Showing papers in "Nature Reviews Neuroscience in 2007"
TL;DR: Recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity are reviewed.
Abstract: The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease.
6,135 citations
TL;DR: A dual-stream model of speech processing is outlined that assumes that the ventral stream is largely bilaterally organized — although there are important computational differences between the left- and right-hemisphere systems — and that the dorsal stream is strongly left- Hemisphere dominant.
Abstract: Despite decades of research, the functional neuroanatomy of speech processing has been difficult to characterize. A major impediment to progress may have been the failure to consider task effects when mapping speech-related processing systems. We outline a dual-stream model of speech processing that remedies this situation. In this model, a ventral stream processes speech signals for comprehension, and a dorsal stream maps acoustic speech signals to frontal lobe articulatory networks. The model assumes that the ventral stream is largely bilaterally organized--although there are important computational differences between the left- and right-hemisphere systems--and that the dorsal stream is strongly left-hemisphere dominant.
4,234 citations
TL;DR: Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
Abstract: Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
3,511 citations
TL;DR: A patient with semantic dementia — a neurodegenerative disease that is characterized by the gradual deterioration of semantic memory — was being driven through the countryside to visit a friend and was able to remind his wife where to turn along the not-recently-travelled route.
Abstract: Mr M, a patient with semantic dementia - a neurodegenerative disease that is characterized by the gradual deterioration of semantic memory - was being driven through the countryside to visit a friend and was able to remind his wife where to turn along the not-recently-travelled route. Then, pointing at the sheep in the field, he asked her "What are those things?" Prior to the onset of symptoms in his late 40s, this man had normal semantic memory. What has gone wrong in his brain to produce this dramatic and selective erosion of conceptual knowledge?
2,237 citations
TL;DR: This Review summarizes the most recent advances in knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those t Tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
Abstract: Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
1,955 citations
TL;DR: Experimental analysis in the hippocampus and the neocortex and computational analysis suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.
Abstract: Gamma frequency oscillations are thought to provide a temporal structure for information processing in the brain. They contribute to cognitive functions, such as memory formation and sensory processing, and are disturbed in some psychiatric disorders. Fast-spiking, parvalbumin-expressing, soma-inhibiting interneurons have a key role in the generation of these oscillations. Experimental analysis in the hippocampus and the neocortex reveals that synapses among these interneurons are highly specialized. Computational analysis further suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.
1,916 citations
TL;DR: It is suggested that processes such as memory can be productively re-conceptualized in light of the concept of the prospective brain, an idea that a crucial function of the brain is to use stored information to imagine, simulate and predict possible future events.
Abstract: A rapidly growing number of recent studies show that imagining the future depends on much of the same neural machinery that is needed for remembering the past. These findings have led to the concept of the prospective brain; an idea that a crucial function of the brain is to use stored information to imagine, simulate and predict possible future events. We suggest that processes such as memory can be productively re-conceptualized in light of this idea.
1,888 citations
TL;DR: Although the classical view is that Aβ is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.
Abstract: The primal role that the amyloid-beta (Abeta) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Abeta exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Abeta is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.
1,660 citations
TL;DR: Recent data regarding the nature of neocortical progenitors is assessed, the roles of individual genes in projection neuron specification are reviewed and the implications for progenitor plasticity are discussed.
Abstract: In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.
1,493 citations
TL;DR: The action potential of the squid giant axon is formed by just two voltage-dependent conductances in the cell membrane, yet mammalian central neurons typically express more than a dozen different types of voltage- dependent ion channels.
Abstract: The action potential of the squid giant axon is formed by just two voltage- dependent conductances in the cell membrane, yet mammalian central neurons typically express more than a dozen different types of voltage-dependent ion channels. This rich repertoire of channels allows neurons to encode information by generating action potentials with a wide range of shapes, frequencies and patterns. Recent work offers an increasingly detailed understanding of how the expression of particular channel types underlies the remarkably diverse firing behaviour of various types of neurons.
1,426 citations
TL;DR: This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
Abstract: Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
TL;DR: Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma and can transiently normalize tumour vessels, creating a window of opportunity for optimally combining chemotherapeutics and radiation.
Abstract: Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma — the most frequent primary brain tumour — and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
TL;DR: This work reviews the cognitive neuroscience literature of both motor and auditory domains, highlighting the value of studying interactions between these systems in a musical context, and proposes some ideas concerning the role of the premotor cortex in integration of higher order features of music with appropriately timed and organized actions.
Abstract: Music performance is both a natural human activity, present in all societies, and one of the most complex and demanding cognitive challenges that the human mind can undertake. Unlike most other sensory-motor activities, music performance requires precise timing of several hierarchically organized actions, as well as precise control over pitch interval production, implemented through diverse effectors according to the instrument involved. We review the cognitive neuroscience literature of both motor and auditory domains, highlighting the value of studying interactions between these systems in a musical context, and propose some ideas concerning the role of the premotor cortex in integration of higher order features of music with appropriately timed and organized actions.
TL;DR: Accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain is presented.
Abstract: Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.
TL;DR: The role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells is discussed in this paper. But the role of this gas in the regulation of the cardiovascular, immune and nervous systems is not discussed.
Abstract: At the end of the 1980s, it was clearly demonstrated that cells produce nitric oxide and that this gaseous molecule is involved in the regulation of the cardiovascular, immune and nervous systems, rather than simply being a toxic pollutant. In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleep-wake cycle and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells. In fact, physiological amounts of this gas are neuroprotective, whereas higher concentrations are clearly neurotoxic.
TL;DR: An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.
Abstract: The number and subunit composition of synaptic N-methyl-D-aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal-lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.
TL;DR: The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.
Abstract: Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.
TL;DR: The methods traditionally used to separate recollection from familiarity instead separate strong memories from weak memories, and it is suggested that these structures work together in a cooperative and complementary way.
Abstract: Recognition memory is widely viewed as consisting of two components, recollection and familiarity, which have been proposed to be dependent on the hippocampus and the adjacent perirhinal cortex, respectively. Here, we propose an alternative perspective: we suggest that the methods traditionally used to separate recollection from familiarity instead separate strong memories from weak memories. A review of work with humans, monkeys and rodents finds evidence for familiarity signals (as well as recollection signals) in the hippocampus and recollection signals (as well as familiarity signals) in the perirhinal cortex. We also indicate ways in which the functions of the medial temporal lobe structures are different, and suggest that these structures work together in a cooperative and complementary way.
TL;DR: This Review summarizes the complex interactions between genes, biological signals, neural circuits and the environment that influence the development and expression of aggressive behaviour.
Abstract: Unchecked aggression and violence exact a significant toll on human societies. Aggression is an umbrella term for behaviours that are intended to inflict harm. These behaviours evolved as adaptations to deal with competition, but when expressed out of context, they can have destructive consequences. Uncontrolled aggression has several components, such as impaired recognition of social cues and enhanced impulsivity. Molecular approaches to the study of aggression have revealed biological signals that mediate the components of aggressive behaviour. These signals may provide targets for therapeutic intervention for individuals with extreme aggressive outbursts. This Review summarizes the complex interactions between genes, biological signals, neural circuits and the environment that influence the development and expression of aggressive behaviour.
TL;DR: An up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications is given.
Abstract: Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.
TL;DR: The data described here strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration.
Abstract: Retinoic acid (RA) is involved in the induction of neural differentiation, motor axon outgrowth and neural patterning. Like other developmental molecules, RA continues to play a role after development has been completed. Elevated RA signalling in the adult triggers axon outgrowth and, consequently, nerve regeneration. RA is also involved in the maintenance of the differentiated state of adult neurons, and disruption of RA signalling in the adult leads to the degeneration of motor neurons (motor neuron disease), the development of Alzheimer's disease and, possibly, the development of Parkinson's disease. The data described here strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration.
TL;DR: It is proposed that lipid rafts are membrane domains in which neurotransmitter signalling might occur through a clustering of receptors and components of receptor-activated signalling cascades, which influences the potency and efficacy of neurotransmitter receptors and transporters.
Abstract: Lipid rafts — specialized plasma membrane microdomains that are thought to regulate various signalling events — are the focus of intensive research into their roles in the nervous system. Here, Rasenick and colleagues review the evidence for their involvement in regulating neurotransmitter signalling. Lipid rafts are specialized structures on the plasma membrane that have an altered lipid composition as well as links to the cytoskeleton. It has been proposed that these structures are membrane domains in which neurotransmitter signalling might occur through a clustering of receptors and components of receptor-activated signalling cascades. The localization of these proteins in lipid rafts, which is affected by the cytoskeleton, also influences the potency and efficacy of neurotransmitter receptors and transporters. The effect of lipid rafts on neurotransmitter signalling has also been implicated in neurological and psychiatric diseases.
TL;DR: Understanding the molecular mechanisms of reconsolidation could provide crucial insights into the dynamic aspects of normal mnemonic function and psychiatric disorders that are characterized by exceptionally strong and salient emotional memories.
Abstract: Memory reconsolidation has been argued to be a distinct process that serves to maintain, strengthen or modify memories. Specifically, the retrieval of a previously consolidated memory has been hypothesized to induce an additional activity-dependent labile period during which the memory can be modified. Understanding the molecular mechanisms of reconsolidation could provide crucial insights into the dynamic aspects of normal mnemonic function and psychiatric disorders that are characterized by exceptionally strong and salient emotional memories.
TL;DR: Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC, and studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning.
Abstract: Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.
TL;DR: Recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling is focused on.
Abstract: Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.
TL;DR: There is evidence for adult neurogenesis in several additional areas, including the neocortex, striatum, amygdala and substantia nigra, but this has been difficult to replicate consistently other than in the damaged brain.
Abstract: It is widely accepted that adult neurogenesis occurs in the hippocampus and olfactory bulb in the mammalian brain, but whether it is restricted to these areas remains controversial. Gould discusses evidence for and against neocortical neurogenesis in the adult, emphasizing some key methodological issues.
TL;DR: After they are born and differentiate, neurons break their previous symmetry, dramatically change their shape, and establish two structurally and functionally distinct compartments — axons and dendrites — within one cell.
Abstract: After they are born and differentiate, neurons break their previous symmetry, dramatically change their shape, and establish two structurally and functionally distinct compartments — axons and dendrites — within one cell. How do neurons develop their morphologically and molecularly distinct compartments? Recent studies have implicated several signalling pathways evoked by extracellular signals as having essential roles in a number of aspects of neuronal polarization.
TL;DR: Evidence from studies of both humans and non-human primates points to focal regions of the higher-level visual cortex that are specialized for the visual perception of the body that have been implicated in the Perception of the self and the 'body schema', the perception of others' emotions and the understanding of actions.
Abstract: Peelen and Downing review recent evidence for body-selective neural mechanisms in the visual cortex and discuss how body-selective brain regions might relate to action perception and the 'mirror' system, perception of the self and the 'body schema', and understanding the emotions of others.
TL;DR: It is argued that a better understanding of both the effects of rT MS and the pathological processes underlying the conditions for which it is used will reveal whether rTMS really does offer therapeutic potential and, if so, for which conditions.
Abstract: Repetitive transcranial magnetic stimulation (rTMS) has in recent years been used to explore therapeutic opportunities in a bewildering variety of conditions. Although there is good evidence that this technique can modify cortical activity, the rationale for its use in many of the conditions investigated so far is not clear. Here we discuss the effects of rTMS in healthy subjects and how it has been used in a number of neurological conditions. We argue that a better understanding of both the effects of rTMS and the pathological processes underlying the conditions for which it is used will reveal whether rTMS really does offer therapeutic potential and, if so, for which conditions.
TL;DR: Recent findings both in rodents and in primates indicate that regulation of the cell cycle, specifically of the G1 phase has a crucial role in controlling area-specific rates of neuron production and the generation of cytoarchitectonic maps.
Abstract: The spatio-temporal timing of the last round of mitosis, followed by the migration of neuroblasts to the cortical plate leads to the formation of the six-layered cortex that is subdivided into functionally defined cortical areas. Whereas many of the cellular and molecular mechanisms have been established in rodents, there are a number of unique features that require further elucidation in primates. Recent findings both in rodents and in primates indicate that regulation of the cell cycle, specifically of the G1 phase has a crucial role in controlling area-specific rates of neuron production and the generation of cytoarchitectonic maps.