Showing papers in "Nature Reviews Neuroscience in 2004"
TL;DR: Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.
Abstract: The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.
3,012 citations
TL;DR: This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
Abstract: Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
2,854 citations
TL;DR: Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure.
Abstract: After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.
2,838 citations
TL;DR: Evidence is discussed from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development, and how these processes maintain stable activity states in the face of destabilizing forces is discussed.
Abstract: Activity has an important role in refining synaptic connectivity during development, in part through 'Hebbian' mechanisms such as long-term potentiation and long-term depression. However, Hebbian plasticity is probably insufficient to explain activity-dependent development because it tends to destabilize the activity of neural circuits. How can complex circuits maintain stable activity states in the face of such destabilizing forces? An idea that is emerging from recent work is that average neuronal activity levels are maintained by a set of homeostatic plasticity mechanisms that dynamically adjust synaptic strengths in the correct direction to promote stability. Here we discuss evidence from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development.
2,315 citations
TL;DR: The emerging view is that cerebroVascular dysregulation is a feature not only of cerebrovascular pathologies, such as stroke, but also of neurodegenerative conditions, suchas Alzheimer's disease.
Abstract: The structural and functional integrity of the brain depends on the delicate balance between substrate delivery through blood flow and energy demands imposed by neural activity. Complex cerebrovascular control mechanisms ensure that active brain regions receive an adequate amount of blood, but the nature of these mechanisms remains elusive. Recent findings implicate perivascular neurons, gliovascular interactions and intramural vascular signalling in the control of the cerebral microcirculation. Neurons, astrocytes and vascular cells seem to constitute a functional unit, the primary purpose of which is to maintain the homeostasis of the brain's microenvironment. Alterations of these vascular regulatory mechanisms lead to brain dysfunction and disease. The emerging view is that cerebrovascular dysregulation is a feature not only of cerebrovascular pathologies, such as stroke, but also of neurodegenerative conditions, such as Alzheimer's disease.
2,055 citations
TL;DR: Much remains unknown about how normal ageing affects the neural basis of cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from pathological origins of age-related cognitive changes.
Abstract: As we grow older, we may grow wiser, but we can also experience memory loss and cognitive slowing that can interfere with our daily routines. The cognitive neuroscience of human ageing, which relies largely on neuroimaging techniques, relates these cognitive changes to their neural substrates, including structural and functional changes in the prefrontal cortex, medial temporal lobe regions and white matter tracts. Much remains unknown about how normal ageing affects the neural basis of cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from pathological origins of age-related cognitive changes.
2,010 citations
TL;DR: New data show that infants use computational strategies to detect the statistical and prosodic patterns in language input, and that this leads to the discovery of phonemes and words.
Abstract: Infants learn language with remarkable speed, but how they do it remains a mystery. New data show that infants use computational strategies to detect the statistical and prosodic patterns in language input, and that this leads to the discovery of phonemes and words. Social interaction with another human being affects speech learning in a way that resembles communicative learning in songbirds. The brain's commitment to the statistical and prosodic patterns that are experienced early in life might help to explain the long-standing puzzle of why infants are better language learners than adults. Successful learning by infants, as well as constraints on that learning, are changing theories of language acquisition.
1,818 citations
TL;DR: As you drive into the centre of town, cars and trucks approach from several directions, and pedestrians swarm into the intersection, the wind blows a newspaper into the gutter and a pigeon does something unexpected on your windshield.
Abstract: As you drive into the centre of town, cars and trucks approach from several directions, and pedestrians swarm into the intersection. The wind blows a newspaper into the gutter and a pigeon does something unexpected on your windshield. This would be a demanding and stressful situation, but you would probably make it to the other side of town without mishap. Why is this situation taxing, and how do you cope?
1,658 citations
TL;DR: By studying the accumulation and cellular distribution of iron during ageing, this work should be able to increase the understanding of these neurodegenerative disorders and develop new therapeutic strategies.
Abstract: There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by Alzheimer's disease and Parkinson's disease. High concentrations of reactive iron can increase oxidative-stress induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endogenous toxins. By studying the accumulation and cellular distribution of iron during ageing, we should be able to increase our understanding of these neurodegenerative disorders and develop new therapeutic strategies.
1,644 citations
TL;DR: PDZ domains are protein-interaction domains that are often found in multi-domain scaffolding proteins that function in the dynamic trafficking of synaptic proteins by assembling cargo complexes for transport by molecular motors.
Abstract: PDZ domains are protein-interaction domains that are often found in multi-domain scaffolding proteins. PDZ-containing scaffolds assemble specific proteins into large molecular complexes at defined locations in the cell. In the postsynaptic density of neuronal excitatory synapses, PDZ proteins such as PSD-95 organize glutamate receptors and their associated signalling proteins and determine the size and strength of synapses. PDZ scaffolds also function in the dynamic trafficking of synaptic proteins by assembling cargo complexes for transport by molecular motors. As key organizers that control synaptic protein composition and structure, PDZ scaffolds are themselves highly regulated by synthesis and degradation, subcellular distribution and post-translational modification.
1,572 citations
TL;DR: Building on previous findings, the knowledge that is available is reviewed, specific mechanisms for the contextual facilitation of object recognition are proposed, and important open questions are highlighted.
Abstract: We see the world in scenes, where visual objects occur in rich surroundings, often embedded in a typical context with other related objects. How does the human brain analyse and use these common associations? This article reviews the knowledge that is available, proposes specific mechanisms for the contextual facilitation of object recognition, and highlights important open questions. Although much has already been revealed about the cognitive and cortical mechanisms that subserve recognition of individual objects, surprisingly little is known about the neural underpinnings of contextual analysis and scene perception. Building on previous findings, we now have the means to address the question of how the brain integrates individual elements to construct the visual experience.
TL;DR: This work has reported the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity in the adult brain.
Abstract: The mitogen-activated protein kinase (MAPK) cascade that leads to the activation of extracellular signal-regulated kinases-1 and -2 (ERK1 and ERK2) has a key role in the differentiation of some cell types and the proliferation of others. However, several recent reports implicate this cascade in the control of synaptic plasticity in the adult brain. ERK signalling seems to be essential for characterized neuronal transcriptional events, and might also regulate synaptic targets to control plasticity. Another recently emerging story is the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity.
TL;DR: Recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning provide evidence that theateral amygdala is a crucial locus of fear memory.
Abstract: The learning and remembering of fearful events depends on the integrity of the amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we review recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies that combine unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex. Understanding the signalling of aversive memory by amygdala neurons opens new avenues for research into the neural systems that support fear behaviour.
TL;DR: Recent neurophysiological evidence is described demonstrating the presence of this inhibitory function in single-cell activity in the frontal eye fields and superior colliculus in patients diagnosed with various neurological and/or psychiatric disorders that affect the frontal lobes or basal ganglia.
Abstract: The anti-saccade task has emerged as an important task for investigating the flexible control that we have over behaviour. In this task, participants must suppress the reflexive urge to look at a visual target that appears suddenly in the peripheral visual field and must instead look away from the target in the opposite direction. A crucial step involved in performing this task is the top-down inhibition of a reflexive, automatic saccade. Here, we describe recent neurophysiological evidence demonstrating the presence of this inhibitory function in single-cell activity in the frontal eye fields and superior colliculus. Patients diagnosed with various neurological and/or psychiatric disorders that affect the frontal lobes or basal ganglia find it difficult to suppress the automatic pro-saccade, revealing a deficit in top-down inhibition.
TL;DR: Current studies of fixational eye movements have focused on determining how visible perception is encoded by neurons in various visual areas of the brain to elucidate how the brain makes the authors' environment visible.
Abstract: Our eyes continually move even while we fix our gaze on an object. Although these fixational eye movements have a magnitude that should make them visible to us, we are unaware of them. If fixational eye movements are counteracted, our visual perception fades completely as a result of neural adaptation. So, our visual system has a built-in paradox — we must fix our gaze to inspect the minute details of our world, but if we were to fixate perfectly, the entire world would fade from view. Owing to their role in counteracting adaptation, fixational eye movements have been studied to elucidate how the brain makes our environment visible. Moreover, because we are not aware of these eye movements, they have been studied to understand the underpinnings of visual awareness. Recent studies of fixational eye movements have focused on determining how visible perception is encoded by neurons in various visual areas of the brain.
TL;DR: The results indicate a specific role for this region in integrating the outcomes of two or more separate cognitive operations in the pursuit of a higher behavioural goal.
Abstract: The anterior prefrontal cortex (aPFC), or Brodmann area 10, is one of the least well understood regions of the human brain. Work with non-human primates has provided almost no indications as to the function of this area. In recent years, investigators have attempted to integrate findings from functional neuroimaging studies in humans to generate models that might describe the contribution that this area makes to cognition. In all cases, however, such explanations are either too tied to a given task to be plausible or too general to be theoretically useful. Here, we use an account that is consistent with the connectional and cellular anatomy of the aPFC to explain the key features of existing models within a common theoretical framework. The results indicate a specific role for this region in integrating the outcomes of two or more separate cognitive operations in the pursuit of a higher behavioural goal.
TL;DR: The authors' eyes send different 'images' of the outside world to the brain — an image of contours (line drawing), a colour image (watercolour painting) or a image of moving objects (movie) — and circuits that involve complex inhibitory and excitatory interactions represent filters that select 'what the eye tells the brain'.
Abstract: Our eyes send different 'images' of the outside world to the brain - an image of contours (line drawing), a colour image (watercolour painting) or an image of moving objects (movie). This is commonly referred to as parallel processing, and starts as early as the first synapse of the retina, the cone pedicle. Here, the molecular composition of the transmitter receptors of the postsynaptic neurons defines which images are transferred to the inner retina. Within the second synaptic layer - the inner plexiform layer - circuits that involve complex inhibitory and excitatory interactions represent filters that select 'what the eye tells the brain'.
TL;DR: The subtle biophysical modifications in channel behaviour that are induced by AEDs are often functionally opposite to defects in channel properties that are caused by mutations associated with epilepsy in humans.
Abstract: Antiepileptic drugs (AEDs) provide satisfactory control of seizures for most patients with epilepsy. The drugs have the remarkable ability to protect against seizures while permitting normal functioning of the nervous system. AEDs act on diverse molecular targets to selectively modify the excitability of neurons so that seizure-related firing is blocked without disturbing non-epileptic activity. This occurs largely through effects on voltage-gated sodium and calcium channels, or by promoting inhibition mediated by GABAA (γ-aminobutyric acid, type A) receptors. The subtle biophysical modifications in channel behaviour that are induced by AEDs are often functionally opposite to defects in channel properties that are caused by mutations associated with epilepsy in humans.
TL;DR: Insight into how these receptors are rapidly moved into and out of synaptic membranes has profound implications for the understanding of the mechanisms of long-term potentiation and long- term depression.
Abstract: Long-term potentiation and long-term depression are processes that have been widely studied to understand the molecular basis of information storage in the brain. Glutamate receptors are required for the induction and expression of these forms of plasticity, and GABA (γ-aminobutyric acid) receptors are involved in their modulation. Recent insights into how these receptors are rapidly moved into and out of synaptic membranes has profound implications for our understanding of the mechanisms of long-term potentiation and long-term depression.
TL;DR: Optimal feedback control theory might provide the important link across these levels of the motor system and help to unravel how the primary motor cortex and other regions of the brain plan and control movement.
Abstract: Skilled motor behaviour, from the graceful leap of a ballerina to a precise pitch by a baseball player, appears effortless but reflects an intimate interaction between the complex mechanical properties of the body and control by a highly distributed circuit in the CNS An important challenge for understanding motor function is to connect these three levels of the motor system — motor behaviour, limb mechanics and neural control Optimal feedback control theory might provide the important link across these levels of the motor system and help to unravel how the primary motor cortex and other regions of the brain plan and control movement
TL;DR: Rapid changes in cytoskeletal and adhesion molecules after learning contribute to short-term plasticity and memory, whereas later changes, which depend on de novo protein synthesis as well as the early modifications, seem to be required for the persistence of long-term memory.
Abstract: Much evidence indicates that, after learning, memories are created by alterations in glutamate-dependent excitatory synaptic transmission. These modifications are then actively stabilized, over hours or days, by structural changes at postsynaptic sites on dendritic spines. The mechanisms of this structural plasticity are poorly understood, but recent findings are beginning to provide clues. The changes in synaptic transmission are initiated by elevations in intracellular calcium and consequent activation of second messenger signalling pathways in the postsynaptic neuron. These pathways involve intracellular kinases and GTPases, downstream from glutamate receptors, that regulate and coordinate both cytoskeletal and adhesion remodelling, leading to new synaptic connections. Rapid changes in cytoskeletal and adhesion molecules after learning contribute to short-term plasticity and memory, whereas later changes, which depend on de novo protein synthesis as well as the early modifications, seem to be required for the persistence of long-term memory.
TL;DR: There is growing evidence that the state of the circuit is determined by aversive and appetitive motivational states, and that this contributes to adaptive behavioural choice.
Abstract: Agonists for the μ-opioid receptor are powerful analgesics and are highly addictive; however, the contribution of the δ- and κ-opioid and opioid receptor-like receptors to motivational states is less clear. Agonists at each receptor modulate neurons in a circuit that selectively controls nociceptive transmission. This circuit can operate in both pain-inhibiting and pain-facilitating states, and the action of opioids contributes to and is determined by the state of the circuit. There is growing evidence that the state of the circuit is determined by aversive and appetitive motivational states, and that this contributes to adaptive behavioural choice.
TL;DR: The neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics are described and how the function of individual drug targets, in particular GABAA-receptor subtypes, can be revealed by genetic studies in vivo is discussed.
Abstract: Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABA(A)-receptor subtypes, can be revealed by genetic studies in vivo.
TL;DR: In the central nervous system, synaptic strength is regulated partly by changes in the function and number of postsynaptic glutamate receptors, and members of the Src family of protein tyrosine kinases upregulate NMDAR function, thereby gating the production of N MDAR-dependent synaptic potentiation.
Abstract: In the central nervous system, synaptic strength is regulated partly by changes in the function and number of postsynaptic glutamate receptors. The NMDA (N-methyl-D-aspartate) subtype of glutamate receptor (NMDAR) is regulated in part by the opposing actions of protein tyrosine kinases and phosphotyrosine phosphatases. Members of the Src family of protein tyrosine kinases upregulate NMDAR function, thereby gating the production of NMDAR-dependent synaptic potentiation. Src family kinases (SFKs) are a crucial point of convergence for signalling pathways that enhance NMDAR activity, so that SFKs act as a molecular hub for the control of NMDARs. These kinases regulate synaptic strength and are therefore vital for processes that underlie physiological and pathological plasticity in the brain and spinal cord.
TL;DR: In this article, a targeted expression of the green fluorescent protein in chemosensory cells is proposed to characterize receptor-ligand interactions, which is a promising approach to achieve this objective.
Abstract: The chemical senses (smell and taste) have evolved complex repertoires of chemosensory receptors — G-protein coupled receptors with a seven-transmembrane domain structure. In the mouse, ∼1,000 odorant receptors are dedicated to the conventional sense of smell, ∼300 vomeronasal receptors mediate the detection of chemical stimuli (such as pheromones) by the vomeronasal organ, and ∼40 taste receptors are implicated in bitter, sweet and umami taste. Nearly all receptor genes have now been identified as the result of genome sequencing, but few receptor–ligand interactions have been characterized. Targeted expression of the green fluorescent protein in chemosensory cells is a promising approach to achieve this objective.
TL;DR: Although the lesion method has important weaknesses, it is argued that it complements the newer activation methods (and their weaknesses).
Abstract: Recent technological advances, such as functional imaging techniques, allow neuroscientists to measure and localize brain activity in healthy individuals. These techniques avoid many of the limitations of the traditional method for inferring brain function, which relies on examining patients with brain lesions. This has fueled the zeitgeist that the classical lesion method is an inferior and perhaps obsolescent technique. However, although the lesion method has important weaknesses, we argue that it complements the newer activation methods (and their weaknesses). Furthermore, recent developments can address many of the criticisms of the lesion method. Patients with brain lesions provide a unique window into brain function, and this approach will fill an important niche in future research.
TL;DR: The developmental generation of dendritic spines is reviewed, covering recent live imaging experiments and older ultrastructural data, and the potential role of dendedritic filopodia in spine development and recent findings of spinogenesis in adult animals are addressed.
Abstract: Dendritic spines are small protrusions from many types of neuron, which receive most of the excitatory inputs to the cell. Spines are thought to have important roles in neural information processing and plasticity, yet we still have a poor understanding of how they emerge during development. Here, we review the developmental generation of dendritic spines, covering recent live imaging experiments and older ultrastructural data. We address the potential role of dendritic filopodia in spine development and recent findings of spinogenesis in adult animals, and conclude by discussing three potential models of spinogenesis.
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TL;DR: The past 30 years have witnessed an explosion of research in affective neuroscience that has addressed questions such as: which brain systems underlie emotions and how do differences in these systems relate to differences in the emotional experience of individuals.
Abstract: The discipline of affective neuroscience is concerned with the neural bases of emotion and mood. The past 30 years have witnessed an explosion of research in affective neuroscience that has addressed questions such as: which brain systems underlie emotions? How do differences in these systems relate to differences in the emotional experience of individuals? Do different regions underlie different emotions, or are all emotions a function of the same basic brain circuitry? How does emotion processing in the brain relate to bodily changes associated with emotion? And, how does emotion processing in the brain interact with cognition, motor behaviour, language and motivation?
TL;DR: Imaging based on voltage-sensitive dyes (VSDI) offers the highest spatial and temporal resolution for imaging neocortical functions in the living brain, and has paved the way for a new era in the functional imaging of cortical dynamics.
Abstract: During the last few decades, neuroscientists have benefited from the emergence of many powerful functional imaging techniques that cover broad spatial and temporal scales. We can now image single molecules controlling cell differentiation, growth and death; single cells and their neurites processing electrical inputs and sending outputs; neuronal circuits performing neural computations in vitro; and the intact brain. At present, imaging based on voltage-sensitive dyes (VSDI) offers the highest spatial and temporal resolution for imaging neocortical functions in the living brain, and has paved the way for a new era in the functional imaging of cortical dynamics. It has facilitated the exploration of fundamental mechanisms that underlie neocortical development, function and plasticity at the fundmental level of the cortical column.
TL;DR: The data that have emerged from in vivo hippocampal recording studies that indicate that the activity of hippocampal place cells during behaviour is an expression of a memory trace are discussed.
Abstract: N-methyl-D-aspartate receptors (NMDARs) in the rodent hippocampus have been shown to be essential for spatial learning and memory, and for the induction of long-term synaptic plasticity at various hippocampal synapses. In this review, we examine the evidence concerning the role of NMDARs in hippocampal memory processes, with an emphasis on the function of NMDARs in area CA1 of the hippocampus in memory acquisition, and the unique role of NMDARs in area CA3 in the rapid acquisition and associative retrieval of spatial information. Finally, we discuss the data that have emerged from in vivo hippocampal recording studies that indicate that the activity of hippocampal place cells during behaviour is an expression of a memory trace.