations, in the range where perceptual sensitivity is governed by Weber's law of sensation. In contrast, physiological processes acting downstream from phototransduction limit sensitivity to high frequencies and temporal resolution. We traced the paradoxical control of visual temporal sensitivity to rod photoresponses themselves. A scenario emerges where perceptual sensitivity is limited by: (1) the kinetics of neural processes acting downstream from phototransduction in scotopic lights, (2) rod response kinetics in mesopic lights, and (3) cone response kinetics as light levels rise into the photopic range.SIGNIFICANCE STATEMENT Our ability to detect flickering lights is constrained by the dynamics of the slowest step in the visual pathway. Cone photoresponse kinetics limit visual temporal sensitivity in bright (photopic) lights, whereas mechanisms in the inner retina limit sensitivity in dim (scotopic) lights. The neural mechanisms underlying the transition between scotopic and photopic vision in mesopic lights, when both rods are cones are active, are unknown. This study provides a missing link in this mechanism by establishing that rod photoresponse kinetics limit temporal sensitivity during the mesopic transition. Surprisingly, this range is where Weber's Law of Sensation governs temporal contrast sensitivity in mouse. Our results will help guide future studies of complex and dynamic interactions between rod–cone signals in the mesopic retina.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.1404-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Interaction of Taste and Place Coding in the Hippocampus
    • Authors: Herzog, L. E; Pascual, L. M, Scott, S. J, Mathieson, E. R, Katz, D. B, Jadhav, S. P.
      Pages: 3057 - 3069
      Abstract: An animal's survival depends on finding food and the memory of food and contexts are often linked. Given that the hippocampus is required for spatial and contextual memory, it is reasonable to expect related coding of space and food stimuli in hippocampal neurons. However, relatively little is known about how the hippocampus responds to tastes, the most central sensory property of food. In this study, we examined the taste-evoked responses and spatial firing properties of single units in the dorsal CA1 hippocampal region as male rats received a battery of taste stimuli differing in both chemical composition and palatability within a specific spatial context. We identified a subset of hippocampal neurons that responded to tastes, some of which were place cells. These taste and place responses had a distinct interaction: taste-responsive cells tended to have less spatially specific firing fields and place cells only responded to tastes delivered inside their place field. Like neurons in the amygdala and lateral hypothalamus, hippocampal neurons discriminated between tastes predominantly on the basis of palatability, with taste selectivity emerging concurrently with palatability-relatedness; these responses did not reflect movement or arousal. However, hippocampal taste responses emerged several hundred milliseconds later than responses in other parts of the taste system, suggesting that the hippocampus does not influence real-time taste decisions, instead associating the hedonic value of tastes with a particular context. This incorporation of taste responses into existing hippocampal maps could be one way that animals use past experience to locate food sources.SIGNIFICANCE STATEMENT Finding food is essential for animals' survival and taste and context memory are often linked. Although hippocampal responses to space and contexts have been well characterized, little is known about how the hippocampus responds to tastes. Here, we identified a subset of hippocampal neurons that discriminated between tastes based on palatability. Cells with stronger taste responses typically had weaker spatial responses and taste responses were confined to place cells' firing fields. Hippocampal taste responses emerged later than in other parts of the taste system, suggesting that the hippocampus does not influence taste decisions, but rather associates the hedonic value of tastes consumed within a particular context. This could be one way that animals use past experience to locate food sources.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2478-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Two Compasses in the Central Complex of the Locust Brain
    • Authors: Pegel, U; Pfeiffer, K, Zittrell, F, Scholtyssek, C, Homberg, U.
      Pages: 3070 - 3080
      Abstract: Many migratory insects rely on a celestial compass for spatial orientation. Several features of the daytime sky, all generated by the sun, can be exploited for navigation. Two of these are the position of the sun and the pattern of polarized skylight. Neurons of the central complex (CX), a group of neuropils in the central brain of insects, have been shown to encode sky compass cues. In desert locusts, the CX holds a topographic, compass-like representation of the plane of polarized light (E-vector) presented from dorsal direction. In addition, these neurons also encode the azimuth of an unpolarized light spot, likely representing the sun. Here, we investigate whether, in addition to E-vector orientation, the solar azimuth is represented topographically in the CX. We recorded intracellularly from eight types of CX neuron while stimulating animals of either sex with polarized blue light from zenithal direction and an unpolarized green light spot rotating around the animal's head at different elevations. CX neurons did not code for elevation of the unpolarized light spot. However, two types of columnar neuron showed a linear correlation between innervated slice in the CX and azimuth tuning to the unpolarized green light spot, consistent with an internal compass representation of solar azimuth. Columnar outputs of the CX also showed a topographic representation of zenithal E-vector orientation, but the two compasses were not linked to each other. Combined stimulation with unpolarized green and polarized blue light suggested that the two compasses interact in a nonlinear way.SIGNIFICANCE STATEMENT In the brain of the desert locust, neurons sensitive to the plane of celestial polarization are arranged like a compass in the slices of the central complex (CX). These neurons, in addition, code for the horizontal direction of an unpolarized light cue possibly representing the sun. We show here that horizontal directions are, in addition to E-vector orientations from the dorsal direction, represented in a compass-like manner across the slices of the CX. However, the two compasses are not linked to each other, but rather seem to interact in a cell-specific, nonlinear way. Our study confirms the role of the CX in signaling heading directions and shows that different cues are used for this task.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.0940-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Priming of Adult Incision Response by Early-Life Injury: Neonatal
           Microglial Inhibition Has Persistent But Sexually Dimorphic Effects in
           Adult Rats
    • Authors: Moriarty, O; Tu, Y, Sengar, A. S, Salter, M. W, Beggs, S, Walker, S. M.
      Pages: 3081 - 3093
      Abstract: Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following reinjury in adulthood. Spinal microglia contribute to this persistent effect, and microglial inhibition at the time of adult reincision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult reincision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation (Emr1) and transformation to a reactive phenotype (Irf8). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to reincision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following reincision in adulthood was prevented in males but unaffected in females. Similarly, reincision induced Emr1 and Irf8 gene expression was downregulated in males, but not in females, following neonatal incision with minocycline. To evaluate the distribution of reincision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was reincised, and was increased following prior incision at ipsilateral, but not contralateral, sites, supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state span developmental stages.SIGNIFICANCE STATEMENT Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances reinjury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on reinjury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in preclinical studies.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.1786-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25
           to Regulate the Behavioral and Cardiovascular Correlates of High-Trait
    • Authors: Zeredo, J. L; Quah, S. K. L, Wallis, C. U, Alexander, L, Cockcroft, G. J, Santangelo, A. M, Xia, J, Shiba, Y, Dalley, J. W, Cardinal, R. N, Roberts, A. C, Clarke, H. F.
      Pages: 3094 - 3107
      Abstract: High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studies of high-trait anxiety reveals dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp) and rodent studies reveal the importance of aHipp glutamatergic hypofunction, the causal involvement of aHipp glutamate and its interaction with these areas in the primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety.SIGNIFICANCE STATEMENT High-trait anxiety predisposes sufferers to the development of anxiety and depression. Although neuroimaging of these disorders and rodent modeling implicate dysregulation in hippocampal glutamate and the subgenual/perigenual cingulate cortices (areas 25/32), the causal involvement of these structures in endogenous high-trait anxiety and their interaction are unknown. Here, we demonstrate that increased trait anxiety in marmoset monkeys correlates with reduced hippocampal glutamate and that increasing hippocampal glutamate release in high-trait-anxious monkeys normalizes the aberrant behavioral and cardiovascular responsivity to potential threats. This normalization was blocked by simultaneous inactivation of area 25, but not area 32. These findings provide casual evidence in primates that hippocampal glutamatergic hypofunction regulates endogenous high-trait anxiety and the hippocampal–area 25 circuit is a potential therapeutic target.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2451-18.2018
      Issue No: Vol. 39, No. 16 (2019)
  • Prelimbic Cortical Neurons Track Preferred Reward Value and Reflect
           Impulsive Choice during Delay Discounting Behavior
    • Authors: Sackett, D. A; Moschak, T. M, Carelli, R. M.
      Pages: 3108 - 3118
      Abstract: In delay discounting, individuals discount the value of a reward based on the delay to its receipt. The prelimbic cortex (PrL) is heavily interconnected with several brain regions implicated in delay discounting, but the specific contributions of the PrL to delay discounting are unknown. Here, we used multineuron electrophysiological recording methods in Long–Evans male (n = 10) and female (n = 9) rats to characterize the firing dynamics of PrL neurons during discrete cue and lever press events in a delay discounting task. Rats' initial preference for the large reward decreased as delays for that outcome increased across blocks, reflecting classic discounting behavior. Electrophysiological recordings revealed that subgroups of neurons exhibited phasic responses to cue presentations and lever presses. These phasic neurons were found to respond to either large/delay, small/immediate, or both trial types and the percentage of these neurons shifted across blocks as the expected value of the reward changed. Critically, this shift was only seen during trials in which animals could choose their preferred option (free choice trials) and not during trials where animals could choose only one option (forced choice trials). Further, this shift was dependent on rats' inherent impulsivity because high impulsive rats demonstrated a greater percentage of small/immediate-responsive neurons as the task progressed. Collectively, these findings suggest a unique role for the PrL in encoding reward value during delay discounting that is influenced by individual differences in impulsivity.SIGNIFICANCE STATEMENT In delay discounting, individuals discount the value of a reward based on the delay to its receipt. Here, we used electrophysiology to investigate the role of the prelimbic cortex (PrL) in this process. We found that subsets of neurons shifted activity as a function of the changing expected delay and reward magnitude, but this shift was only evident during trials in which animals could choose their preferred option. Further, this dynamic neural activity depended on rats' inherent impulsivity, with impulsive rats exhibiting a stronger neural shift toward the immediate reward as the task progressed. These findings suggest a role for the PrL in encoding reward value during delay discounting that is influenced by goal-directed context and individual differences in impulsivity.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2532-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Stimulus-Driven Brain Rhythms within the Alpha Band: The
           Attentional-Modulation Conundrum
    • Authors: Keitel, C; Keitel, A, Benwell, C. S. Y, Daube, C, Thut, G, Gross, J.
      Pages: 3119 - 3129
      Abstract: Two largely independent research lines use rhythmic sensory stimulation to study visual processing. Despite the use of strikingly similar experimental paradigms, they differ crucially in their notion of the stimulus-driven periodic brain responses: one regards them mostly as synchronized (entrained) intrinsic brain rhythms; the other assumes they are predominantly evoked responses [classically termed steady-state responses (SSRs)] that add to the ongoing brain activity. This conceptual difference can produce contradictory predictions about, and interpretations of, experimental outcomes. The effect of spatial attention on brain rhythms in the alpha band (8–13 Hz) is one such instance: alpha-range SSRs have typically been found to increase in power when participants focus their spatial attention on laterally presented stimuli, in line with a gain control of the visual evoked response. In nearly identical experiments, retinotopic decreases in entrained alpha-band power have been reported, in line with the inhibitory function of intrinsic alpha. Here we reconcile these contradictory findings by showing that they result from a small but far-reaching difference between two common approaches to EEG spectral decomposition. In a new analysis of previously published human EEG data, recorded during bilateral rhythmic visual stimulation, we find the typical SSR gain effect when emphasizing stimulus-locked neural activity and the typical retinotopic alpha suppression when focusing on ongoing rhythms. These opposite but parallel effects suggest that spatial attention may bias the neural processing of dynamic visual stimulation via two complementary neural mechanisms.SIGNIFICANCE STATEMENT Attending to a visual stimulus strengthens its representation in visual cortex and leads to a retinotopic suppression of spontaneous alpha rhythms. To further investigate this process, researchers often attempt to phase lock, or entrain, alpha through rhythmic visual stimulation under the assumption that this entrained alpha retains the characteristics of spontaneous alpha. Instead, we show that the part of the brain response that is phase locked to the visual stimulation increased with attention (as do steady-state evoked potentials), while the typical suppression was only present in non-stimulus-locked alpha activity. The opposite signs of these effects suggest that attentional modulation of dynamic visual stimulation relies on two parallel cortical mechanisms—retinotopic alpha suppression and increased temporal tracking.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.1633-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Post-Encoding Amygdala-Visuosensory Coupling Is Associated with Negative
           Memory Bias in Healthy Young Adults
    • Authors: Kark, S. M; Kensinger, E. A.
      Pages: 3130 - 3143
      Abstract: The amygdala is well documented as the critical nexus of emotionally enhanced memory, yet its role in the creation of negative memory biases, better memory for negative compared with positive stimuli, has not been clarified. Although prior work suggests valence-specific effects at the moment of "online" encoding and retrieval, with enhanced visuosensory processes supporting negative memories in particular, here we tested the novel hypothesis that the amygdala engages with distant cortical regions after encoding in a manner that predicts inter-individual differences in negative memory biases in humans. Twenty-nine young adults (males and females) were scanned while they incidentally encoded negative, neutral, and positive scenes, each preceded by a line-drawing sketch of the scene. Twenty-four hours later, participants were scanned during an Old/New recognition memory task with only the line-drawings presented as retrieval cues. We replicated and extended our prior work, showing that enhanced online visuosensory recapitulation supports negative memory. Critically, resting-state scans flanked the encoding task, allowing us to show for the first time that individual differences in "off-line" increases in amygdala resting-state functional connectivity (RSFC) immediately following encoding relate to negative and positive memory bias at test. Specifically, post-encoding increases in amygdala RSFC with visuosensory and frontal regions were associated with the degree of negative and positive memory bias, respectively. These findings provide new evidence that valence-specific negative memory biases can be linked to the way that sensory processes are integrated into amygdala-centered emotional memory networks.SIGNIFICANCE STATEMENT Decades of research has placed the amygdala at the center of the emotional memory network. Despite the clinical importance of disproportionate memory for negative compared with positive events, it is not known whether post-encoding increases in amygdala-cortical coupling, possibly reflective of early consolidation processes, bear any influence on the degree or direction of such emotional memory biases. We demonstrate that, across participants, increases in post-encoding amygdala coupling with visuosensory and frontal regions are associated with more pronounced negative and positive memory biases, respectively. These findings provide the first evidence linking post-encoding amygdala modulation to the degree of negative or positive memory bias, emphasizing the need for valence-based accounts of the amygdala's role in emotional memory.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.2834-18.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Altered DNA Methylation in the Developing Brains of Rats Genetically Prone
           to High versus Low Anxiety
    • Authors: McCoy, C. R; Glover, M. E, Flynn, L. T, Simmons, R. K, Cohen, J. L, Ptacek, T, Lefkowitz, E. J, Jackson, N. L, Akil, H, Wu, X, Clinton, S. M.
      Pages: 3144 - 3158
      Abstract: There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder [LR]) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats. Prior work revealed distinct limbic brain development in HR versus LR rats, including altered expression of genes involved in DNA methylation. This led us to hypothesize that DNA methylation differences in the developing brain drive the disparate HR/LR neurobehavioral phenotypes. Here we report altered DNA methylation markers (altered DNA methyltransferase protein levels and increased global DNA methylation levels) in the early postnatal amygdala of LR versus HR male rats. Next-generation sequencing methylome profiling identified numerous differentially methylated regions across the genome in the early postnatal HR/LR amygdala. We also contrasted methylation profiles of male HRs and LRs with a control rat strain that displays an intermediate behavioral phenotype relative to the HR/LR extremes; this revealed that the LR amygdalar methylome was abnormal, with the HR profile more closely resembling that of the control group. Finally, through two methylation manipulations in early life, we found that decreasing DNA methylation in the developing male and female amygdala improves adult anxiety- and depression-like behavior. These findings suggest that inborn DNA methylation differences play important roles in shaping brain development and lifelong emotional behavior.SIGNIFICANCE STATEMENT Epigenetic changes are biological mechanisms that regulate the expression and function of genes throughout the brain and body. DNA methylation, one type of epigenetic mechanism, is known to be altered in brains of psychiatric patients, which suggests a role for DNA methylation in the pathogenesis of psychiatric disorders, such as depression and anxiety. The present study examines brains of rats that display high versus low levels of anxiety- and depression-like behavior to investigate how neural DNA methylation levels differ in these animals and how such differences shape their emotional behavioral differences. Studying how epigenetic processes affect emotional behavior may improve our understanding of the neurobiology of psychiatric disorders and lead to improved treatments.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.1157-15.2019
      Issue No: Vol. 39, No. 16 (2019)
  • Epilepsy Gene Therapy Using an Engineered Potassium Channel
    • Authors: Snowball, A; Chabrol, E, Wykes, R. C, Shekh-Ahmad, T, Cornford, J. H, Lieb, A, Hughes, M. P, Massaro, G, Rahim, A. A, Hashemi, K. S, Kullmann, D. M, Walker, M. C, Schorge, S.
      Pages: 3159 - 3169
      Abstract: Refractory focal epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon optimized for human expression and mutated to accelerate the recovery of the channels from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a nonintegrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled preclinical trial, the EKC lentivector robustly reduced seizure frequency in a male rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. When packaged into an adeno-associated viral vector (AAV2/9), the EKC gene was also effective at suppressing seizures in a male rat model of temporal lobe epilepsy. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as being ready for clinical translation in the treatment of refractory focal epilepsy.SIGNIFICANCE STATEMENT Pharmacoresistant epilepsy affects up to 0.3% of the population. Although epilepsy surgery can be effective, it is limited by risks to normal brain function. We have developed a gene therapy that builds on a mechanistic understanding of altered neuronal and circuit excitability in cortical epilepsy. The potassium channel gene KCNA1 was mutated to bypass post-transcriptional editing and was packaged in a nonintegrating lentivector to reduce the risk of insertional mutagenesis. A randomized, blinded preclinical study demonstrated therapeutic effectiveness in a rodent model of focal neocortical epilepsy. Adeno-associated viral delivery of the channel to both hippocampi was also effective in a model of temporal lobe epilepsy. These results support clinical translation to address a major unmet need.
      PubDate: 2019-04-17T09:31:50-07:00
      DOI: 10.1523/JNEUROSCI.1143-18.2019
      Issue No: Vol. 39, No. 16 (2019)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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