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10.1126/science.1109676 | 123,938,881 | To find a target object in a crowded scene, a face in a crowd for example, the visual system might turn the neural representation of each object on and off in a serial fashion, testing each representation against a template of the target item. Alternatively, it might allow the processing of all objects in parallel but ... | 10.1038/nrn2315 | This paper provided support for the idea that feature-based attention is mediated by synchrony in the gamma frequency range. |
10.1126/science.1124593 | 18,956,243 | Sensory stimuli reach the brain via the thalamocortical projection, a group of axons thought to be among the most powerful in the neocortex. Surprisingly, these axons account for only ∼15% of synapses onto cortical neurons. The thalamocortical pathway might thus achieve its effectiveness via high-efficacy thalamocortic... | 10.1038/nrn2315 | The authors of this paper used an innovative technique to show that although the synapses from thalamocortical projection cells make up only a small fraction of the synapses on layer 4 SSCs, and have only an average unitary strength, they are effective in driving the cells because of their synchronous activation. |
10.1126/science.1139597 | 104,236,062 | Brain processing depends on the interactions between neuronal groups. Those interactions are governed by the pattern of anatomical connections and by yet unknown mechanisms that modulate the effective strength of a given connection. We found that the mutual influence among neuronal groups depends on the phase relation ... | 10.1038/nrn2315 | Local cortical networks project to a large number of other local networks. The authors of this study observed that communication seems to be selective, because each local network has a different phase of gamma oscillation and only pairs of networks with a good phase relationship can exchange information. |
10.1126/science.1128115 | 83,529,970 | We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at hig... | 10.1038/nrn2315 | This study reported the existence of spatially-specific and task-dependent correlations between the amplitude of high-gamma rhythms and the phase of theta oscillations. |
10.1126/science.7973728 | 103,909,390 | Nucleotide sequence analysis was performed on 12 natural isolates of Escherichia coli in four loci located in close proximity on the chromosome. A comparison of gene genealogies indicated that three recombination events have occurred in a subset of the strains (ECOR group A) in the time since their divergence from a co... | 10.1038/nrmicro904 | This insightful analysis provides a strong argument for the significance of homologous recombination in E. coli , despite the high degree of clonality in this species. |
10.1146/annurev.micro.56.012302.160634 | 60,525,293 | ▪ Abstract Bacterial systematics has not yet reached a consensus for defining the fundamental unit of biological diversity, the species. The past half-century of bacterial systematics has been characterized by improvements in methods for demarcating species as phenotypic and genetic clusters, but species demarcation ha... | 10.1038/nrmicro904 | This review presents a bold argument for the promotion of genotypic clusters to species status on the basis of their specific ecological adaptations and the resistance of these clusters to periodic selection events from outside the cluster. |
10.1099/mic.0.26457-0 | 61,058,299 | The bacterial genome projects have suggested a central role for horizontal transfer in bacterial adaptation, but it is difficult to rule out an adaptive role for ordinary genetic change in existing genes. The bacterial systematics literature can readily address the importance of gene acquisition in adaptive evolution, ... | 10.1038/nrmicro904 | An interesting paper that challenges current thinking by reasserting the adaptive significance of small incremental changes in existing genes rather than changes in gene content. |
10.1126/science.1134108 | 62,618,222 | Ubiquitin-positive, tau- and α-synuclein–negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease pro... | 10.1038/nrn3430 | This is this first study to link ALS with FTLD, and identifies TDP43 as a major disease protein in the ubiquitin-positive, tau-negative inclusions of affected tissue of patients with ALS and patients with FTLD. The subsequent identification of C9ORF72 as a major disease-causing protein in both ALS and FTLD confirmed th... |
10.1126/science.1227157 | 20,881,057 | Synthetic Parkinson's Parkinson's disease (PD) and related α-synucleinopathies are defined by the accumulation of α-synuclein (α-Syn)–containing intraneuronal inclusions—Lewy bodies (LBs) and Lewy neurites (LNs)—in association with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and other ... | 10.1038/nrn3430 | This paper shows that non-transgenic mice inoculated with synthetic α-synuclein fibrils acquire Parkinson-like Lewy body disease, which propagates from cell to cell, causing dopaminergic loss of the substantia nigra pars compacta. This could be an interesting disease mechanism through which prion domain-containing prot... |
10.1126/science.1123511 | 20,833,246 | Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phas... | 10.1038/nrn3430 | This is the first paper to evaluate the individual contribution of different cell types to the phenotype of the SOD1 G37R mouse model and supports the idea that glial cells contribute to motor neuron disease. |
10.1126/science.1158799 | 62,565,148 | The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient's disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have dem... | 10.1038/nrn3430 | This is the first paper to describe the generation of motor neurons from fibroblasts from an elderly patient with FALS. Fibroblasts from a patient with ALS were reprogrammed into a pluripotent state and subsequently differentiated into motor neurons, which could then be used for a whole range of new therapeutic applica... |
10.1073/pnas.87.24.9868 | 107,141,550 | Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high fields, we demonstrate in vivo images of brain microvasculature with image contrast reflecting the bloo... | 10.1038/nrn730 | The first demonstration of BOLD MRI. This paper was followed two years later by several concurrent reports (references 2–5 ) of the use of BOLD fMRI to measure activity non-invasively in the human brain. |
10.1002/hbm.460010207 | 104,118,048 | Abstract A method for detecting significant and regionally specific correlations between sensory input and the brain's physiological response, as measured with functional magnetic resonance imaging (MRI), is presented in this paper. The method involves testing for correlations between sensory input and the hemodynamic ... | 10.1038/nrn730 | Developed methods, widely used to analyse fMRI data, that rely on the linear transform hypothesis. |
10.1111/j.1469-7793.1998.555be.x | 41,091,010 | Mechanisms of activity‐dependent increases in cerebral blood flow (CBF) were examined in rat cerebellar cortex using the laser Doppler flow technique and extracellular recordings of single unit activity and field potentials. Stimulation of the monosynaptic climbing fibre system evoked long‐lasting complex spikes in Pur... | 10.1038/nrn730 | A compelling demonstration that blood flow can be decoupled from spiking activity. |
10.1073/pnas.170205497 | 123,298,644 | How well does the functional MRI (fMRI) signal reflect underlying electrophysiology? Despite the ubiquity of the technique, this question has yet to be adequately answered. Therefore, we have compared cortical maps generated based on the indirect blood oxygenation level-dependent signal of fMRI with maps from microelec... | 10.1038/nrn730 | Reported a profound discordance between fMRI and electrophysiological recordings of somatosensory cortical maps in the anaesthetized monkey. |
10.1126/science.286.5444.1555 | 26,620,296 | Modern functional brain mapping relies on interactions of neuronal electrical activity with the cortical microcirculation. The existence of a highly localized, stimulus-evoked initial deoxygenation has remained a controversy. Here, the activity-dependent oxygen tension changes in the microcirculation were measured dire... | 10.1038/nrn730 | The most compelling in a series of influential papers about the initial dip, the proposed initial increase in oxygen consumption that occurs immediately after the onset of neuronal activity. See also references 66 67 and 87 |
10.1126/science.3260686 | 41,672,929 | Brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with positron emission tomography, and a resting-state molar ratio of oxygen to glucose consumption of 4.1:1 was obtained. Physiological neural activity, however, increased glucose uptake and blood flow much more (51 and 50 percent, respect... | 10.1038/nrn730 | A classic study showing that oxygen consumption did not match blood flow and glucose consumption, indicating that increases in brain activation are supported by non-oxidative glucose metabolism. See also reference 69 |
10.1002/mrm.1910390602 | 19,199,456 | Abstract A biomechanical model is presented for the dynamic changes in deoxyhemoglobin content during brain activation. The model incorporates the conflicting effects of dynamic changes in both blood oxygenation and blood volume. Calculations based on the model show pronounced transients in the deoxyhemoglobin content ... | 10.1038/nrn730 | An influential model of blood flow, volume and oxygenation that explains many of the properties of the haemodynamic response. See also references 72 and 73 |
10.1098/rstb.1999.0471 | 18,578,502 | Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associate... | 10.1038/nrn730 | An excellent review of the literature on neurotransmitter recycling and its relationship to neuroimaging measurements. |
10.1097/00004647-199701000-00009 | 61,387,965 | A general mathematical model for the delivery of O 2 to the brain is presented, based on the assumptions that all of the brain capillaries are perfused at rest and that all of the oxygen extracted from the capillaries is metabolized. The model predicts that disproportionately large changes in blood flow are required in... | 10.1038/nrn730 | A model showing that the apparent mismatch between blood flow and oxygen consumption might be required to support a change in oxygen metabolism, because extraction (through passive diffusion) of oxygen from the blood is less efficient at higher flow rates. See also references 93 and 94 |
10.1097/00004647-200110000-00001 | 125,150,076 | Anatomic and physiologic data are used to analyze the energy expenditure on different components of excitatory signaling in the grey matter of rodent brain. Action potentials and postsynaptic effects of glutamate are predicted to consume much of the energy (47% and 34%, respectively), with the resting potential consumi... | 10.1038/nrn730 | An excellent review of energy consumption in the brain, which concludes that action potentials and postsynaptic effects of glutamate consume much of the energy (47% and 34%, respectively), with the resting potential consuming a smaller amount (13%) and glutamate recycling using only 3%. |
10.1162/089976602760407955 | 104,396,670 | A key challenge for neural modeling is to explain how a continuous stream of multimodal input from a rapidly changing environment can be processed by stereotypical recurrent circuits of integrate-and-fire neurons in real time. We propose a new computational model for real-time computing on time-varying input that provi... | 10.1038/nrn2558 | Introduced the liquid-computing model and analysed its computational power theoretically and through computer simulations. |
10.1126/science.7863330 | 41,096,344 | Neurons exhibit a wide range of properties in addition to postsynaptic potential (PSP) summation and spike generation. Although other neuronal properties such as paired-pulse facilitation (PPF) and slow PSPs are well characterized, their role in information processing remains unclear. It is possible that these properti... | 10.1038/nrn2558 | This paper showed that the hidden states created by short-term synaptic plasticity and slow IPSPs could underlie interval discrimination and spatiotemporal processing. This was the first theoretical study to propose that temporal and spatiotemporal processing could rely on the interaction between external stimuli and b... |
10.1126/science.1091277 | 104,268,649 | We present a method for learning nonlinear systems, echo state networks (ESNs). ESNs employ artificial recurrent neural networks in a way that has recently been proposed independently as a learning mechanism in biological brains. The learning method is computationally efficient and easy to use. On a benchmark task of p... | 10.1038/nrn2558 | Demonstrated that echo-state networks — that is, implementations of liquid-state machines through recurrent networks of sigmoidal neurons with static synapses — can be trained quite easily and perform extremely well for time series prediction benchmark tasks. |
10.1162/neco.1994.6.1.38 | 62,299,381 | Substantial evidence has established that the cerebellum plays an important role in the generation of movements. An important aspect of motor output is its timing in relation to external stimuli or to other components of a movement. Previous studies suggest that the cerebellum plays a role in the timing of movements. H... | 10.1038/nrn2558 | Using a computer simulation of the cerebellum, this paper demonstrated that the timing of motor responses could emerge from the interaction between the internal active state and a steady-state incoming stimulus. This paper was the first to propose that a temporal code for time could be generated as a result of the recu... |
10.1152/jn.00828.2007 | 47,875,725 | To explore the effects of acoustic and behavioral context on neuronal responses in the core of auditory cortex (fields A1 and R), two monkeys were trained on a go/no-go discrimination task in which they learned to respond selectively to a four-note target (S+) melody and withhold response to a variety of other nontarge... | 10.1038/nrn2558 | This paper provides robust examples of state-dependent neural responses in the auditory cortex of monkeys: some cells exhibited very weak responses to presentations of single tones but strong responses to the same tones presented in sequence. Such responses were more prevalent in neurons from monkeys that were trained ... |
10.1126/science.1168878 | 45,561,463 | Rewarding Bursts of Dopamine Dopaminergic neurons are thought to be involved in the cognitive and hedonic underpinnings of motivated behaviors. However, it is still unclear whether dopaminergic neuron activation is sufficient to elicit reward-related behavior and which type of neuronal activity pattern serves this purp... | 10.1038/nrn3171 | The initial behavioural application of the double-floxed inverted open reading frame tool enabling selective opsin expression in neurons positive for Cre recombinase. This is used in the TH::Cre mouse to demonstrate the hedonic properties of phasic dopamine neuron firing. |
10.1126/science.1193771 | 38,281,988 | Few But Powerful Drug activation of the different types of acetylcholine receptors in cholinergic neurons often generates opposing or conflicting effects. Using optogenetic techniques in transgenic mice, Witten et al. (p. 1677 ) investigated the function of a rather enigmatic subpopulation of cholinergic neurons, the g... | 10.1038/nrn3171 | The first behavioural loss-of-function in mammals achieved using optogenetics. This study involved the introduction of an inhibitory opsin into cholinergic interneurons using the double-floxed inverted open reading frame tool in a choline acetyltransferase (ChAT)::Cre mouse to demonstrate the role of cholinergic neuron... |
10.1126/science.1167093 | 83,069,052 | Deep brain stimulation (DBS) is a therapeutic option for intractable neurological and psychiatric disorders, including Parkinson's disease and major depression. Because of the heterogeneity of brain tissues where electrodes are placed, it has been challenging to elucidate the relevant target cell types or underlying me... | 10.1038/nrn3171 | This study provided a mechanistic explanation for how DBS alleviates parkinsonian symptoms using optogenetic techniques in animal models. |
10.1126/science.1188472 | 20,644,302 | BDNF, Dopamine, and Cocaine Reward The nucleus accumbens plays a crucial role in mediating the rewarding effects of drugs of abuse. Different subpopulations of nucleus accumbens projection neurons exhibit balanced but antagonistic influences on their downstream outputs and behaviors. However, their roles in regulating ... | 10.1038/nrn3171 | This study showed that D1 and D2 neurons in the NAc have distinctly different effects on cocaine-conditioned place preference. |
10.1111/j.1460-9568.2004.03563.x | 26,994,656 | Abstract We have disrupted the retinoid signalling pathway in adult rats by a dietary deficiency of vitamin A. After 1 year of this dietary deficiency, there was a deposition of amyloid β in the cerebral blood vessels. There is a downregulation of retinoic acid receptor α in the forebrain neurons of the retinoid‐defici... | 10.1038/nrn2212 | This study shows that, in the absence of RA, the cellular characteristics of Alzheimer's disease appear in rats. |
10.1002/cne.10369 | 60,101,625 | Abstract We used transgenic reporter mice to determine whether brain regions that respond to retinoic acid (RA) during development do so in maturity. We focused on two prominent sites of embryonic RA signaling: the dorsal spinal cord and the olfactory bulb. In the mature dorsal spinal cord, expression of a direct repea... | 10.1038/nrn2212 | This study reveals the sites in the adult brain where RA signalling continues to be activated. |
10.1073/pnas.91.16.7772 | 19,279,502 | Retinoic acid is synthesized from retinaldehyde by several different dehydrogenases, which are arranged in conserved spatial and developmentally regulated patterns. Here we show for the mouse that a class-1 aldehyde dehydrogenase, characterized by oxidation and disulfiram sensitivity, is found in the brain at high leve... | 10.1038/nrn2212 | This study found that high levels of RA synthesis are seen specifically in dopaminergic neurons in the adult brain. |
10.1126/science.279.5352.863 | 124,983,769 | In the adult mouse, single and compound null mutations in the genes for retinoic acid receptor β and retinoid X receptors β and γ resulted in locomotor defects related to dysfunction of the mesolimbic dopamine signaling pathway. Expression of the D1 and D2 receptors for dopamine was reduced in the ventral striatum of m... | 10.1038/nrn2212 | This paper shows that RA signalling is involved in striatal function in the adult brain. |
10.1242/dev.01867 | 102,481,644 | Neurogenesis persists throughout life in the rodent subventricular zone(SVZ)-olfactory bulb pathway. The molecular regulation of this neurogenic circuit is poorly understood. Because the components for retinoid signaling are present in this pathway, we examined the influence of retinoic acid (RA)on postnatal SVZ-olfact... | 10.1038/nrn2212 | This study reveals the effects of RA in promoting nerve cell production from neural stem cells. |
10.1242/dev.124.2.373 | 20,780,555 | The vertebrate central nervous system (CNS) is induced by signals emanating from the dorsal mesoderm, or organizer, that divert the ectoderm away from an epidermal and towards a neural fate. Additional signals from the organizer pattern the neural ectoderm along the anteroposterior axis. We devised highly specific meth... | 10.1038/nrn2212 | This study shows how normal, upregulated and downregulated RA signalling affects on the expression of various genes in the anteroposterior axis of the developing CNS. |
10.1111/j.0956-7976.2004.00696.x | 81,104,800 | If the visual world is artificially shifted by only 10°, people initially experience difficulty in directing their actions toward visual goals, but then rapidly compensate the visual distortion. The consequence of such adaptation can be measured as visual and proprioceptive aftereffects, as well as by performance on po... | 10.1038/nrn1684 | This paper shows that not only can prism adaptation improve perceptual neglect, but it also alleviates neglect of the left side of the mental number line. |
10.1152/jn.1998.79.1.126 | 61,386,850 | Duhamel, Jean-René, Carol L. Colby, and Michael E. Goldberg. Ventral intraparietal area of the macaque: congruent visual and somatic response properties. J. Neurophysiol. 79: 126–136, 1998. In a previous report, we described the visual response properties in the ventral intraparietal area (area VIP) of the awake macaqu... | 10.1038/nrn1684 | Two physiology papers showing that area LIP in the monkey IPS represents the target of a saccadic eye movement, even before the eye movement is performed, and even in the absence of a target stimulus. These data indicate that area LIP responses represent memory traces or attention to a specific target location, rather ... |
10.1126/science.1063695 | 103,802,258 | The internal organization of a higher level visual area in the human parietal cortex was mapped. Functional magnetic resonance images were acquired while the polar angle of a peripheral target for a delayed saccade was gradually changed. A region in the superior parietal cortex showed robust retinotopic mapping of the ... | 10.1038/nrn1684 | This fMRI study used delayed saccades to map out the eye-centred attention and memory responses in the IPS, which indicates a clear homology between monkey and human area LIP, which is involved in eye movements and attention. |
10.1126/science.1106138 | 103,770,694 | Inferior parietal lobule (IPL) neurons were studied when monkeys performed motor acts embedded in different actions and when they observed similar acts done by an experimenter. Most motor IPL neurons coding a specific act (e.g., grasping) showed markedly different activations when this act was part of different actions... | 10.1038/nrn2024 | This single-cell recording study of area PF of the macaque shows that mirror neurons do not simply code the observed action, but rather the intention associated with it, thereby predicting probable future actions. |
10.1126/science.286.5449.2526 | 104,255,806 | How does imitation occur? How can the motor plans necessary for imitating an action derive from the observation of that action? Imitation may be based on a mechanism directly matching the observed action onto an internal motor representation of that action (“direct matching hypothesis”). To test this hypothesis, normal... | 10.1038/nrn2024 | This fMRI study of imitation of hand actions shows that the human inferior frontal cortex (Broca's area) and rostral posterior parietal cortex have mirror neuron properties, showing activation during observation and execution of action, and increased activation during imitation. |
10.1046/j.1460-9568.2003.02530.x | 19,033,878 | Abstract The posterior sector of Broca's area (Brodmann area 44), a brain region critical for language, may have evolved from neurons active during observation and execution of manual movements. Imaging studies showing increased Broca's activity during execution, imagination, imitation and observation of hand movements... | 10.1038/nrn2024 | In this repetitive TMS study, a transient lesion induced in Broca's area caused imitative deficits. This study shows that the activation of Broca's area during imaging studies of imitation is not epiphenomenal, but rather causally related to imitation. |
10.1002/ana.20031 | 62,348,038 | Abstract Subjects with Asperger's syndrome (AS) are impaired in social interaction and imitation, but the underlying brain mechanisms are poorly understood. Because the mirror‐neuron system (MNS) that matches observed and executed actions has been suggested to play an important role in imitation and in reading of other... | 10.1038/nrn2024 | This MEG study shows that the temporal progression of activation in MNS areas is delayed in patients with Asperger's syndrome, suggesting a deficit of connectivity between these areas. |
10.1146/annurev.neuro.23.1.155 | 41,767,235 | The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisiti... | 10.1038/nrn3945 | A classic review that covers the seminal work on the role of the amygdala in fear conditioning. |
10.1126/science.1103944 | 26,805,432 | To elucidate molecular, cellular, and circuit changes that occur in the brain during learning, we investigated the role of a glutamate receptor subtype in fear conditioning. In this form of learning, animals associate two stimuli, such as a tone and a shock. Here we report that fear conditioning drives AMPA-type glutam... | 10.1038/nrn3945 | An early demonstration that AMPA receptor trafficking mediates fear memory formation. |
10.1126/science.1085818 | 100,684,581 | The amygdalohippocampal circuit plays a pivotal role in Pavlovian fear memory. We simultaneously recorded electrical activity in the lateral amygdala (LA) and the CA1 area of the hippocampus in freely behaving fear-conditioned mice. Patterns of activity were related to fear behavior evoked by conditioned and indifferen... | 10.1038/nrn3945 | An important contribution that establishes a role for synchronized oscillations between brain regions in fear conditioning. |
10.1126/science.2820058 | 20,316,314 | Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [ 3 H]mazindol bin... | 10.1038/nrn1008 | This paper related the effects of cocaine with dopamine transporter inhibition. |
10.1126/science.1975955 | 80,429,308 | A complementary DNA clone (designated GAT-1) encoding a transporter for the neurotransmitter γ-aminobutyric acid (GABA) has been isolated from rat brain, and its functional properties have been examined in Xenopus oocytes. Oocytes injected with GAT-1 synthetic messenger RNA accumulated [ 3 H]GABA to levels above contro... | 10.1038/nrn1008 | In references 18 and 19, the cloning of NET and the GABA transporter identified a new family of plasma membrane transporters, and provided the templates for the cloning of the related transporters DAT and SERT. |
10.1126/science.1948036 | 2,609,678 | A complementary DNA clone for a serotonin (5HT) transporter has been isolated from rat basophilic leukemia cells. The complementary DNA sequence predicts a 653-amino acid protein with 12 to 13 putative transmembrane domains. The 5HT transporter has significant homology to the γ-aminobutyric acid, dopamine, and norepine... | 10.1038/nrn1008 | In references 20–25, the cloning of DAT and SERT provided the starting point for structural, functional and genetic studies. |
10.1523/jneurosci.17-03-00960.1997 | 83,370,447 | Electrophysiological and pharmacological studies of a cloned human dopamine transporter (hDAT) were undertaken to investigate the mechanisms of transporter function and the actions of drugs at this target. Using two-electrode voltage-clamp techniques with hDAT-expressing Xenopus laevis oocytes, we show that hDAT can be... | 10.1038/nrn1008 | References 83–85 show that monoamine transporters are associated with conductances that are similar to ion channels. |
10.1126/science.285.5428.763 | 39,877,179 | Many psychotropic drugs interfere with the reuptake of dopamine, norepinephrine, and serotonin. Transport capacity is regulated by kinase-linked pathways, particularly those involving protein kinase C (PKC), resulting in transporter phosphorylation and sequestration. Phosphorylation and sequestration of the serotonin t... | 10.1038/nrn1008 | This paper shows that substrates of SERT, such as serotonin and amphetamine, blocked the PKC-dependent SERT internalization, providing a new mechanism through which the activity of SERT is regulated. |
10.1073/pnas.091039298 | 40,663,019 | Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial u... | 10.1038/nrn1008 | References 136 and 138 provide evidence that mechanisms other than DAT blockade might contribute to the rewarding properties of psychostimulants. |
10.1126/science.283.5400.397 | 122,405,769 | The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was... | 10.1038/nrn1008 | This study showed that in the absence of a functional DAT, psychostimulants can inhibit hyperactivity primarily through their actions with SERT. |
10.1126/science.274.5292.1527 | 103,816,661 | Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in... | 10.1038/nrn1008 | References 155 and 156 provided the initial suggestions that genetic variations in monoamine transporter genes might contribute to pathological conditions |
10.1126/science.288.5475.2379 | 38,418,338 | With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular treatment of mice with fatty acid synthase (FAS) inhibito... | 10.1038/nrn1245 | The original demonstration that FAS inibition potently reduces food intake and body weight. |
10.1073/pnas.1214696110 | 37,328,232 | Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulate... | 10.1038/nrn3381 | This study demonstrates that the G protein regulatory protein RGS4, acting in the NAc, promotes therapeutic-like responses to standard monoamine-dependent antidepressants. By contrast, RGS4 opposes the antidepressant-like actions of non-monoamine-based drugs such as ketamine. |
10.1073/pnas.95.11.6480 | 102,368,876 | Loss of neurotransmitter receptors, especially glutamate and dopamine receptors, is one of the pathologic hallmarks of brains of patients with Huntington disease (HD). Transgenic mice that express exon 1 of an abnormal human HD gene (line R6/2) develop neurologic symptoms at 9–11 weeks of age through an unknown mechani... | 10.1038/nrn1989 | The first study to show abnormal transcriptional regulation in HD. |
10.1073/pnas.100110097 | 62,614,496 | Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear functi... | 10.1038/nrn1989 | The first paper to implicate aberrant interactions between CBP and HTT in transcriptional repression in HD. |
10.1126/science.1056784 | 83,182,384 | Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted f... | 10.1038/nrn1989 | Highlights the implications of CBP in the pathogenic mechanism of polyglutamine repeat disease. |
10.1073/pnas.0437870100 | 81,577,360 | Huntington's disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view... | 10.1038/nrn1989 | The first published study of the use of an HDAC inhibitor as a therapeutic agent in a mouse model of HD. |
10.1126/science.1106036 | 38,257,200 | The degradation of undesirable cellular components or organelles, including invading microbes, by autophagy is crucial for cell survival. Here, Shigella , an invasive bacteria, was found to be able to escape autophagy by secreting IcsB by means of the type III secretion system. Mutant bacteria lacking IcsB were trapped... | 10.1038/nrmicro3160 | This work shows that some bacterial pathogens can avoid autophagy recognition by camouflaging themselves with effector proteins. |
10.1126/science.1227026 | 82,817,874 | Axing Autophagy When intracellular pathogens like Legionella pneumophila take up residence in mammalian host cells, they must combat the efforts of the host cell to attack them. Autophagy is a process by which cells digest their own constituents, often involved in response to starvation or pathogen attack. Choy et al. ... | 10.1038/nrmicro3160 | This study shows that a bacterial effector can directly uncouple the LC3–PE conjugation to inhibit autophagy. |
10.1126/science.1103966 | 41,644,611 | We found that the autophagic machinery could effectively eliminate pathogenic group A Streptococcus (GAS) within nonphagocytic cells. After escaping from endosomes into the cytoplasm, GAS became enveloped by autophagosome-like compartments and were killed upon fusion of these compartments with lysosomes. In autophagy-d... | 10.1038/nrmicro3160 | This is the first study to show that autophagy is an innate immune defence mechanism against an intracellular bacterial pathogen during natural infection. |
10.1073/pnas.1218674109 | 104,176,786 | Autophagy, a cytoplasmic catabolic process, plays a critical role in defense against intracellular infection. In turn, evasion or inhibition of autophagy has emerged as an important virulence factor for intracellular pathogens. However, Anaplasma phagocytophilum , the obligatory intracellular bacterium that causes huma... | 10.1038/nrmicro3160 | This study shows that a bacterial effector directly binds autophagy components to actively recruit the autophagosome to the bacteria-containing inclusions to promote bacterial replication. |
10.1126/science.275.5300.674 | 59,478,971 | The N -methyl-D-aspartate (NMDA) receptor mediates synaptic transmission and plasticity in the central nervous system (CNS) and is regulated by tyrosine phosphorylation. In membrane patches excised from mammalian central neurons, the endogenous tyrosine kinase Src was shown to regulate the activity of NMDA channels. Th... | 10.1038/nrn1368 | The authors show that endogenous Src upregulates the activity of NMDAR channels. They also find that the action of Src requires a sequence within the unique domain of Src (Src(40–58)) and that Src is a component of the NMDAR complex. |
10.1126/science.279.5355.1363 | 121,876,332 | Long-term potentiation (LTP) is an activity-dependent strengthening of synaptic efficacy that is considered to be a model of learning and memory. Protein tyrosine phosphorylation is necessary to induce LTP. Here, induction of LTP in CA1 pyramidal cells of rats was prevented by blocking the tyrosine kinase Src, and Src ... | 10.1038/nrn1368 | This paper presents evidence that Src activation is necessary and sufficient for the induction of LTP in CA1 pyramidal neurons in hippocampal slices. LTP induction is prevented by blocking Src and occluded by directly activating Src. Src activity is increased in CA1 hippocampal slices after tetanic stimulation of Schaf... |
10.1073/pnas.91.9.3954 | 16,765,211 | The postsynaptic density (PSD) is a specialization of the submembranous cytoskeleton that is visible in the electron microscope on the cytoplasmic face of the postsynaptic membrane. A subcellular fraction enriched in structures with the morphology of PSDs contains signal-transduction molecules thought to regulate recep... | 10.1038/nrn1368 | This paper is the first to report tyrosine phosphorylation of an NR2 subunit, namely NR2B. The results indicate that NMDAR function might be regulated by tyrosine phosphorylation of a receptor subunit protein and/or that NMDARs participate in signalling through tyrosine phosphorylation. |
10.1126/science.1065983 | 102,472,461 | Protein-protein interactions and calcium entry through the N -methyl- d -aspartate (NMDA)–type glutamate receptor regulate synaptic development and plasticity in the central nervous system. The EphB receptor tyrosine kinases are localized at excitatory synapses where they cluster and associate with NMDA receptors. We i... | 10.1038/nrn1368 | This is the first report of a receptor protein tyrosine kinase pathway upstream of NMDAR potentiation by SFKs. Activation of EphB receptors results in increased NMDAR-dependent Ca 2+ responses and tyrosine phosphorylation of NR2B subunits. SFK activation is necessary for the EphB-mediated NR2B phosphorylation. |
10.1523/jneurosci.23-25-08692.2003 | 125,207,340 | Interleukin (IL)-1β is a proinflammatory cytokine implicated in various pathophysiological conditions of the CNS involving NMDA receptor activation. Circumstantial evidence suggests that IL-1β and NMDA receptors can functionally interact. Using primary cultures of rat hippocampal neurons, we investigated whether IL-1β ... | 10.1038/nrn1368 | Activation of IL-1RI enhances NMDAR-mediated Ca 2+ responses in cultured hippocampal neurons and this is prevented by SFK inhibition. SFKs do not directly facilitate IL-1RI-mediated signal transduction and thus the IL-1RI pathway is upstream of SFK activity. |
10.1073/pnas.140219097 | 16,752,432 | Members of the Src family of nonreceptor protein tyrosine kinases (PTKs) have been implicated in the regulation of cellular excitability and synaptic plasticity. We have investigated the role of these PTKs in in vitro models of epileptiform activity. Spontaneous epileptiform discharges were induced in vitro in the CA3 ... | 10.1038/nrn1368 | This paper shows that Src kinase activity is increased in an in vitro model of epileptiform activity in the CA3 region of hippocampal slices. The frequency of epileptiform discharges is reduced by inhibition of SFKs, consistent with a role for SFKs in epilepsy. |
10.1098/rstb.1998.0333 | 86,243,960 | Figures that can be seen in more than one way are invaluable tools for the study of the neural basis of visual awareness, because such stimuli permit the dissociation of the neural responses that underlie what we perceive at any given time from those forming the sensory representation of a visual pattern. To study the ... | 10.1038/nrn701 | Overview of psychophysical and neurophysiological work on rivalry, with emphasis on converging lines of evidence that implicate higher visual areas as the site of rivalry. |
10.1098/rstl.1838.0019 | 62,546,087 | When an object is viewed at so great a distance that the optic axes of both eyes are sensibly parallel when directed towards it, the perspective projections of it, seen by each eye separately, are similar, and the appearance to the two eyes is precisely the same as when the object is seen by one eye only. There is, in ... | 10.1038/nrn701 | Classic monograph providing systematic accounts of stereopsis and binocular rivalry. |
10.1126/science.280.5371.1930 | 102,372,685 | When dissimilar images are presented to the two eyes, perception alternates spontaneously between each monocular view, a phenomenon called binocular rivalry. Functional brain imaging in humans was used to study the neural basis of these subjective perceptual changes. Cortical regions whose activity reflected perceptual... | 10.1038/nrn701 | First of several recent brain-imaging studies reporting fluctuations in BOLD signal coincident with fluctuations in rivalry state. See also references 75 76 and 78 |
10.1126/science.2772635 | 16,676,625 | Neuronal activity in the superior temporal sulcus of monkeys, a cortical region that plays an important role in analyzing visual motion, was related to the subjective perception of movement during a visual task. Single neurons were recorded while monkeys ( Macaca mulatta ) discriminated the direction of motion of stimu... | 10.1038/nrn701 | First in a series of influential papers recording single-unit activity from alert monkeys experiencing binocular rivalry. See also references 86 and 89 |
10.1126/scitranslmed.3007529 | 60,985,366 | Antisense oligonucleotides can correct disease-specific phenotypes in cultured motor neurons differentiated from iPSCs derived from ALS patients with a C9ORF72 repeat expansion. | 10.1038/nrn.2016.38 | This paper describes altered transcription of C9orf72 in iPSC-derived motor neurons expressing the expanded allele and the correction of these defects with ASOs. |
10.1073/pnas.1318835110 | 62,501,024 | Significance The most frequent genetic cause of ALS and frontotemporal degeneration is a hexanucleotide expansion in a noncoding region of the C9orf72 gene. Similar to other repeat expansion diseases, we characterize the hallmark feature of repeat expansion RNA-mediated toxicity: nuclear RNA foci. Remarkably, two disti... | 10.1038/nrn.2016.38 | This study reveals the presence of (C 4 G 2 ) RNA foci in ALS and FTD and shows that antisense knockdown of C9orf72 in the adult rodent does not induce neurodegeneration. |
10.1126/science.1256800 | 83,447,812 | Dipeptide repeat peptides on the attack Certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are associated with expanded dipeptides translated from RNA transcripts of disease-associated genes (see the Perspective by West and Gitler). Kwon et al. show that the peptides encoded by the expan... | 10.1038/nrn.2016.38 | This paper reports that selected RAN translation peptides, when overexpressed in fly, can be neurotoxic. |
10.1073/pnas.1219643110 | 80,893,668 | Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we develop... | 10.1038/nrn.2016.38 | The first study to show that (G 4 C 2 ) RNA expression in Drosophila is neurotoxic. |
10.1126/science.aaa9344 | 83,451,006 | A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneratio... | 10.1038/nrn.2016.38 | This report shows that adeno-associated virus-mediated overexpression of (G 4 C 2 ) RNA in rodent brain causes RNA foci, generates RANT products and induces neurodegeneration. |
10.1126/science.aab0983 | 83,414,621 | Mechanistic surprise in ALS-FTD Intense efforts have focused on identifying therapeutic targets for misfolded proteins that cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ling et al. show that the main culprit of proteinopathy, TDP-43, acts as a splicing suppressor of nonconserved cryptic ex... | 10.1038/nrn.2016.38 | This paper reports that loss of TDP43 enhances the presence of cryptic exons. |
10.1126/science.1114037 | 41,702,572 | Hippocampal neurons were recorded under conditions in which the recording chamber was varied but its location remained unchanged versus conditions in which an identical chamber was encountered in different places. Two forms of neuronal pattern separation occurred. In the variable cue-constant place condition, the firin... | 10.1038/nrn1932 | Evidence that hippocampal place cells can simultaneously transmit information about the location and content of an experience. |
10.1162/jocn.1991.3.2.190 | 20,492,384 | Behavioral and neurophysiological evidence strongly suggests that, within certain limits, rodents and humans can keep track of their directional heading relative to an inertial, and hence allocentric coordinate system. This “sense of direction” appears to involve the integration of angular velocity signals that arise p... | 10.1038/nrn1932 | An early version of the head direction path integrator model which formed the conceptual basis of subsequent continuous attractor models for path integration. |
10.1162/neco_a_00087 | 57,151,530 | The pattern of spikes recorded from place cells in the rodent hippocampus is strongly modulated by both the spatial location in the environment and the theta rhythm. The phases of the spikes in the theta cycle advance during movement through the place field. Recently intracellular recordings from hippocampal neurons (H... | 10.1038/nrn1932 | One of the first papers to advance the concept of a system of continuous attractors. |
10.1126/science.8351520 | 103,640,479 | Ensemble recordings of 73 to 148 rat hippocampal neurons were used to predict accurately the animals' movement through their environment, which confirms that the hippocampus transmits an ensemble code for location. In a novel space, the ensemble code was initially less robust but improved rapidly with exploration. Duri... | 10.1038/nrn1932 | Modern empirical understanding of hippocampal neurodynamics is strongly aided by the ability to record simultaneously from many neurons in the freely behaving animal, for which this paper was a landmark. |
10.1126/science.1099901 | 125,076,956 | As the interface between hippocampus and neocortex, the entorhinal cortex is likely to play a pivotal role in memory. To determine how information is represented in this area, we measured spatial modulation of neural activity in layers of medial entorhinal cortex projecting to the hippocampus. Close to the postrhinal-e... | 10.1038/nrn1932 | Preceding the discovery of grid cells, this study reports that spatial position is represented accurately among ensembles of principal neurons in superficial layers of the MEC. The scale of representation increases along the dorsoventral axis of the MEC. |
10.1126/science.1125572 | 103,833,149 | Grid cells in the medial entorhinal cortex (MEC) are part of an environment-independent spatial coordinate system. To determine how information about location, direction, and distance is integrated in the grid-cell network, we recorded from each principal cell layer of MEC in rats that explored two-dimensional environm... | 10.1038/nrn1932 | Reports the discovery of head direction cells and cells with conjunctive grid and head direction properties in separate layers of the MEC. |
10.1002/hipo.10144 | 82,156,922 | Abstract Neurons providing connections between the deep and superficial layers of the entorhinal cortex (EC) constitute a pivotal link in the network underlying reverberation and gating of neuronal activity in the entorhinal‐hippocampal system. To learn more of these deep‐to‐superficial neurons and their targets, we ap... | 10.1038/nrn1932 | Provides direct electron microscopic evidence for synaptic interactions between cells in deep and superficial layers of the MEC. |
10.1002/hipo.450010207 | 62,034,926 | Abstract Understanding the empirical rules that regulate alterations of hippocampal firing fields will enhance our understanding of hippocampal function. The current study sought to extend previous research in this area by examining the effect of substituting a new stimulus for a familiar stimulus in a familiar environ... | 10.1038/nrn1932 | The first systematic report of remapping in hippocampal place cells. |
10.1002/hipo.20114 | 83,347,119 | Abstract Spatial scaling of place specific activity in the hippocampus varies systematically from the septal pole (high resolution) to the temporal pole (low resolution). Place fields get progressively larger, and the probability of observing a field in a given environment gets progressively smaller. It was previously ... | 10.1038/nrn1932 | Suggests that the increase in spatial scale along the dorsoventral axis of the hippocampus is accompanied by a systematic reduction in the gain of self-motion signals to the hippocampus. |
10.1098/rspb.1980.0051 | 4,756,463 | The paper describes a model of competition that explains the formation of the ocular dominance stripes found in layer IVc of cat and monkey visual cortex. The main proposal is that synapses exert effects on the growth of other synapses, and that these effects extend over distances of at least 600 μm and vary in magnitu... | 10.1038/nrn1932 | A neuronal model for the development of ocular dominance columns based on short-range excitation and long-range inhibition is proposed. The conceptual resemblance to Turing's theory is pointed out. |
10.1126/science.290.5500.2319 | 20,872,408 | Scientists working with large volumes of high-dimensional data, such as global climate patterns, stellar spectra, or human gene distributions, regularly confront the problem of dimensionality reduction: finding meaningful low-dimensional structures hidden in their high-dimensional observations. The human brain confront... | 10.1038/nrn1932 | A method for the visualization of metric and topological structure in high-dimensional data sets starting from distance information. |
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/nrn.2017.30 | This paper illustrated the developmental origins and dependence on Dlx genes of cortical interneurons from the ventral telencephalon. |
10.1073/pnas.1012994108 | 123,002,001 | Elongation factor 4 (EF4) is one of the most conserved proteins present in bacteria as well as in mitochondria and chloroplasts of eukaryotes. Although EF4 has the unique ability to catalyze the back-translocation reaction on posttranslocation state ribosomes, the physiological role of EF4 remains unclear. Here we demo... | 10.1038/nrmicro3176 | An in vivo and in vitro study suggesting that EF4 rescues stalled ribosomes. |
10.1073/pnas.1103820108 | 122,281,785 | EF4 (LepA), a strongly conserved protein, is important for bacterial growth and functional protein biosynthesis under certain conditions and is quite similar structurally to the translocase EF-G. The elongation cycle in protein synthesis is characterized by ribosome oscillation between pretranslocation (PRE) and posttr... | 10.1038/nrmicro3176 | This study suggests that the PRE-state is the preferential target for EF4. |
10.1126/science.1179709 | 38,301,948 | Ribosomes Caught in Translation To synthesize proteins, the ribosome must select cognate transfer RNAs (tRNAs) based on base-pairing with the messenger RNA (mRNA) template (a process known as decoding), form a peptide bond, and then move the mRNA:tRNA assembly relative to the ribosome (a process known as translocation)... | 10.1038/nrmicro3176 | This paper shows the crystal structure of an EF-G–70S complex in the POST-state. |
10.1126/science.1117230 | 62,253,505 | We describe two structures of the intact bacterial ribosome from Escherichia coli determined to a resolution of 3.5 angstroms by x-ray crystallography. These structures provide a detailed view of the interface between the small and large ribosomal subunits and the conformation of the peptidyl transferase center in the ... | 10.1038/nrmicro3176 | This paper reports the first crystal structure of an E. coli ribosome and also demonstrates the closure of the A790 gate. |
10.1126/science.1236086 | 62,479,628 | Translocation of messenger and transfer RNA (mRNA and tRNA) through the ribosome is a crucial step in protein synthesis, whose mechanism is not yet understood. The crystal structures of three Thermus ribosome-tRNA-mRNA–EF-G complexes trapped with β,γ-imidoguanosine 5′-triphosphate (GDPNP) or fusidic acid reveal conform... | 10.1038/nrmicro3176 | This paper reports the crystal structure of a translocation intermediate showing 16S rRNA bases C1397 and A1503 intercalating with the mRNA, thereby preventing back-translocation. |
10.1101/gad.1696108 | 103,791,666 | Introns may affect gene expression by increasing the time required to transcribe the gene. One way for extended transcription times to affect the behavior of a gene expression program is through a negative feedback loop. Here, we show that a logically engineered negative feedback loop in animal cells produces expressio... | 10.1038/nsmb.3320 | Generation of oscillations by using a negative feedback with a tunable time delay mediated by intron length |
10.1126/science.aaa3794 | 19,179,243 | Engineering cell population behavior Attaining the full promise of synthetic biology will require designing population-level behaviors of multiple interacting cell types. As a start, Chen et al. engineered two strains of the bacterium Escherichia coli to produce signaling molecules that regulate transcription in the co... | 10.1038/nsmb.3320 | Robust synchronized population-level oscillations in synthetic bacterial consortia, based on the positive and negative feedback between two strains |
10.1126/science.1109173 | 61,733,831 | Using an active approach to preventing biofilm formation, we implemented a microfluidic bioreactor that enables long-term culture and monitoring of extremely small populations of bacteria with single-cell resolution. We used this device to observe the dynamics of Escherichia coli carrying a synthetic “population contro... | 10.1038/nsmb.3320 | Cell-cell communication is used to couple gene expression with growth dynamics to create a population that controls its own density, thus resulting in oscillations in overall cell density |
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