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J Neurosci [journal]
- Different Neuronal Computations of Spatial Working Memory for Multiple Locations within versus across Visual Hemifields. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5621-6.
Spatial working memory is one of the most studied cognitive functions, serving as a model system to decipher computational principles of the brain. Although neuronal mechanisms for remembering a single location have been well elucidated, little is known about memory for multiple locations. Here, we examined the activities of prefrontal neurons during monkeys remembered positions of one or two visual cue(s). When the two cues were presented across the left and right visual fields, neurons exhibited a comparable response to the activity for the preferred cue presented alone. When the two cues were presented within the same hemifield, neurons exhibited an intermediate response between those to the individual cues. Subsequent computer simulations predicted a lower signal-to-noise ratio in the latter condition, which was further verified by behavioral experiments. Considering the separation of contralateral and ipsilateral visual processing, the lateral inhibition in local circuits might implicitly determine different neuronal computations and memory capacities for bilateral and unilateral displays.
- Neuroanatomical profiles of deafness in the context of native language experience. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5613-20.
The study of congenitally deaf adult humans provides an opportunity to examine neuroanatomical plasticity resulting from altered sensory experience. However, attributing the source of the brain's structural variance in the deaf is complicated by the fact that deaf individuals also differ in their language experiences (e.g., sign vs spoken), which likely influence brain anatomy independently. Although the majority of deaf individuals in the United States are born to hearing parents and are exposed to English, not American Sign Language (ASL) as their first language, most studies on deafness have been conducted with deaf native users of ASL (deaf signers). This raises the question of whether observations made in deaf signers can be generalized. Using a factorial design, we compared gray (GMV) and white (WMV) matter volume in deaf and hearing native users of ASL, as well as deaf and hearing native users of English. Main effects analysis of sensory experience revealed less GMV in the deaf groups combined (compared with hearing groups combined) in early visual areas and less WMV in a left early auditory region. The interaction of sensory experience and language experience revealed that deaf native users of English had fewer areas of anatomical differences than did deaf native users of ASL (each compared with their hearing counterparts). For deaf users of ASL specifically, WMV differences resided in language areas such as the left superior temporal and inferior frontal regions. Our results demonstrate that cortical plasticity resulting from deafness depends on language experience and that findings from native signers cannot be generalized.
- TMS-EEG Signatures of GABAergic Neurotransmission in the Human Cortex. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5603-12.
Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (<50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.
- Neural mechanisms of gain-loss asymmetry in temporal discounting. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5595-602.
Humans typically discount future gains more than losses. This phenomenon is referred to as the "sign effect" in experimental and behavioral economics. Although recent studies have reported associations between the sign effect and important social problems, such as obesity and incurring multiple debts, the biological basis for this phenomenon remains poorly understood. Here, we hypothesized that enhanced loss-related neural processing in magnitude and/or delay representation are causes of the sign effect. We examined participants performing intertemporal choice tasks involving future gains or losses and compared the brain activity of those who exhibited the sign effect and those who did not. When predicting future losses, significant differences were apparent between the two participant groups in terms of striatal activity representing delay length and in insular activity representing sensitivity to magnitude. Furthermore, participants with the sign effect exhibited a greater insular response to the magnitude of loss than to that of gain, and also a greater striatal response to the delay of loss than to that of gain. These findings may provide a new biological perspective for the development of novel treatments and preventive measures for social problems associated with the sign effect.
- A Neural Code for Looming and Receding Motion Is Distributed over a Population of Electrosensory ON and OFF Contrast Cells. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5583-94.
Object saliency is based on the relative local-to-background contrast in the physical signals that underlie perceptual experience. As such, contrast-detecting neurons (ON/OFF cells) are found in many sensory systems, responding respectively to increased or decreased intensity within their receptive field centers. This differential sensitivity suggests that ON and OFF cells initiate segregated streams of information for positive and negative sensory contrast. However, while recording in vivo from the ON and OFF cells of Apteronotus leptorhynchus, we report that the reversal of stimulus motion triggers paradoxical responses to electrosensory contrast. By considering the instantaneous firing rates of both ON and OFF cell populations, a bidirectionally symmetric representation of motion is achieved for both positive and negative contrast stimuli. Whereas the firing rates of the individual contrast detecting neurons convey scalar information, such as object distance, it is their sequential activation over longer timescales that track changes in the direction of movement.
- Biphasic mechanisms of amphetamine action at the dopamine terminal. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5575-82.
In light of recent studies suggesting that amphetamine (AMPH) increases electrically evoked dopamine release ([DA]o), we examined discrepancies between these findings and literature that has demonstrated AMPH-induced decreases in [DA]o. The current study has expanded the inventory of AMPH actions by defining two separate mechanisms of AMPH effects on [DA]o at high and low doses, one dopamine transporter (DAT) independent and one DAT dependent, respectively. AMPH concentrations were measured via microdialysis in rat nucleus accumbens after intraperitoneal injections of 1 and 10 mg/kg and yielded values of ∼10 and 200 nm, respectively. Subsequently, voltammetry in brain slices was used to examine the effects of low (10 nm), moderate (100 nm), and high (10 μm) concentrations of AMPH across a range of frequency stimulations (one pulse; five pulses, 20 Hz; 24 pulses, 60 Hz). We discovered biphasic, concentration-dependent effects in WT mice, in which AMPH increased [DA]o at low concentrations and decreased [DA]o at high concentrations across all stimulation types. However, in slices from DAT-KO mice, [DA]o was decreased by all concentrations of AMPH, demonstrating that AMPH-induced increases in [DA]o are DAT dependent, whereas the decreases at high concentrations are DAT independent. We propose that low AMPH concentrations are insufficient to disrupt vesicular sequestration, and therefore AMPH acts solely as a DAT inhibitor to increase [DA]o. When AMPH concentrations are high, the added mechanism of vesicular depletion leads to reduced [DA]o. The biphasic mechanisms observed here confirm and extend the traditional actions of AMPH, but do not support mechanisms involving increased exocytotic release.
- Vocal generalization depends on gesture identity and sequence. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5564-74.
Generalization, the brain's ability to transfer motor learning from one context to another, occurs in a wide range of complex behaviors. However, the rules of generalization in vocal behavior are poorly understood, and it is unknown how vocal learning generalizes across an animal's entire repertoire of natural vocalizations and sequences. Here, we asked whether generalization occurs in a nonhuman vocal learner and quantified its properties. We hypothesized that adaptive error correction of a vocal gesture produced in one sequence would generalize to the same gesture produced in other sequences. To test our hypothesis, we manipulated the fundamental frequency (pitch) of auditory feedback in Bengalese finches (Lonchura striata var. domestica) to create sensory errors during vocal gestures (song syllables) produced in particular sequences. As hypothesized, error-corrective learning on pitch-shifted vocal gestures generalized to the same gestures produced in other sequential contexts. Surprisingly, generalization magnitude depended strongly on sequential distance from the pitch-shifted syllables, with greater adaptation for gestures produced near to the pitch-shifted syllable. A further unexpected result was that nonshifted syllables changed their pitch in the direction opposite from the shifted syllables. This apparently antiadaptive pattern of generalization could not be explained by correlations between generalization and the acoustic similarity to the pitch-shifted syllable. These findings therefore suggest that generalization depends on the type of vocal gesture and its sequential context relative to other gestures and may reflect an advantageous strategy for vocal learning and maintenance.
- Bridging the Gap between the Human and Macaque Connectome: A Quantitative Comparison of Global Interspecies Structure-Function Relationships and Network Topology. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5552-63.
Resting state functional connectivity MRI (rs-fcMRI) may provide a powerful and noninvasive "bridge" for comparing brain function between patients and experimental animal models; however, the relationship between human and macaque rs-fcMRI remains poorly understood. Here, using a novel surface deformation process for species comparisons in the same anatomical space (Van Essen, 2004, 2005), we found high correspondence, but also unique hub topology, between human and macaque functional connectomes. The global functional connectivity match between species was moderate to strong (r = 0.41) and increased when considering the top 15% strongest connections (r = 0.54). Analysis of the match between functional connectivity and the underlying anatomical connectivity, derived from a previous retrograde tracer study done in macaques (Markov et al., 2012), showed impressive structure-function correspondence in both the macaque and human. When examining the strongest structural connections, we found a 70-80% match between structural and functional connectivity matrices in both species. Finally, we compare species on two widely used metrics for studying hub topology: degree and betweenness centrality. The data showed topological agreement across the species, with nodes of the posterior cingulate showing high degree and betweenness centrality. In contrast, nodes in medial frontal and parietal cortices were identified as having high degree and betweenness in the human as opposed to the macaque. Our results provide: (1) a thorough examination and validation for a surface-based interspecies deformation process, (2) a strong theoretical foundation for making interspecies comparisons of rs-fcMRI, and (3) a unique look at topological distinctions between the species.
- Myocilin Is Involved in NgR1/Lingo-1-Mediated Oligodendrocyte Differentiation and Myelination of the Optic Nerve. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5539-51.
Myocilin is a secreted glycoprotein that belongs to a family of olfactomedin domain-containing proteins. Although myocilin is detected in several ocular and nonocular tissues, the only reported human pathology related to mutations in the MYOCILIN gene is primary open-angle glaucoma. Functions of myocilin are poorly understood. Here we demonstrate that myocilin is a mediator of oligodendrocyte differentiation and is involved in the myelination of the optic nerve in mice. Myocilin is expressed and secreted by optic nerve astrocytes. Differentiation of optic nerve oligodendrocytes is delayed in Myocilin-null mice. Optic nerves of Myocilin-null mice contain reduced levels of several myelin-associated proteins including myelin basic protein, myelin proteolipid protein, and 2'3'-cyclic nucleotide 3'-phosphodiesterase compared with those of wild-type littermates. This leads to reduced myelin sheath thickness of optic nerve axons in Myocilin-null mice compared with wild-type littermates, and this difference is more pronounced at early postnatal stages compared with adult mice. Myocilin also affects differentiation of oligodendrocyte precursors in vitro. Its addition to primary cultures of differentiating oligodendrocyte precursors increases levels of tested markers of oligodendrocyte differentiation and stimulates elongation of oligodendrocyte processes. Myocilin stimulation of oligodendrocyte differentiation occurs through the NgR1/Lingo-1 receptor complex. Myocilin physically interacts with Lingo-1 and may be considered as a Lingo-1 ligand. Myocilin-induced elongation of oligodendrocyte processes may be mediated by activation of FYN and suppression of RhoA GTPase.
- Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. [Journal Article]
- J Neurosci 2014 Apr 16; 34(16):5529-38.
Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization.