Showing papers in "Nature Neuroscience in 2001"

Abstract reward and punishment representations in the human orbitofrontal cortex.

Abstract: The orbitofrontal cortex (OFC) is implicated in emotion and emotion-related learning. Using event-related functional magnetic resonance imaging (fMRI), we measured brain activation in human subjects doing an emotion-related visual reversal-learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward and choice of the incorrect stimulus led to a monetary loss. Distinct areas of the OFC were activated by monetary rewards and punishments. Moreover, in these areas, we found a correlation between the magnitude of the brain activation and the magnitude of the rewards and punishments received. These findings indicate that one emotional involvement of the human orbitofrontal cortex is its representation of the magnitudes of abstract rewards and punishments, such as receiving or losing money.

Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons

Abstract: Dendritic spines serve as preferential sites of excitatory synaptic connections and are pleomorphic. To address the structure-function relationship of the dendritic spines, we used two-photon uncaging of glutamate to allow mapping of functional glutamate receptors at the level of the single synapse. Our analyses of the spines of CA1 pyramidal neurons reveal that AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors are abundant (up to 150/spine) in mushroom spines but sparsely distributed in thin spines and filopodia. The latter may be serving as the structural substrates of the silent synapses that have been proposed to play roles in development and plasticity of synaptic transmission. Our data indicate that distribution of functional AMPA receptors is tightly correlated with spine geometry and that receptor activity is independently regulated at the level of single spines.

Cerebral mechanisms of word masking and unconscious repetition priming.

Abstract: We used functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs) to visualize the cerebral processing of unseen masked words. Within the areas associated with conscious reading, masked words activated left extrastriate, fusiform and precentral areas. Furthermore, masked words reduced the amount of activation evoked by a subsequent conscious presentation of the same word. In the left fusiform gyrus, this repetition suppression phenomenon was independent of whether the prime and target shared the same case, indicating that case-independent information about letter strings was extracted unconsciously. In comparison to an unmasked situation, however, the activation evoked by masked words was drastically reduced and was undetectable in prefrontal and parietal areas, correlating with participants' inability to report the masked words.

The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.

Abstract: Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.

The fundamental plan of the retina

Abstract: The retina, like many other central nervous system structures, contains a huge diversity of neuronal types. Mammalian retinas contain approximately 55 distinct cell types, each with a different function. The census of cell types is nearing completion, as the development of quantitative methods makes it possible to be reasonably confident that few additional types exist. Although much remains to be learned, the fundamental structural principles are now becoming clear. They give a bottom-up view of the strategies used in the retina’s processing of visual information and suggest new questions for physiological experiments and modeling.

Effect of subjective perspective taking during simulation of action: a PET investigation of agency

Abstract: Perspective taking is an essential component in the mechanisms that account for intersubjectivity and agency. Mental simulation of action can be used as a natural protocol to explore the cognitive and neural processing involved in agency. Here we took PET measurements while subjects simulated actions with either a first-person or a third-person perspective. Both conditions were associated with common activation in the SMA, the precentral gyrus, the precuneus and the MT/V5 complex. When compared to the first-person perspective, the third-person perspective recruited right inferior parietal, precuneus, posterior cingulate and frontopolar cortex. The opposite contrast revealed activation in left inferior parietal and somatosensory cortex. We suggest that the right inferior parietal, precuneus and somatosensory cortex are specifically involved in distinguishing self-produced actions from those generated by others.

Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation.

Abstract: Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation

BACE1 is the major beta-secretase for generation of Abeta peptides by neurons.

Abstract: Two β-secretases, BACE1 and BACE2, are involved in generation of Alzheimer's disease Aβ peptides1,2,3. We report that secretion of Aβ peptides (Aβ1–40/42 and Aβ11–40/42) is abolished in cultures of BACE1-deficient embryonic cortical neurons, and that whereas both human and murine BACE1 can cleave either human or murine β-amyloid precursor protein (APP) at the +1 site of Aβ, cleavage at the +11 site is species specific. We establish that BACE1 is the principal neuronal protease required to cleave APP at +1 and +11 sites that generate N-termini of Aβ.

CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity.

Abstract: Astrocytes actively participate in synaptic integration by releasing transmitter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the chemokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the ensuing signaling cascade is the rapid extracellular release of tumor necrosis factor-alpha (TNFalpha). Autocrine/paracrine TNFalpha-dependent signaling leading to prostaglandin (PG) formation not only controls glutamate release and astrocyte communication, but also causes their derangement when activated microglia cooperate to dramatically enhance release of the cytokine in response to CXCR4 stimulation. We demonstrate that altered glial communication has direct neuropathological consequences and that agents interfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120IIIB. Our results identify a new pathway for glia-glia and glia-neuron communication that is relevant to both normal brain function and neurodegenerative diseases.

Genetic influences on brain structure

Abstract: Here we report on detailed three-dimensional maps revealing how brain structure is influenced by individual genetic differences. A genetic continuum was detected in which brain structure was increasingly similar in subjects with increasing genetic affinity. Genetic factors significantly influenced cortical structure in Broca's and Wernicke's language areas, as well as frontal brain regions (r2MZ > 0.8, p < 0.05). Preliminary correlations were performed suggesting that frontal gray matter differences may be linked to Spearman's g, which measures successful test performance across multiple cognitive domains (p < 0.05). These genetic brain maps reveal how genes determine individual differences, and may shed light on the heritability of cognitive and linguistic skills, as well as genetic liability for diseases that affect the human cortex.

TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.

Abstract: Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone. Unexpectedly, the lack of TNF alpha led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis. Failure of repair correlated with a reduction in the pool of proliferating oligodendrocyte progenitors (bromodeoxyuridine-labeled NG2(+) cells) followed by a reduction in the number of mature oligodendrocytes. Analysis of mice lacking TNF receptor 1 (TNFR1) or TNFR2 indicated that TNFR2, not TNFR1, is critical to oligodendrocyte regeneration. This unexpected reparative role for TNF alpha in the CNS is important for understanding oligodendrocyte regeneration/proliferation, nerve remyelination and the design of new therapeutics for demyelinating diseases.

A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories.

Abstract: The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

Activation of the left amygdala to a cognitive representation of fear

Abstract: We examined the neural substrates involved when subjects encountered an event linked verbally, but not experientially, to an aversive outcome. This instructed fear task models a primary way humans learn about the emotional nature of events. Subjects were told that one stimulus (threat) represents an aversive event (a shock may be given), whereas another (safe) represents safety (no shock will be given). Using functional magnetic resonance imaging (fMRI), activation of the left amygdala was observed in response to threat versus safe conditions, which correlated with the expression of the fear response as measured by skin conductance. Additional activation observed in the insular cortex is proposed to be involved in conveying a cortical representation of fear to the amygdala. These results suggest that the neural substrates that support conditioned fear across species have a similar but somewhat different role in more abstract representations of fear in humans.

Musical syntax is processed in Broca's area: An MEG study.

Abstract: The present experiment was designed to localize the neural substrates that process music-syntactic incongruities, using magnetoencephalography (MEG). Electrically, such processing has been proposed to be indicated by early right-anterior negativity (ERAN), which is elicited by harmonically inappropriate chords occurring within a major-minor tonal context. In the present experiment, such chords elicited an early effect, taken as the magnetic equivalent of the ERAN (termed mERAN). The source of mERAN activity was localized in Broca's area and its right-hemisphere homologue, areas involved in syntactic analysis during auditory language comprehension. We find that these areas are also responsible for an analysis of incoming harmonic sequences, indicating that these regions process syntactic information that is less language-specific than previously believed.

Natural signal statistics and sensory gain control

Abstract: We describe a form of nonlinear decomposition that is well-suited for efficient encoding of natural signals. Signals are initially decomposed using a bank of linear filters. Each filter response is then rectified and divided by a weighted sum of rectified responses of neighboring filters. We show that this decomposition, with parameters optimized for the statistics of a generic ensemble of natural images or sounds, provides a good characterization of the nonlinear response properties of typical neurons in primary visual cortex or auditory nerve, respectively. These results suggest that nonlinear response properties of sensory neurons are not an accident of biological implementation, but have an important functional role.

Prototype-referenced shape encoding revealed by high-level aftereffects

Abstract: We used high-level configural aftereffects induced by adaptation to realistic faces to investigate visual representations underlying complex pattern perception. We found that exposure to an individual face for a few seconds generated a significant and precise bias in the subsequent perception of face identity. In the context of a computationally derived ‘face space,’ adaptation specifically shifted perception along a trajectory passing through the adapting and average faces, selectively facilitating recognition of a test face lying on this trajectory and impairing recognition of other faces. The results suggest that the encoding of faces and other complex patterns draws upon contrastive neural mechanisms that reference the central tendency of the stimulus category.

Compulsory averaging of crowded orientation signals in human vision

Abstract: A shape can be more difficult to identify when other shapes are near it. For example, when several grating patches are viewed parafoveally, observers are unable to report the orientation of the central patch. This phenomenon, known as 'crowding,' has historically been confused with lateral masking, in which one stimulus attenuates signals generated by another stimulus. Here we show that despite their inability to report the orientation of an individual patch, observers can reliably estimate the average orientation, demonstrating that the local orientation signals are combined rather than lost. Our results imply that crowding is distinct from ordinary masking, and is perhaps related to texture perception. Under crowded conditions, the orientation signals in primary visual cortex are pooled before they reach consciousness.

The evolution of brain activation during temporal processing.

Abstract: Timing is crucial to many aspects of human performance. To better understand its neural underpinnings, we used event-related fMRI to examine the time course of activation associated with different components of a time perception task. We distinguished systems associated with encoding time intervals from those related to comparing intervals and implementing a response. Activation in the basal ganglia occurred early, and was uniquely associated with encoding time intervals, whereas cerebellar activation unfolded late, suggesting an involvement in processes other than explicit timing. Early cortical activation associated with encoding of time intervals was observed in the right inferior parietal cortex and bilateral premotor cortex, implicating these systems in attention and temporary maintenance of intervals. Late activation in the right dorsolateral prefrontal cortex emerged during comparison of time intervals. Our results illustrate a dynamic network of cortical-subcortical activation associated with different components of temporal information processing.

Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling.

Abstract: In humans, distinct processes within the hippocampus and rhinal cortex support declarative memory formation But do these medial temporal lobe (MTL) substructures directly cooperate in encoding new memories? Phase synchronization of gamma-band electroencephalogram (EEG) oscillations (around 40 Hz) is a general mechanism of transiently connecting neural assemblies We recorded depth-EEG from within the MTL of epilepsy patients performing a memorization task Successful as opposed to unsuccessful memory formation was accompanied by an initial elevation of rhinal-hippocampal gamma synchronization followed by a later desynchronization, suggesting that effective declarative memory formation is accompanied by a direct and temporarily limited cooperation between both MTL substructures

Optic flow is used to control human walking

Abstract: How is human locomotion visually controlled? Fifty years ago, it was proposed that we steer to a goal using optic flow, the pattern of motion at the eye that specifies the direction of locomotion. However, we might also simply walk in the perceived direction of a goal. These two hypotheses normally predict the same behavior, but we tested them in an immersive virtual environment by displacing the optic flow from the direction of walking, violating the laws of optics. We found that people walked in the visual direction of a lone target, but increasingly relied on optic flow as it was added to the display. The visual control law for steering toward a goal is a linear combination of these two variables weighted by the magnitude of flow, thereby allowing humans to have robust locomotor control under varying environmental conditions.

Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons.

Abstract: Using a thrombin cleavage assay in cultured hippocampal neurons, we studied the kinetics, regulation and site of AMPA receptor surface delivery. Surface insertion of the GluR1 subunit occurs slowly in basal conditions and is stimulated by NMDA receptor activation and insulin, whereas GluR2 exocytosis is constitutively rapid. Although both subunits ultimately concentrate in synapses, GluR1 and GluR2 show different spatial patterns of surface accumulation, consistent with GluR1 being inserted initially at extrasynaptic sites and GluR2 being inserted more directly at synapses. The spatiotemporal pattern of surface accumulation is determined by the cytoplasmic tails of GluR subunits, and in heteromeric receptors, GluR1 acts dominantly over GluR2. We propose that GluR1 controls the exocytosis and GluR2/3, the recycling and endocytosis of AMPA receptors.

Center-periphery organization of human object areas.

Abstract: The organizing principles that govern the layout of human object-related areas are largely unknown. Here we propose a new organizing principle in which object representations are arranged according to a central versus peripheral visual field bias. The proposal is based on the finding that building-related regions overlap periphery-biased visual field representations, whereas face-related regions are associated with center-biased representations. Furthermore, the eccentricity maps encompass essentially the entire extent of object-related occipito-temporal cortex, indicating that most object representations are organized with respect to retinal eccentricity. A control experiment ruled out the possibility that the results are due exclusively to unequal feature distribution in these images. We hypothesize that brain regions representing object categories that rely on detailed central scrutiny (such as faces) are more strongly associated with processing of central information, compared to representations of objects that may be recognized by more peripheral information (such as buildings or scenes).

Two modes of radial migration in early development of the cerebral cortex.

Abstract: Layer formation in the developing cerebral cortex requires the movement of neurons from their site of origin to their final laminar position. We demonstrate, using time-lapse imaging of acute cortical slices, that two distinct forms of cell movement, locomotion and somal translocation, are responsible for the radial migration of cortical neurons. These modes are distinguished by their dynamic properties and morphological features. Locomotion and translocation are not cell-type specific; although at early ages some cells may move by translocation only, locomoting cells also translocate once their leading process reaches the marginal zone. The existence of two modes of radial migration may account for the differential effects of certain genetic mutations on cortical development.

Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine.

Abstract: A compelling model of experience-dependent plasticity is the long-lasting sensitization to the locomotor stimulatory effects of drugs of abuse. Adaptations in the nucleus accumbens (NAc), a component of the mesolimbic dopamine system, are thought to contribute to this behavioral change. Here we examine excitatory synaptic transmission in NAc slices prepared from animals displaying sensitization 10-14 days after repeated in vivo cocaine exposure. The ratio of AMPA (alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) receptor- to NMDA (N-methyl-d-aspartate) receptor-mediated excitatory postsynaptic currents (EPSCs) was decreased at synapses made by prefrontal cortical afferents onto medium spiny neurons in the shell of the NAc. The amplitude of miniature EPSCs at these synapses also was decreased, as was the magnitude of long-term depression. These data suggest that chronic in vivo administration of cocaine elicits a long-lasting depression of excitatory synaptic transmission in the NAc, a change that may contribute to behavioral sensitization and addiction.

Visuo-haptic object-related activation in the ventral visual pathway

Abstract: The ventral pathway is involved in primate visual object recognition. In humans, a central stage in this pathway is an occipito‐temporal region termed the lateral occipital complex (LOC), which is preferentially activated by visual objects compared to scrambled images or textures. However, objects have characteristic attributes (such as three-dimensional shape) that can be perceived both visually and haptically. Therefore, object-related brain areas may hold a representation of objects in both modalities. Using fMRI to map object-related brain regions, we found robust and consistent somatosensory activation in the occipito‐temporal cortex. This region showed clear preference for objects compared to textures in both modalities. Most somatosensory object-selective voxels overlapped a part of the visual object-related region LOC. Thus, we suggest that neuronal populations in the occipito‐temporal cortex may constitute a multimodal object-related network.

Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum.

Abstract: In recent years, it has become clear that motor learning, as revealed by associative eyelid conditioning and adaptation of the vestibulo-ocular reflex, contributes to the well-established cerebellar functions of sensorimotor integration and control. Long-term depression of the parallel fiber-Purkinje cell synapse (which is often called 'cerebellar LTD') is a cellular phenomenon that has been suggested to underlie these forms of learning. However, it is clear that parallel fiber LTD, by itself, cannot account for all the properties of cerebellar motor learning. Here we review recent electrophysiological experiments that have described a rich variety of use-dependent plasticity in cerebellum, including long-term potentiation (LTP) and LTD of excitatory and inhibitory synapses, and persistent modulation of intrinsic neuronal excitability. Finally, using associative eyelid conditioning as an example, we propose some ideas about how these cellular phenomena might function and interact to endow the cerebellar circuit with particular computational and mnemonic properties.

Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.

Abstract: Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/WldS mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.

Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation.

Abstract: Astrocytes respond to chemical, electrical and mechanical stimuli with transient increases in intracellular calcium concentration ([Ca2+]i). We now show that astrocytes in situ display intrinsic [Ca2+]i oscillations that are not driven by neuronal activity. These spontaneous astrocytic oscillations can propagate as waves to neighboring astrocytes and trigger slowly decaying NMDA receptor-mediated inward currents in neurons located along the wave path. These findings show that astrocytes in situ can act as a primary source for generating neuronal activity in the mammalian central nervous system.

Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC.

Abstract: Following CNS injury in the adult mammal, axon regeneration fails in scar regions containing a number of different chondroitin sulfate-bearing proteoglycans (CSPGs)1. Degradation of chondroitin sulfate using chondroitinase ABC reduces growth inhibition associated with many CSPGs2,3,4,5,6,7,8,9,10,11,12,13. Here we demonstrate that it is possible to enhance CNS axon regeneration in the adult rat nigrostriatal tract following chondroitinase ABC degradation of chondroitin sulfate.

Characterization of an ocular photopigment capable of driving pupillary constriction in mice

Abstract: This work demonstrates that transgenic mice lacking both rod and cone photoreceptors (rd/rd cl) retain a pupillary light reflex (PLR) that does not rely on local iris photoreceptors These data, combined with previous reports that rodless and coneless mice show circadian and pineal responses to light, suggest that multiple non-image-forming light responses use non-rod, non-cone ocular photoreceptors in mice An action spectrum for the PLR in rd/rd cl mice demonstrates that over the range 420-625 nm, this response is driven by a single opsin/vitamin A-based photopigment with peak sensitivity around 479 nm (opsin photopigment/OP479) These data represent the first functional characterization of a non-rod, non-cone photoreceptive system in the mammalian CNS