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10.1523/jneurosci.4286-07.2008 | 104,267,248 | Understanding how organisms deal with probabilistic stimulus-reward associations has been advanced by a convergence between reinforcement learning models and primate physiology, which demonstrated that the brain encodes a reward prediction error signal. However, organisms must also predict the level of risk associated ... | 10.1038/nrn2682 | This study uses an elegant design to disambiguate the role of the insular cortex in risk-related processing. In particular, the authors suggest that the insula is important for both generating prediction errors and risk (variance) related processing. |
10.1073/pnas.0702308104 | 20,402,785 | Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the in... | 10.1038/nrn2867 | This paper describes experiments that show that effects of acute stress on hippocampal LTD cause spatial memory retrieval deficits. |
10.1073/pnas.0710548105 | 19,992,444 | Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy, which involves enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a ... | 10.1038/nrn2867 | One of a series of experiments that implicate AMPAR endocytosis in amygdala depotentiation and fear extinction. |
10.1073/pnas.0901305106 | 15,247,126 | The classic example of experience-dependent cortical plasticity is the ocular dominance (OD) shift in visual cortex after monocular deprivation (MD). The experimental model of homosynaptic long-term depression (LTD) was originally introduced to study the mechanisms that could account for deprivation-induced loss of vis... | 10.1038/nrn2867 | A crucial demonstration of the specific role of LTD in visual cortex development. |
10.1126/science.1116894 | 102,232,759 | Drug-dependent neural plasticity related to drug addiction and schizophrenia can be modeled in animals as behavioral sensitization, which is induced by repeated noncontingent or self-administration of many drugs of abuse. Molecular mechanisms that are critical for behavioral sensitization have yet to be specified. Long... | 10.1038/nrn2867 | The first study that used the GluA2 3Y peptide to examine the role of AMPAR LTD in behaviour. |
10.1126/science.151.3707.209 | 123,308,039 | Glucose, sorbitol, fructose, and inositol are present in peripheral nerve and spinal cord. Marked elevation of these substances occurs in these tissues in mildly diabetic animals. These alterations provide biochemical mechanisms which could be significant in the etiology of diabetic neuropathy. | 10.1038/nrneurol.2016.201 | An original key paper describing elevated levels of glucose and sorbitol in diabetic nervous tissue. |
10.2337/db05-1497 | 56,483,058 | The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR−/−) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. U... | 10.1038/nrneurol.2016.201 | An important study that used aldose reductase-deficient mice to demonstrate that increased polyol pathway flux through aldose reductase in Schwann cells is a major contributing factor to the early signs of diabetic neuropathy. |
10.1113/jphysiol.1967.sp008146 | 104,003,878 | 1. An examination of the physiological properties of cells in cat lumbar dorsal horn shows that there are three horizontal laminae which correspond approximately to Rexed (1952) laminae 4, 5, and 6. 2. A summary diagram (Fig. 9) suggests the relation of the laminae to each other and to afferent and descending fibres. A... | 10.1038/nrn1431 | This is a seminal description of dorsal horn neurons as feature detectors with response properties that are subject to top–down modulation. Wall demonstrated that each dorsal horn lamina contained neurons with distinct physiological properties, and he placed the main focus of pain research on the spinal cord. |
10.1152/jn.1995.74.4.1742 | 60,274,345 | 1. The rostral ventromedial medulla (RVM) participates in the modulation of nociceptive transmission by spinal cord neurons. Previous anatomic studies have demonstrated that RVM neurons project to laminae I, II, and V of the dorsal horn; laminae VII and VIII of the intermediate and ventral horns; the intermediolateral ... | 10.1038/nrn1431 | Microstimulation is used to track the terminals of on and off cells into dorsal horn laminae I, II and V. |
10.1152/jn.1999.81.2.584 | 123,492,750 | Physiological properties of raphe magnus neurons during sleep and waking. Neurons in the medullary raphe magnus (RM) that are important in the descending modulation of nociceptive transmission are classified by their response to noxious tail heat as on,off, or neutral cells. Experiments in anesthetized animals demonstr... | 10.1038/nrn1431 | This study uses single unit recording in awake rats to demonstrate state dependence of firing patterns in on, off and neutral cells in the rostral ventromedial medulla. |
10.1113/jphysiol.1990.sp018185 | 18,999,669 | 1. Intracellular recordings were made from neurons of the nucleus raphe magnus (NRM) from rat (n = 128) and guinea‐pig (n = 115). Two types of cells were found in each, primary (103 in rat, 27 in guinea‐pig) and secondary cells (25 in rat, 88 in guinea‐pig). 2. Primary cells had input resistances of 186 +/‐ 9 M omega (... | 10.1038/nrn1431 | The first in vitro study of RVM neurons. The authors use sharp electrodes and demonstrate distinct populations of neurons that are either directly inhibited or disinhibited by opioid agonists. |
10.1126/science.1067176 | 20,666,574 | It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomogr... | 10.1038/nrn1431 | Using positron emission tomography, the authors show extensive overlap between brain areas that are activated by the short-acting MOR agonist remifentanyl and a placebo manipulation that produces analgesia. |
10.1126/science.1155942 | 16,830,984 | Sleep is an essential process conserved from flies to humans. The importance of sleep is underscored by its tight homeostatic control. Through a forward genetic screen, we identified a gene, sleepless , required for sleep in Drosophila . The sleepless gene encodes a brain-enriched, glycosylphosphatidylinositol-anchored... | 10.1038/nrn2683 | Second gene with strong effects on sleep duration to be identified in flies using mutagenesis screening. |
10.1073/pnas.0505414102 | 16,724,366 | Slow, rhythmic oscillations (<5 Hz) in the sleep electroencephalogram may be a sign of synaptic plasticity occurring during sleep. The oscillations, referred to as slow-wave activity (SWA), reflect sleep need and sleep intensity. The amount of SWA is homeostatically regulated. It is enhanced after sleep loss and dec... | 10.1038/nrn2683 | First study in humans to identify a gene polymorphism that affects the duration of NREM sleep and SLA. |
10.1111/j.1460-9568.1990.tb00018.x | 18,879,747 | Abstract Sleep deprivation (SD) experiments have suggested that specific endogenous substances mediate the control of sleep and waking. However, such ‘sleep substances’ have not yet been unambiguously identified. The isolation of specific molecular markers would make it possible to obtain new insights into the regulato... | 10.1038/nrn2683 | Pioneer study that used subtractive cDNA cloning to identify rat forebrain transcripts affected by sleep deprivation. |
10.1677/joe.1.06631 | 874,482 | IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer’s disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I −/− ), resulting in an approximately 80–85% reduction of circulating IGF... | 10.1038/nrn2336 | In this study, IGF1 production was inactivated in the liver of adult mice, resulting in impaired spatial working and reference memory as well as neurochemical disturbances that suggested synaptic dysfunction and early neurodegeneration. The decline in serum IGF1 with increasing age might therefore be important for the ... |
10.1111/j.1365-2869.1993.tb00064.x | 20,376,676 | SUMMARY A new theory of sleep function is presented within the context of the neuronal group selection hypothesis, which emphasizes that neuronal groups compete for neurons via use‐dependent synaptic formation and atrophy. It is hypothesized that sleep serves to stabilize these competitive processes by providing a patt... | 10.1038/nrn2521 | This was the first statement of the hypothesis that sleep is a local use-dependent process. |
10.1111/j.1365-2869.1994.tb00123.x | 18,279,991 | SUMMARY The hypothesis that local activation of brain regions during wakefulness affects the EEG recorded from these regions during sleep was tested by applying vibratory stimuli to one hand prior to sleep. Eight subjects slept in the laboratory for five consecutive nights. During a 6‐h period prior to night 3, either ... | 10.1038/nrn2521 | The authors tested the hypothesis put forward in reference 4 that sleep is a local activity-dependent process. Much research has since extended and confirmed this pioneering study. |
10.1002/jemt.20187 | 20,757,444 | Abstract Alzheimer's disease is characterized in part by the aggregation of tau protein into filamentous inclusions. Because tau filaments form in brain regions associated with memory retention, and because their appearance correlates well with the degree of dementia, they have emerged as robust markers of disease prog... | 10.1038/nrn2194 | This review provides a model to rationalize the multistep pathway to tau fibril formation, as well as experimental methods for tau fibrillization assays. |
10.1073/pnas.0500466102 | 19,193,003 | Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition ca... | 10.1038/nrn2194 | Study that validates GSK3β as a target for tau-directed therapies. |
10.1073/pnas.092136199 | 83,183,079 | Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar β-amyloid peptide (Aβ); neurofibrillary tangles represent intracellular bu... | 10.1038/nrn2194 | Study that substantiates the notion that tau may be a mediator of upstream pathological events, namely Aβ-induced neurotoxicity. |
10.1126/science.1141736 | 100,515,169 | Many potential treatments for Alzheimer's disease target amyloid-β peptides (Aβ), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Aβ-induced cognitive impairments. Here, we found that re... | 10.1038/nrn2194 | Study that suggests the role tau might have as a mediator of neurodegeneration. This study also suggests that tau reduction may be therapeutically beneficial. |
10.1126/science.1113694 | 103,827,988 | Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, ne... | 10.1038/nrn2194 | Interesting study that shows that suppression of tau improves memory function even though NFTs continue to grow. |
10.1126/science.1105681 | 103,817,875 | We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associate... | 10.1038/nrn2194 | Together with reference 61, this study shows that axonal transport defects may be early pathological events in tau-mediated neurodegeneration. |
10.1097/00000542-200402000-00031 | 80,570,535 | Background Anatomic and physiologic data show that multiple regions of the forebrain are activated by pain. However, the effect of anesthetic level on nociceptive input to these regions is not well understood. Methods The authors used positron emission tomography to measure the effect of various concentrations of propo... | 10.1038/nrn1496 | Provides clear evidence that loss of consciousness and pain sensation correlates with propofol-induced interruption of thalamic information processing. |
10.1097/00000542-200106000-00010 | 16,755,440 | Background Functional magnetic resonance imaging of blood oxygenation level-dependent signal changes offers a very promising approach to investigate activated neural networks during anesthesia. Methods Sixteen healthy male volunteers, assigned into two groups of eight subjects (isoflurane group, control group), were in... | 10.1038/nrn1496 | Reports that higher-level cortical information processing is more sensitive to anaesthetic treatment than sensory processing in primary cortices and subcortical structures. |
10.1097/00000542-199803000-00030 | 62,518,822 | Background The mammalian gamma-aminobutyric acid type A (GABA(A)) receptor, a likely target of anesthetic action, exhibits remarkable subunit heterogeneity. In vitro expression studies suggest that there is subunit specificity to anesthetic responses at the GABA(A) receptor. The authors tested whether genetically engin... | 10.1038/nrn1496 | Provides the first report on responses to general anaesthetics being altered by the knockout of a GABA A -receptor subunit. |
10.1073/pnas.94.20.11031 | 121,965,705 | The γ-aminobutyric acid type A (GABA A ) receptor is a transmitter-gated ion channel mediating the majority of fast inhibitory synaptic transmission within the brain. The receptor is a pentameric assembly of subunits drawn from multiple classes (α 1–6 , β 1–3 , γ 1–3 , δ 1 , and ɛ 1 ). Positive allosteric modulation of... | 10.1038/nrn1496 | Identification of amino-acid residues in the β-subunits that render GABA A receptors etomidate-sensitive or insensitive. This electrophysiological study on recombinant receptors is the basis for the development of the β2(N265S) and β3(N265M) mouse models. |
10.1146/annurev.neuro.26.041002.131058 | 123,050,805 | ▪ Abstract The forebrain comprises an intricate set of structures that are required for some of the most complex and evolved functions of the mammalian brain. As a reflection of its complexity, cell migration in the forebrain is extremely elaborated, with widespread dispersion of cells across multiple functionally dist... | 10.1038/nrn2074 | Together with references 1–6, this provides a thorough review of neuronal migration during embryonic development. |
10.1126/science.278.5337.474 | 60,985,659 | Although previous analyses indicate that neocortical neurons originate from the cortical proliferative zone, evidence suggests that a subpopulation of neocortical interneurons originates within the subcortical telencephalon. For example, γ-aminobutyric acid (GABA)–expressing cells migrate in vitro from the subcortical ... | 10.1038/nrn2074 | Revealed evidence supporting the idea that GABA-containing interneurons migrate tangentially from the subpallium to the pallidum and the dependence of this process on Dlx transcription factors. |
10.1073/pnas.0605177103 | 83,433,702 | Stem cells generate neurons in discrete regions in the postnatal mammalian brain. However, the extent of neurogenesis in the adult human brain has been difficult to establish. We have taken advantage of the integration of 14 C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons ... | 10.1038/nrn2074 | Establishes that no newborn neurons are present in the adult human neocortex. |
10.1101/gad.1462506 | 79,430,362 | The diversity of neuronal morphologies and the complexity of synaptic connections in the mammalian brain provide striking examples of cell polarity. Over the past decade, the identification of the PAR (for partitioning-defective) proteins, their function in polarity in the Caenorhabditis elegans zygote, and the conserv... | 10.1038/nrn2074 | Outlines recent advances in our understanding of neuronal polarity and its relevance to developmental events, including neuronal migration. |
10.1126/science.8178174 | 123,166,713 | During the development of the mammalian brain, neuronal precursors migrate to their final destination from their site of birth in the ventricular and subventricular zones (VZ and SVZ, respectively). SVZ cells in the walls of the lateral ventricle continue to proliferate in the brain of adult mice and can generate neuro... | 10.1038/nrn2074 | Together with reference 25, this demonstrates how long-distance migration of new neurons occurs in the adult mammalian brain. |
10.1126/science.1119133 | 26,994,136 | In the adult brain, neuroblasts born in the subventricular zone migrate from the walls of the lateral ventricles to the olfactory bulb. How do these cells orient over such a long distance and through complex territories? Here we show that neuroblast migration parallels cerebrospinal fluid (CSF) flow. Beating of ependym... | 10.1038/nrn2074 | Shows how the activity of ependymal cell cilia in the lateral ventricles may convey gradients of migration-influencing cues to newly generated neuroblasts in the SVZ. |
10.1126/science.7939663 | 79,440,186 | Interval mapping of data from two independent samples of sib pairs, at least one member of whom was reading disabled, revealed evidence for a quantitative trait locus (QTL) on chromosome 6. Results obtained from analyses of reading performance from 114 sib pairs genotyped for DNA markers localized the QTL to 6p21.3. An... | 10.1038/nrn936 | An early demonstration of the value of applying QTL mapping methods to continuous measures of cognitive ability. Strong evidence was provided for a locus on 6p, which was subsequently verified in several independent populations. |
10.1126/science.8091226 | 104,221,313 | Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissecti... | 10.1038/nrn936 | An excellent introduction to key concepts of complex genetic analysis. |
10.1146/annurev.neuro.31.061307.090711 | 19,076,344 | Many major human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), display axonal pathologies including abnormal accumulations of proteins and organelles. Such pathologies highlight damage to the axon as part of the pathogenic process and, in partic... | 10.1038/nrn3253 | This articles provides an excellent review of the pathological effects caused by defects in the axonal transport process as they pertain to various neurodegenerative diseases. |
10.1126/science.1134930 | 20,092,141 | The PhoP/PhoQ two-component system is a master regulator of Salmonella pathogenicity. Here we report that induction of the PhoP/PhoQ system results in an initial surge of PhoP phosphorylation; the occupancy of target promoters by the PhoP protein; and the transcription of PhoP-activated genes, which then subsides to re... | 10.1038/nrmicro2667 | This study demonstrates the physiological importance of network dynamics for a virulent microorganism. |
10.1073/pnas.1015397108 | 107,325,102 | Spatial asymmetry is crucial to development. One mechanism for generating asymmetry involves the localized synthesis of a key regulatory protein that diffuses away from its source, forming a spatial gradient. Although gradients are prevalent in eukaryotes, at both the tissue and intracellular levels, it is unclear whet... | 10.1038/nrmicro2667 | An experimentally driven study of the C. crescentus cell cycle, making use of mathematical modelling and simulation to circumvent experimental constraints and arrive at a compelling conceptual model. |
10.1126/science.1166859 | 18,478,289 | The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting modulation of adult neurogenesis is unknown. Here we identify Gadd45b as a neural activity–induced immediate early gene in... | 10.1038/nrn3379 | This article shows that BDNF transcription could be increased by convulsive activity-induced epigenetic DNA modification, which is mediated by GADD45B, leading to increased neurogenesis of granules cells in the adult hippocampus. |
10.1083/jcb.201201038 | 17,768,003 | Although brain-derived neurotrophic factor (BDNF) regulates numerous and complex biological processes including memory retention, its extremely low levels in the mature central nervous system have greatly complicated attempts to reliably localize it. Using rigorous specificity controls, we found that antibodies reactin... | 10.1038/nrn3379 | This study provides the ultrastructural evidence that endogenous BDNF is present exclusively in the secretory granules in the presynaptic axons, together with cleaved pro-peptide, in the adult hippocampus. |
10.1126/science.1152864 | 107,176,399 | Long-term potentiation (LTP) at glutamatergic synapses is considered to underlie learning and memory and is associated with the enlargement of dendritic spines. Because the consolidation of memory and LTP require protein synthesis, it is important to clarify how protein synthesis affects spine enlargement. In rat brain... | 10.1038/nrn3379 | This study provides the best evidence so far that links the action of endogenously secreted BDNF and the structural change (gradual enlargement) of dendritic spines associated with the induction of LTP. |
10.1073/pnas.1115907108 | 103,697,200 | A critical step in neuronal development is the formation of axon/dendrite polarity, a process involving symmetry breaking in the newborn neuron. Local self-amplifying processes could enhance and stabilize the initial asymmetry in the distribution of axon/dendrite determinants, but the identity of these processes remain... | 10.1038/nrn3379 | This study shows that BDNF secreted at the growth cone could serve as an autocrine factor for axon initiation and growth via positive feedback mechanisms involving BDNF-induced BDNF release and local insertion of TRKB into the membrane. |
10.1073/pnas.92.19.8856 | 102,845,946 | Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) gene family, has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently be... | 10.1038/nrn3379 | The first study showing that endogenous BDNF is essential for activity-induced LTP in the CA1 region of the hippocampus. |
10.1126/science.1057415 | 19,492,661 | Neurotrophins such as brain-derived neurotrophic factor (BDNF) are thought to be transferred from post- to presynaptic neurons and to be involved in the formation and plasticity of neural circuits. However, direct evidence for a transneuronal transfer of BDNF and its relation to neuronal activity remains elusive. We si... | 10.1038/nrn3379 | This study provides a direct demonstration of activity-dependent transneuronal transfer of BDNF protein in cultured neurons. |
10.1126/science.1067766 | 122,101,364 | Brain-derived neurotrophic factor (BDNF) and other neurotrophins are critically involved in long-term potentiation (LTP). Previous reports point to a presynaptic site of neurotrophin action. By imaging dentate granule cells in mouse hippocampal slices, we identified BDNF-evoked Ca 2+ transients in dendrites and spines,... | 10.1038/nrn3379 | This study demonstrates that the postsynaptic dendrite is the main site of BDNF's action during LTP induction, although the source of secreted BDNF is not addressed. |
10.1126/science.1142614 | 125,326,794 | Synaptic vesicles loaded with neurotransmitters are exocytosed in a soluble N -ethylmaleimide–sensitive factor attachment protein receptor (SNARE)–dependent manner after presynaptic depolarization induces calcium ion (Ca 2+ ) influx. The Ca 2+ sensor required for fast fusion is synaptotagmin-1. The activation energy of... | 10.1038/nsmb.1455 | The work demonstrates the ability of synaptotagmin C 2 to bend membranes into 17-nm-diameter tubes with fusogenic end caps and suggests a new model of protein mediated membrane fusion based on calcium-dependent insertion of the synaptotagmin C 2 domain into the membrane matrix. |
10.1083/jcb.140.6.1369 | 101,184,089 | The mechanism of bilayer unification in biological fusion is unclear. We reversibly arrested hemagglutinin (HA)-mediated cell–cell fusion right before fusion pore opening. A low-pH conformation of HA was required to form this intermediate and to ensure fusion beyond it. We present evidence indicating that outer monolay... | 10.1038/nsmb.1455 | The first work (i) describing hemifusion mediated by wild-type protein fusogen, (ii) identifying restricted hemifusion intermediates and (iii) reporting the dependence of fusion pore formation on the lipid composition of the distal membrane leaflets |
10.1073/pnas.0606032103 | 83,442,117 | Membrane fusion in eukaryotic cells is thought to be mediated by a highly conserved family of proteins called SNAREs (soluble N -ethyl maleimide sensitive-factor attachment protein receptors). The vesicle-associated v-SNARE engages with its partner t-SNAREs on the target membrane to form a coiled coil that bridges two ... | 10.1038/nsmb.1455 | By imaging real-time dynamics of single fusion events between the SNARE-carrying liposomes, this work identifies fusion intermediates with distinct extents of lipid mixing and characterizes the dwell times of docked and hemifused states and the lifetime of early fusion pores |
10.1016/0014-5793(93)81330-3 | 17,815,390 | Membrane fusion in exocytosis, intracellular trafficking, and enveloped viral infection is thought to be mediated by specialized proteins acting to merge membrane lipid bilayers. We now show that one class of naturally‐occurring phospholipids, lysolipids, inhibits fusion between cell membranes, organelles, and between ... | 10.1038/nsmb.1455 | This paper demonstrates that lipids known to inhibit hemifusion stage of fusion between protein-free bilayers also inhibit disparate biological fusion reactions, suggesting that these reactions proceed through a common hemifusion intermediate |
10.1073/pnas.0501864102 | 27,651,544 | Viral fusion proteins catalyze merger of viral and cell membranes through a series of steps that have not yet been well defined. To elucidate the mechanism of virus entry, we have imaged fusion between single virions bearing avian sarcoma and leukosis virus (ASLV) envelope glycoprotein (Env) and the cell membrane. Vira... | 10.1038/nsmb.1455 | Different stages of virus–cell fusion mediated by avian sarcoma and leukosis virus envelope glycoproteins were dissected by imaging single virions. The findings suggest that fusion involves a direct transition from hemifusion into a small and then growing pore within a small virus-2013 cell contact zone |
10.1126/science.1127683 | 83,042,626 | The vesicular stomatitis virus has an atypical membrane fusion glycoprotein (G) exhibiting a pH-dependent equilibrium between two forms at the virus surface. Membrane fusion is triggered during the transition from the high- to low-pH form. The structure of G in its low-pH form shows the classic hairpin conformation obs... | 10.1038/nsmb.1455 | This high resolution x-ray study, along with an earlier work of this group, characterizes a new class of viral fusion proteins (class III) that uses a bipartite fusion domain consisting of two short, noncontiguous hydrophobic loops |
10.1073/pnas.0504084102 | 123,871,377 | Teichoic acids (TAs), and especially lipoteichoic acids (LTAs), are one of the main immunostimulatory components of pathogenic Gram-positive bacteria. Their contribution to the immunomodulatory properties of commensal bacteria and especially of lactic acid bacteria has not yet been investigated in detail. To evaluate t... | 10.1038/nrmicro2690 | This work provides the first direct evidence, using both in vitro and in vivo models, that a bacterial cell wall compound (LTA) can modulate the host immune response. |
10.1038/ismej.2010.61 | 123,826,835 | Abstract Probiotic bacteria provide unique opportunities to study the global responses and molecular mechanisms underlying the effects of gut-associated microorganisms in the human digestive tract. In this study, we show by comparative transcriptome analysis using DNA microarrays that the established probiotic Lactobac... | 10.1038/nrmicro2690 | The first report on the in situ transcriptome of a Lactobacillus sp. in the human intestinal tract. |
10.1073/pnas.0810305105 | 41,477,182 | Dendritic cells (DCs) are antigen-presenting cells that play an essential role in mucosal tolerance. They regularly encounter beneficial intestinal bacteria, but the nature of these cellular contacts and the immune responses elicited by the bacteria are not entirely elucidated. Here, we examined the interactions of Lac... | 10.1038/nrmicro2690 | The first study to identify the ligand of a pivotal immature-DC receptor that is involved in immunomodulation by a probiotic Lactobacillus strain. |
10.1073/pnas.0700440104 | 62,561,641 | The mechanisms by which probiotic strains enhance the health of the host remain largely uncharacterized. Here we demonstrate that Lactobacillus salivarius UCC118, a recently sequenced and genetically tractable probiotic strain of human origin, produces a bacteriocin in vivo that can significantly protect mice against i... | 10.1038/nrmicro2690 | An elegantly designed in vivo investigation that robustly proves the probiotic role of Lactobacillus spp. bacteriocins in the prevention or attenuation of intestinal pathogen infection ( Listeria monocytogenes ) in mice. |
10.1073/pnas.0809919106 | 19,573,491 | How do we acquire immune tolerance against food microorganisms and commensal bacteria that constitute the intestinal microbiota? We investigated this by stimulating the immune system of adults with commensal Lactobacillus plantarum bacteria. We studied the in vivo human responses to L. plantarum in a randomized double-... | 10.1038/nrmicro2690 | Pioneering work that addresses the transcriptional response of the healthy human duodenal mucosa to the oral intake of probiotic-containing products, highlighting the differential responses to different preparations of the same probiotic strain. |
10.1073/pnas.1000079107 | 122,969,836 | Probiotic bacteria, specific representatives of bacterial species that are a common part of the human microbiota, are proposed to deliver health benefits to the consumer by modulation of intestinal function through largely unknown molecular mechanisms. To explore in vivo mucosal responses of healthy adults to probiotic... | 10.1038/nrmicro2690 | An in vivo study showing that, in healthy humans, there are differential duodenal transcriptome responses to three commercial probiotic strains; this study also highlights human individuality in baseline transcriptome patterns. |
10.1111/j.1749-6632.2011.06001.x | 4,801,415 | The past two decades have witnessed tremendous advances in noninvasive and postmortem neuroscientific techniques, advances that have made it possible, for the first time, to compare in detail the organization of the human brain to that of other primates. Studies comparing humans to chimpanzees and other great apes reve... | 10.1038/nrn3372 | A comprehensive review of the current issues of debate in human brain evolution, including questions on the uniqueness of frontal cortex expansion in humans, human brain lateralization and connectivity. |
10.1073/pnas.0605938103 | 123,910,732 | Comparisons of gene expression between human and non-human primate brains have identified hundreds of differentially expressed genes, yet translating these lists into key functional distinctions between species has proved difficult. Here we provide a more integrated view of human brain evolution by examining the large-... | 10.1038/nrn3372 | This paper introduces the use of co-expressed gene groups for analysing species transcriptome data. |
10.1101/gr.127324.111 | 101,041,961 | Over the course of ontogenesis, the human brain and human cognitive abilities develop in parallel, resulting in a phenotype strikingly distinct from that of other primates. Here, we used microarrays and RNA-sequencing to examine human-specific gene expression changes taking place during postnatal brain development in t... | 10.1038/nrn3372 | This paper reports an extreme delay in synaptic maturation in the human PFC compared to other primates. The study further predicts the regulatory network involved in this change. |
10.1073/pnas.1117943109 | 38,399,969 | Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the hum... | 10.1038/nrn3372 | This recent study reports that the prolonged myelinization process, which is known to extend into the third and fourth decades in humans, subsides by sexual maturity in chimpanzees and thus could represent another extreme case of delayed human neurodevelopment. |
10.1073/pnas.0911249107 | 4,913,489 | Changes in non–protein-coding regulatory DNA sequences have been proposed to play distinctive roles in adaptive evolution. We analyzed correlations between gene functions and evidence for positive selection in a common statistical framework across several large surveys of coding and noncoding sequences throughout the h... | 10.1038/nrn3372 | A meta-analysis of genome-scans for human-specific changes in protein-coding sequence and cis -regulatory changes. They find that human-specific genetic changes in neural genes mainly involve cis -regulatory but not protein-coding changes. |
10.1126/science.7777856 | 82,991,984 | Analysis of data collected on 131 species of primates, bats, and insectivores showed that the sizes of brain components, from medulla to forebrain, are highly predictable from absolute brain size by a nonlinear function. The order of neurogenesis was found to be highly conserved across a wide range of mammals and to co... | 10.1038/nrn3372 | This work demonstrates how evolutionary changes in brain size follow common rules across mammals. |
10.1152/jn.00531.2001 | 41,285,896 | Recently, we cloned and began to characterize a new N-methyl-d-aspartate receptor (NMDAR) subunit, NR3A. Here we extend our earlier findings by showing that recombinantly expressed NR3A in COS cells is biochemically associated with both NR1 and NR2 subunits. In the oocyte or HEK 293 cell expression systems, co-injectio... | 10.1038/nrn.2016.92 | References 14, 16 and 17 describe the atypical biophysical properties of GluN3A-NMDARs. |
10.1073/pnas.1312211110 | 59,145,733 | Significance More than 95% of excitatory synaptic contacts form on spines, highly motile dendritic protrusions that emerge, grow, or disappear in response to specific patterns of synaptic activity. This physical rearrangement is most prominent during critical periods of early postnatal life, when young brains are resha... | 10.1038/nrn.2016.92 | This paper reports an inhibitory role of GluN3A-NMDARs on spine rearrangements by diminishing the activation of the RAC1–PAK pathway in dendritic spines. |
10.1073/pnas.93.21.11962 | 62,110,366 | Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion... | 10.1038/nrn4002 | This report describes the role of NMDARs in the generation of MMNs in an intracortical study in non-human primates. |
10.1126/science.1103617 | 82,130,893 | The amygdala was more responsive to fearful (larger) eye whites than to happy (smaller) eye whites presented in a masking paradigm that mitigated subjects' awareness of their presence and aberrant nature. These data demonstrate that the amygdala is responsive to elements of biologically relevant configural stimuli. | 10.1038/nrn1766 | Establishes that, at least with faces close to the viewer, the amygdala responds to the proportion of white around the pupil. |
10.1073/pnas.1005940107 | 104,115,276 | Local Ca 2+ signaling occurring within nanometers of voltage-gated Ca 2+ (Cav) channels is crucial for CNS function, yet the molecular composition of Cav channel nano-environments is largely unresolved. Here, we used a proteomic strategy combining knockout-controlled multiepitope affinity purifications with high-resolu... | 10.1038/nrn3311 | A study providing a comprehensive picture of the proteins that interact with N-type calcium channels. |
10.1073/pnas.0504183102 | 123,189,594 | All auxiliary α 2 δ subunits of voltage-gated Ca 2+ (Ca V ) channels contain an extracellular Von Willebrand factor-A (VWA) domain that, in α 2 δ-1 and -2, has a perfect metal-ion-dependent adhesion site (MIDAS). Modeling of the α 2 δ-2 VWA domain shows it to be highly likely to bind a divalent cation. Mutating the thr... | 10.1038/nrn3311 | This study identified the importance of the VWA domain in α 2 δ subunits for calcium channel trafficking and function. |
10.1073/pnas.0409066103 | 40,720,783 | Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unl... | 10.1038/nrn3311 | This paper conclusively shows that gabapentin and pregabalin act through interaction with α 2 δ-1 in the alleviation of neuropathic pain, as their effects are lost in a knock-in mouse harbouring a mutation in α 2 δ-1 rendering it insensitive to these drugs. |
10.1152/ajpheart.00122.2009 | 101,007,206 | Cardiac L-type voltage-dependent Ca 2+ channels are heteromultimeric polypeptide complexes of α 1 -, α 2 /δ-, and β-subunits. The α 2 /δ-1-subunit possesses a stereoselective, high-affinity binding site for gabapentin, widely used to treat epilepsy and postherpetic neuralgic pain as well as sleep disorders. Mutations i... | 10.1038/nrn3311 | This paper reports the generation of viable α 2 δ-1 knockout mice, despite prior reports in the literature that this knockout is neonatally lethal. The mice are reported to have a cardiac defect. |
10.1002/neu.1038 | 102,858,285 | Abstract The expression of aromatase, the enzyme that catalyzes the biosynthesis of estrogens from precursor androgens, is increased in the brain after injury, suggesting that aromatase may be involved in neuroprotection. In the present study, the effect of inactivating aromatase has been assessed in a model of neurode... | 10.1038/nrn3856 | Shows that brain aromatase inhibition increases excitotoxic neuronal death in the hippocampus after kainic acid administration in male rats. |
10.1002/glia.20594 | 40,918,314 | Abstract Mechanical or anoxic/ischemic brain insult results in reactive gliosis and a pronounced wave of apoptotic secondary degeneration (WSD). Reactive glia express aromatase (estrogen synthase) and glial estrogen synthesis decreases apoptosis and the volume of degeneration. Whether aromatization by glia affects glio... | 10.1038/nrn3856 | Shows that inhibition of brain aromatase in songbirds increases gliosis and neuronal degeneration after brain injury. |
10.1073/pnas.1104391108 | 81,460,384 | Recent work suggests that timing of 17β-estradiol (E2) therapy may be critical for observing a beneficial neural effect. Along these lines, E2 neuroprotection, but not its uterotropic effect, was shown to be lost following long-term E2 deprivation (LTED), and this effect was associated with a significant decrease of es... | 10.1038/nrn3856 | Provides the molecular basis for the critical period hypothesis of oestradiol on neuroprotection, showing degradation of ERs in the hippocampus with ageing and after long-term oestradiol deprivation. |
10.1073/pnas.0600236103 | 28,153,667 | Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I saf... | 10.1038/nrn2685 | Important demonstration of stable, long-term delivery of CNTF using genetically modified cells transplanted into the vitreous humor. |
10.1073/pnas.0600559103 | 104,112,501 | Nanotechnology is often associated with materials fabrication, microelectronics, and microfluidics. Until now, the use of nanotechnology and molecular self assembly in biomedicine to repair injured brain structures has not been explored. To achieve axonal regeneration after injury in the CNS, several formidable barrier... | 10.1038/nrn2685 | Important demonstration that nanoscaffolds foster regeneration. In this study, the optic tract in hamsters regenerated following implantation of a self-assembled nanofibre scaffold resulting in histological and visual recovery. |
10.1126/science.1093783 | 83,493,060 | Neural progenitor cells were encapsulated in vitro within a three-dimensional network of nanofibers formed by self-assembly of peptide amphiphile molecules. The self-assembly is triggered by mixing cell suspensions in media with dilute aqueous solutions of the molecules, and cells survive the growth of the nanofibers a... | 10.1038/nrn2685 | Important demonstration of the capacity of nanofibres to rapidly and predictably control stem cell differentiation. |
10.1073/pnas.1107297108 | 104,433,811 | The neuronal correlate of perceptual decision making has been extensively studied in the monkey somatosensory system by using a vibrotactile discrimination task, showing that stimulus encoding, retention, and comparison are widely distributed across cortical areas. However, from a network perspective, it is not known w... | 10.1038/nrn3137 | This monkey electrophysiology study demonstrated decision-related modulations of beta-band oscillations across several frontal areas during a vibro-tactile discrimination task. |
10.1126/science.1171402 | 82,969,531 | Attention and Synchrony Neural activity in the visual cortex becomes synchronized with attention and other behavioral states. However, the source of this synchrony is still unknown. Gregoriou et al. (p. 1207 ) tested the hypothesis that synchronized activity from the frontal eye field is one of the causes of the synchr... | 10.1038/nrn3137 | This monkey electrophysiology study demonstrated spatially selective attentional modulation of coherence between frontal and visual cortices and characterized in detail the temporal dynamics and directionality of oscillatory interactions. |
10.1073/pnas.0404944101 | 38,403,239 | Because of attentional limitations, the human visual system can process for awareness and response only a fraction of the input received. Lesion and functional imaging studies have identified frontal, temporal, and parietal areas as playing a major role in the attentional control of visual processing, but very little i... | 10.1038/nrn3137 | This human MEG study was the first to demonstrate that frontoparietal beta-band coherence predicts performance in a demanding visual detection task. |
10.1126/science.1138071 | 62,065,475 | Attention can be focused volitionally by “top-down” signals derived from task demands and automatically by “bottom-up” signals from salient stimuli. The frontal and parietal cortices are involved, but their neural activity has not been directly compared. Therefore, we recorded from them simultaneously in monkeys. Prefr... | 10.1038/nrn3137 | This monkey electrophysiology study was the first to directly compare bottom-up and top-down attention and demonstrated frontoparietal coherence in the gamma- and beta-band for bottom-up and top-down attention, respectively. |
10.1080/j.1440-1614.2006.01816.x | 79,824,552 | Objective: To review the accumulated literature on the efficacy, safety and predictors of response for repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. Methods: A descriptive review of the more than 25 published sham-controlled rTMS studies in depression was undertaken, focusing on re... | 10.1038/nrn2169 | One of the most recent meta-analyses examining the efficacy of rTMS for the treatment of depression. Concludes that although rTMS has a statistically significant effect on measures of depression the clinical significance is questionable. |
10.1113/jphysiol.2002.023317 | 122,396,197 | Associative stimulation has been shown to enhance excitability in the human motor cortex ( Stefan et al. 2000 ); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delive... | 10.1038/nrn2169 | Provided evidence that the lasting effects of rTMS protocols may be due to LTP-like mechanisms. Demonstrated that PAS effects are blocked by an NMDA-receptor antagonist. |
10.1161/01.str.0000231390.58967.6b | 82,144,470 | Background and Purpose— It has been recently shown that a single session of repetitive transcranial magnetic stimulation (rTMS) of the unaffected hemisphere can improve motor function in stroke patients; however, this improvement is short-lasting. We therefore conducted a randomized, sham-controlled, phase II trial to ... | 10.1038/nrn2169 | A sham-controlled study examining the efficacy of an alternative approach for rehabilitation of stroke patients; namely the application of inhibitory rTMS over the unaffected motor cortical region |
10.1073/pnas.95.24.14500 | 123,049,781 | The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neurons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional chemokine receptors. Fura-2-based Ca imaging showed that numerous chemokines, including SDF-1α, RANTES, and fract... | 10.1038/nrn1116 | The first paper to demonstrate the diverse short- and long-term effects produced by chemokines on neurons. |
10.1073/pnas.95.16.9448 | 41,767,320 | The chemokine stromal cell-derived factor 1, SDF-1, is an important regulator of leukocyte and hematopoietic precursor migration and pre-B cell proliferation. The receptor for SDF-1, CXCR4, also functions as a coreceptor for T-tropic HIV-1 entry. We find that mice deficient for CXCR4 die perinatally and display profoun... | 10.1038/nrn1116 | References 27 and 28 were the first to demonstrate the importance of SDF-1/CXCR4 signalling in the development of the cerebellum. |
10.1242/dev.128.11.1971 | 83,367,780 | The chemokine SDF-1α (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1α both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proli... | 10.1038/nrn1116 | This paper examines the mechanism of SDF-1 action on granule cells in the EGL and how SDF-1 and Shh interact to control granule cell precursor proliferation. |
10.1002/cne.10554 | 101,723,513 | Abstract Chemokines are small, soluble proteins that regulate leukocyte migration, adhesion, and proliferation. Recent evidence suggests that chemokine receptors are expressed in the central nervous system and that their functions extend beyond their roles in inflammation. Specific chemokines and their receptors are im... | 10.1038/nrn1116 | A recent study that strongly indicates the importance of MIP1-α/CCR1 signalling in the development of the cerebellum. |
10.1242/dev.129.18.4249 | 20,808,872 | The dentate gyrus is the primary afferent pathway into the hippocampus, but there is little information concerning the molecular influences that govern its formation. In particular, the control of migration and cell positioning of dentate granule cells is not clear. We have characterized more fully the timing and route... | 10.1038/nrn1116 | References 37 and 38 demonstrated the importance of SDF-1/CXCR4 signalling in the normal development of the dentate gyrus. |
10.1523/jneurosci.22-14-05865.2002 | 123,584,088 | The chemoattractant stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) are key modulators of immune function. In the developing brain, SDF-1 is crucial for neuronal guidance; however, cerebral functions of SDF-1/CXCR4 in adulthood are unclear. Here, we examine the cellular expressio... | 10.1038/nrn1116 | The most complete description so far of the distribution of SDF-1 and CXCR4 in the adult brain and changes in their expression in response to stroke. |
10.1002/glia.10079 | 81,036,512 | Abstract Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3–10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein‐1α and ‐β [MIP‐1α, MIP‐1β]) induced transcripts for KC, monocy... | 10.1038/nrn1116 | This paper provides a good example of how astrocytes can potentially mediate the production of chemokines as part of the neuroinflammatory process. |
10.1093/oso/9780198566960.003.0014 | 149,076,941 | Abstract A long tradition conceptualizes pain processing according to sensory-discriminative and affective-motivational domains (Melzack & Casey, 1968; Melzack, 1975; Kenshalo & Willis, 1991). The sensory-discriminative domain engages stimulus localization and can be assessed with visual analogue scales for int... | 10.1038/nrn2994 | The authors propose a novel hypothesis about the contribution of the cingulate premotor areas to pain. |
10.1093/oso/9780198566960.003.0005 | 149,079,764 | Abstract The cingulate gyrus forms a prominent part of the medial wall of the cerebral cortex. In traditional terms, it is a major component of the limbic lobe and is uniquely characterized by its vast network of interconnections with other limbic cortices, as well as with a number of multimodal association regions thr... | 10.1038/nrn2994 | This chapter reviews the anatomy, physiology and function of the cingulate premotor areas, including their connections with the facial nucleus. |
10.1111/j.1469-8986.2007.00609.x | 45,389,851 | Abstract We examined the neurocognitive correlates of the Behavioral Inhibition and Behavioral Activation Systems (BIS/BAS) in an effort to clarify ambiguities concerning interpretations of BIS as reflecting inhibition versus avoidance. We hypothesized that self‐reported BIS should relate to neural mechanisms associate... | 10.1038/nrn2994 | This paper demonstrated that trait-like individual differences in anxiety and behavioural inhibition are predictive of ERP indices of cognitive control thought to be generated in MCC. |
10.1111/j.1467-9280.2008.02053.x | 122,725,639 | The error-related negativity (ERN) is a negative deflection in the event-related potential that is maximal approximately 50 ms after the commission of an error. The ERN is generated in the anterior cingulate cortex, a region of the medial prefrontal cortex implicated in both cognitive and emotional processing. Affectiv... | 10.1038/nrn2994 | This paper demonstrated that response errors on a standard cognitive control task are associated with enhanced negative affect, indexed using the fear-potentiated startle reflex. |
10.1073/pnas.90.5.1977 | 41,590,662 | Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A... | 10.1038/nrn2620 | References 6 and 7 were the first to report a genetic association between the ɛ4 allele of the APOE gene and LOAD. |
10.1126/science.3283935 | 107,201,417 | Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant form of apolipoprotein E that is defective in binding to low densi... | 10.1038/nrn2620 | A classic review on the biochemical properties and cholesterol transport function of APOE. |
10.1523/jneurosci.23-26-08844.2003 | 124,543,497 | Soluble amyloid-β (Aβ) peptide converts to structures with high β-sheet content in Alzheimer's disease (AD). Soluble Aβ is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Aβ levels may provide unique insights into Aβ metabolism and AD... | 10.1038/nrn2620 | This paper described an in vivo microdialysis technique to assess Aβ concentration in brain interstitial fluid. It also showed that Aβ's half-life in the mouse brain is 2–4 h. |
10.1073/pnas.050004797 | 81,549,145 | Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (ɛ4 > ɛ3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-β (Aβ) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Aβ deposition and AD pathology, we compared... | 10.1038/nrn2620 | This paper described the differential in vivo effects of human APOE isoforms on amyloid deposition in mouse models. |
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