- Home
- A-Z Publications
- Annual Review of Neuroscience
- Previous Issues
- Volume 24, 2001
Annual Review of Neuroscience - Volume 24, 2001
Volume 24, 2001
- Review Articles
-
-
-
PDZ Domains and the Organization of Supramolecular Complexes
Morgan Sheng, and Carlo SalaVol. 24 (2001), pp. 1–29More Less▪ AbstractPDZ domains are modular protein interaction domains that bind in a sequence-specific fashion to short C-terminal peptides or internal peptides that fold in a β-finger. The diversity of PDZ binding specificities can be explained by variable amino acids lining the peptide-binding groove of the PDZ domain. Abundantly represented in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes, PDZ domains are frequently found in multiple copies or are associated with other protein-binding motifs in multidomain scaffold proteins. PDZ-containing proteins are typically involved in the assembly of supramolecular complexes that perform localized signaling functions at particular subcellular locations. Organization around a PDZ-based scaffold allows the stable localization of interacting proteins and enhances the rate and fidelity of signal transduction within the complex. Some PDZ-containing proteins are more dynamically regulated in distribution and may also be involved in the trafficking of interacting proteins within the cell.
-
-
-
-
The Role and Regulation of Adenosine in the Central Nervous System
Vol. 24 (2001), pp. 31–55More Less▪ AbstractAdenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.
-
-
-
Localization and Globalization in Conscious Vision
Vol. 24 (2001), pp. 57–86More Less▪ AbstractThe primate visual brain consists of many separate, functionally specialized processing systems, each consisting of several apparently hierarchical stages or nodes. The evidence reviewed here leads me to speculate (a) that the processing systems are autonomous with respect to one another, (b) that activity at each node reaches a perceptual end point at a different time, resulting in a perceptual asynchrony in vision, and (c) that, consequently, activity at each node generates a microconsciousness. Visual consciousness is therefore distributed in space and time, with the universal organizing principle of abstraction applied separately within each processing system. The consequence of spatially and temporally distributed microconsciousnesses is that their integration is a multistage, nonhierarchical process that may involve a neural “glue.”
-
-
-
Glial Control of Neuronal Development
Vol. 24 (2001), pp. 87–105More Less▪ AbstractReciprocal interactions between differentiating glial cells and neurons define the course of nervous system development even before the point at which these two cell types become definitively recognizable. Glial cells control the survival of associated neurons in both Drosophila and mammals, but this control is dependent on the prior neuronal triggering of glial cell fate commitment and trophic factor expression. In mammals, the growth factor neuregulin-1 and its receptors of the ErbB family play crucial roles in both events. Similarly, early differentiating neurons and their associated glia rely on reciprocal signaling to establish the basic axon scaffolds from which neuronal connections evolve. The importance of this interactive signaling is illustrated by the action of glial transcription factors and of glial axon guidance cues such as netrin and slit, which together regulate the commissural crossing of pioneer axons at the neural midline. In these and related events, the defining principle is one of mutually reinforced and mutually dependent signaling that occurs in a network of developing neurons and glia.
-
-
-
Touch and Go: Decision-Making Mechanisms in Somatosensation
Vol. 24 (2001), pp. 107–137More Less▪ AbstractA complex sequence of neural events unfolds between sensory receptor activation and motor activity. To understand the underlying decision-making mechanisms linking somatic sensation and action, we ask what components of the neural activity evoked by a stimulus are directly related to psychophysical performance, and how are they related. We find that single-neuron responses in primary and secondary somatosensory cortices account for the observed performance of monkeys in vibrotactile discrimination tasks, and that neuronal and behavioral responses covary in single trials. This sensory activity, which provides input to memory and decision-making mechanisms, is modulated by attention and behavioral context, and microstimulation experiments indicate that it may trigger normal perceptual experiences. Responses recorded in motor areas seem to reflect the output of decision-making operations, which suggests that the ability to make decisions occurs at the sensory-motor interface.
-
-
-
Synaptic Modification by Correlated Activity: Hebb's Postulate Revisited
Guo-qiang Bi, and Mu-ming PooVol. 24 (2001), pp. 139–166More Less▪ AbstractCorrelated spiking of pre- and postsynaptic neurons can result in strengthening or weakening of synapses, depending on the temporal order of spiking. Recent findings indicate that there are narrow and cell type–specific temporal windows for such synaptic modification and that the generally accepted input- (or synapse-) specific rule for modification appears not to be strictly adhered to. Spike timing–dependent modifications, together with selective spread of synaptic changes, provide a set of cellular mechanisms that are likely to be important for the development and functioning of neural networks.
When an axon of cell A is near enough to excite cell B or repeatedly or consistently takes part in firing it, some growth or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased. Donald Hebb (1949)
-
-
-
An Integrative Theory of Prefrontal Cortex Function
Vol. 24 (2001), pp. 167–202More Less▪ AbstractThe prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed
-
-
-
The Physiology of Stereopsis
Vol. 24 (2001), pp. 203–238More Less▪ AbstractBinocular disparity provides the visual system with information concerning the three-dimensional layout of the environment. Recent physiological studies in the primary visual cortex provide a successful account of the mechanisms by which single neurons are able to signal disparity. This work also reveals that additional processing is required to make explicit the types of signal required for depth perception (such as the ability to match features correctly between the two monocular images). Some of these signals, such as those encoding relative disparity, are found in extrastriate cortex. Several other lines of evidence also suggest that the link between perception and neuronal activity is stronger in extrastriate cortex (especially MT) than in the primary visual cortex.
-
-
-
Paraneoplastic Neurologic Disease Antigens: RNA-Binding Proteins and Signaling Proteins in Neuronal Degeneration
Vol. 24 (2001), pp. 239–262More Less▪ AbstractStudies of the disorders known as paraneoplastic neurologic degenerations exemplify the successful application of modern molecular biological techniques to diseases, yielding, even for these extremely rare disorders, wide-ranging insight into basic neurobiology, tumor immunity, and autoimmune neurologic disease. Immune responses to paraneoplastic neurologic degeneration antigens, also called onconeural antigens, have been exploited to clone and characterize a number of neuron-specific proteins, including several RNA-binding proteins and new kinds of signaling molecules. The biology and functions of these proteins are reviewed, and a model in which their functions are related to the pathogenesis of autoimmune neurologic disease is discussed.
-
-
-
Odor Encoding as an Active, Dynamical Process: Experiments, Computation, and Theory
Vol. 24 (2001), pp. 263–297More Less▪ AbstractWe examine early olfactory processing in the vertebrate and insect olfactory systems, using a computational perspective. What transformations occur between the first and second olfactory processing stages? What are the causes and consequences of these transformations? To answer these questions, we focus on the functions of olfactory circuit structure and on the role of time in odor-evoked integrative processes. We argue that early olfactory relays are active and dynamical networks, whose actions change the format of odor-related information in very specific ways, so as to refine stimulus identification. Finally, we introduce a new theoretical framework (“winnerless competition”) for the interpretation of these data.
-
-
-
Protein Synthesis at Synaptic Sites on Dendrites
Vol. 24 (2001), pp. 299–325More Less▪ AbstractStudies over the past 20 years have revealed that gene expression in neurons is carried out by a distributed network of translational machinery. One component of this network is localized in dendrites, where polyribosomes and associated membranous elements are positioned beneath synapses and translate a particular population of dendritic mRNAs. The localization of translation machinery and mRNAs at synapses endows individual synapses with the capability to independently control synaptic strength through the local synthesis of proteins. The present review discusses recent studies linking synaptic plasticity to dendritic protein synthesis and mRNA trafficking and considers how these processes are regulated. We summarize recent information about how synaptic signaling is coupled to local translation and to the delivery of newly transcribed mRNAs to activated synaptic sites and how local translation may play a role in activity-dependent synaptic modification.
-
-
-
Signaling and Transcriptional Mechanisms in Pituitary Development
Vol. 24 (2001), pp. 327–355More Less▪ AbstractDuring the development of the pituitary gland, distinct hormone-producing cell types arise from a common population of ectodermal progenitors, providing an instructive model system for elucidating the molecular mechanisms of patterning and cell type specification in mammalian organogenesis. Recent studies have established that the development of the pituitary occurs through multiple sequential steps, allowing the coordinate control of the commitment, early patterning, proliferation, and positional determination of pituitary cell lineages in response to extrinsic and intrinsic signals. The early phases of pituitary development appear to be mediated through the activities of multiple signaling gradients emanating from key organizing centers that give rise to temporally and spatially distinct patterns of transcription factor expression. The induction of these transcriptional mediators in turn acts to positionally organize specific pituitary cell lineages within an apparently uniform field of ectodermal progenitors. Ultimately, pituitary cell types have proven to be both specified and maintained through the combinatorial interactions of a series of cell-type-restricted transcription factors that dictate the cell autonomous programs of differentiation in response to the transient signaling events.
-
-
-
Neuropeptides and the Integration of Motor Responses to Dehydration
Vol. 24 (2001), pp. 357–384More Less▪ AbstractDrinking and eating are critically important motivated behaviors whose expression is usually tightly linked; under conditions of spontaneous intake, disruption of one usually disturbs the other. This characteristic is exemplified by dehydration-induced anorexia in which increasing plasma osmolality leads to a centrally generated reduction in food intake, which is then rapidly reversed as water is again made available. This review discusses, at a systems level, how the brain is organized to generate these behaviors and how dehydration affects the expression of neuropeptides in sets of anatomically defined forebrain circuits that contribute to the integration of motor outputs. These findings are then used to consider how altered neuropeptidergic signaling operates within motor drive networks and how these changes may impact the way neuroendocrine, autonomic, and behavioral motor systems respond to this fundamental homeostatic challenge.
-
-
-
The Developmental Biology of Brain Tumors
Vol. 24 (2001), pp. 385–428More Less▪ AbstractTumors of the central nervous system (CNS) can be devastating because they often affect children, are difficult to treat, and frequently cause mental impairment or death. New insights into the causes and potential treatment of CNS tumors have come from discovering connections with genes that control cell growth, differentiation, and death during normal development. Links between tumorigenesis and normal development are illustrated by three common CNS tumors: retinoblastoma, glioblastoma, and medulloblastoma. For example, the retinoblastoma (Rb) tumor suppressor protein is crucial for control of normal neuronal differentiation and apoptosis. Excessive activity of the epidermal growth factor receptor and loss of the phosphatase PTEN are associated with glioblastoma, and both genes are required for normal growth and development. The membrane protein Patched1 (Ptc1), which controls cell fate in many tissues, regulates cell growth in the cerebellum, and reduced Ptc1 function contributes to medulloblastoma. Just as elucidating the mechanisms that control normal development can lead to the identification of new cancer-related genes and signaling pathways, studies of tumor biology can increase our understanding of normal development. Learning that Ptc1 is a medulloblastoma tumor suppressor led directly to the identification of the Ptc1 ligand, Sonic hedgehog, as a powerful mitogen for cerebellar granule cell precursors. Much remains to be learned about the genetic events that lead to brain tumors and how each event regulates cell cycle progression, apoptosis, and differentiation. The prospects for beneficial work at the boundary between oncology and developmental biology are great.
-
-
-
To Eat or to Sleep? Orexin in the Regulation of Feeding and Wakefulness
Vol. 24 (2001), pp. 429–458More Less▪ AbstractOrexin-A and orexin-B are neuropeptides originally identified as endogenous ligands for two orphan G-protein–coupled receptors. Orexin neuropeptides (also known as hypocretins) are produced by a small group of neurons in the lateral hypothalamic and perifornical areas, a region classically implicated in the control of mammalian feeding behavior. Orexin neurons project throughout the central nervous system (CNS) to nuclei known to be important in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis, and autonomic regulation. orexin mRNA expression is upregulated by fasting and insulin-induced hypoglycemia. C-fos expression in orexin neurons, an indicator of neuronal activation, is positively correlated with wakefulness and negatively correlated with rapid eye movement (REM) and non-REM sleep states. Intracerebroventricular administration of orexins has been shown to significantly increase food consumption, wakefulness, and locomotor activity in rodent models. Conversely, an orexin receptor antagonist inhibits food consumption. Targeted disruption of the orexin gene in mice produces a syndrome remarkably similar to human and canine narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and other pathological manifestations of the intrusion of REM sleep-related features into wakefulness. Furthermore, orexin knockout mice are hypophagic compared with weight and age-matched littermates, suggesting a role in modulating energy metabolism. These findings suggest that the orexin neuropeptide system plays a significant role in feeding and sleep-wakefulness regulation, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions.
-
-
-
Spatial Processing in the Brain: The Activity of Hippocampal Place Cells
Vol. 24 (2001), pp. 459–486More Less▪ AbstractThe startling discovery by O'Keefe & Dostrovsky (Brain Res. 1971; 34: 171–75) that hippocampal neurons fire selectively in different regions or “place fields” of an environment and the subsequent development of the comprehensive theory by O'Keefe & Nadel (The Hippocampus as a Cognitive Map. Oxford, UK: Clarendon, 1978) that the hippocampus serves as a cognitive map have stimulated a substantial body of literature on the characteristics of hippocampal “place cells” and their relevance for our understanding of the mechanisms by which the brain processes spatial information. This paper reviews the major dimensions of the empirical research on place-cell activity and the development of computational models to explain various characteristics of place fields.
-
-
-
The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway
Vol. 24 (2001), pp. 487–517More Less▪ AbstractThe detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation of heat-evoked pain.
-
-
-
Prion Diseases of Humans and Animals: Their Causes and Molecular Basis
Vol. 24 (2001), pp. 519–550More Less▪ AbstractPrion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of α-helical structure, into a disease specific isoform rich in β-sheet structure. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns. The ability of a protein to encode phenotypic information has important biological implications. The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, and the barriers limiting intermammalian transmission. It is unclear if a large epidemic of variant CJD will occur in the years ahead.
-
-
-
Viktor Hamburger and Rita Levi-Montalcini: The Path to the Discovery of Nerve Growth Factor
Vol. 24 (2001), pp. 551–600More Less▪ AbstractThe announcement in October 1986 that the Nobel Prize for physiology or medicine was to be awarded to Rita Levi-Montalcini and Stanley Cohen for the discoveries of NGF and EGF, respectively, caused many to wonder why Viktor Hamburger (in whose laboratory the initial work was done) had not been included in the award. Now that the dust has settled, the time seems opportune to reconsider the antecedent studies on the relation of the developing nervous system to the peripheral structures it innervates. The studies undertaken primarily to investigate this issue culminated in the late 1950s in the discovery that certain tissues produce a nerve growth–promoting factor that is essential for the survival and maintenance of spinal (sensory) ganglion cells and sympathetic neurons. In this review, the many contributions that Viktor and Rita made to this problem, both independently and jointly, are reexamined by considering chronologically each of the relevant research publications together with some of the retrospective memoirs they have published in the years since the discovery of NGF was first reported.
This review is dedicated to Viktor Hamburger on the occasion of his 100th birthday on July 9, 2000, and to Rita Levi-Montalcini to mark her 91st birthday on April 22, 2000, with admiration and affection.
-
-
-
Early Days of the Nerve Growth Factor Proteins
Vol. 24 (2001), pp. 601–629More Less▪ AbstractAdult male mouse submaxillary glands served as the preferred starting material for the isolation of the nerve growth factor (NGF) proteins in most of the isolation studies done. Two types of NGF proteins were isolated from extracts of the gland, a high-molecular-weight 7S NGF complex and a low-molecular-weight protein variously called NGF, βNGF, or 2.5S NGF. The latter, which mediated all known biological functions of NGF, were closely related forms of a basic NGF dimer in which the N and C termini of two monomers (chains) were modified by proteolytic enzymes to different extents with no effect on biological activity. The βNGF dimer showed a novel protein structure in which the two chains interacted non-covalently over a wide surface. Correspondingly, the βNGF dimer was found to be unusually stable and the form through which NGFs actions were mediated at physiological concentrations. The βNGF dimer was one of three subunits in 7S NGF; the other two were the γ subunit, an arginine esteropeptidase or kallikrein, and the α subunit, an inactive kallikrein. Two zinc ions were also present in the complex and contributed greatly to its stability. There was much debate about whether 7S NGF was a specific protein complex of interacting subunits and, if so, what functions it might play in the biology of NGF. Observations of the inhibition of the enzyme activity of the γ subunit and of the biological activity of βNGF in 7S NGF were important in determining that 7S NGF was a naturally occurring complex and the sole source of NGF in the gland extract or in saliva. Specific interactions between the active site of the γ subunit and the C-terminal arginine residues of the NGF chains, confirmed in the three-dimensional structure of 7S NGF, suggested a role for the γ subunit in pro-NGF processing during the assembly of 7S NGF. In spite of the detailed knowledge of 7S NGF structure, no information on the role of this complex in the neurobiology of NGF has emerged. With the exception of the submaxillary gland of an African rodent, no other source of NGF has been convincingly shown to synthesize the α and γ subunits, and they may well be irrelevant to NGFs actions.
-
-
-
Sequential Organization of Multiple Movements: Involvement of Cortical Motor Areas
Vol. 24 (2001), pp. 631–651More Less▪ AbstractMuch of our normal behavior depends on the sequential execution of multiphased movements, or the execution of multiple movements arranged in a correct temporal order. This article deals with the issue of motor selection to arrange multiple movements in an appropriate temporal order, rather than the issue of constructing spatio-temporal structures in a single action. Planning, generating, and controlling the sequential motor behavior involves multiple cortical and subcortical neural structures. Studies on human subjects and nonhuman primates, however, have revealed that the medial motor areas in the frontal cortex and the basal ganglia play particularly important roles in the temporal sequencing of multiple movements. Cellular activity observed in the supplementary and presupplementary motor areas while performing specifically designed motor tasks suggests the way in which these areas take part in constructing the time structure for the sequential execution of multiple movements.
-
-
-
Influence of Dendritic Conductances on the Input-Output Properties of Neurons
Vol. 24 (2001), pp. 653–675More Less▪ AbstractA fundamental problem in neuroscience is understanding how a neuron transduces synaptic input into action potentials. The dendrites form the substrate for consolidating thousands of synaptic inputs and are the first stage for signal processing in the neuron. Traditionally, dendrites are viewed as passive structures whose main function is to funnel synaptic input into the soma. However, dendrites contain a wide variety of voltage- and time-dependent ion channels. When activated, the currents through these channels can alter the amplitude and time course of the synaptic input and under certain conditions even evoke all-or-none regenerative potentials. The synaptic input that ultimately reaches the soma is likely to be a highly transformed version of the original signal. Thus, a key step in understanding the relationship between synaptic input and neuronal firing is to elucidate the signal processing that occurs in the dendrites.
-
-
-
Neurotrophins: Roles in Neuronal Development and Function1
Vol. 24 (2001), pp. 677–736More Less▪ AbstractNeurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
-
-
-
Contributions of the Medullary Raphe and Ventromedial Reticular Region to Pain Modulation and Other Homeostatic Functions
Vol. 24 (2001), pp. 737–777More Less▪ AbstractThe raphe magnus is part of an interrelated region of medullary raphe and ventromedial reticular nuclei that project to all areas of the spinal gray. Activation of raphe and reticular neurons evokes modulatory effects in sensory, autonomic, and motor spinal processes. Two physiological types of nonserotonergic cells are observed in the medullary raphe and are thought to modulate spinal pain processing in opposing directions. Recent evidence suggests that these cells may modulate stimulus-evoked arousal or alerting rather than pain-evoked withdrawals. Nonserotonergic cells are also likely to modulate spinal autonomic and motor circuits involved in thermoregulation and sexual function. Medullary serotonergic cells have state-dependent discharge and are likely to contribute to the modulation of pain processing, thermoregulation, and sexual function in the spinal cord. The medullary raphe and ventromedial reticular region may set sensory, autonomic, and motor spinal circuits into configurations that are appropriate to the current behavioral state.
-
-
-
Activation, Deactivation, and Adaptation in Vertebrate Photoreceptor Cells
Vol. 24 (2001), pp. 779–805More Less▪ AbstractVisual transduction captures widespread interest because its G-protein signaling motif recurs throughout nature yet is uniquely accessible for study in the photoreceptor cells. The light-activated currents generated at the photoreceptor outer segment provide an easily observed real-time measure of the output of the signaling cascade, and the ease of obtaining pure samples of outer segments in reasonable quantity facilitates biochemical experiments. A quiet revolution in the study of the mechanism has occurred during the past decade with the advent of gene-targeting techniques. These have made it possible to observe how transduction is perturbed by the deletion, overexpression, or mutation of specific components of the transduction apparatus.
-
-
-
Activity-Dependent Spinal Cord Plasticity in Health and Disease
Vol. 24 (2001), pp. 807–843More Less▪ AbstractActivity-dependent plasticity occurs in the spinal cord throughout life. Driven by input from the periphery and the brain, this plasticity plays an important role in the acquisition and maintenance of motor skills and in the effects of spinal cord injury and other central nervous system disorders. The responses of the isolated spinal cord to sensory input display sensitization, long-term potentiation, and related phenomena that contribute to chronic pain syndromes; they can also be modified by both classical and operant conditioning protocols. In animals with transected spinal cords and in humans with spinal cord injuries, treadmill training gradually modifies the spinal cord so as to improve performance. These adaptations by the isolated spinal cord are specific to the training regimen and underlie new approaches to restoring function after spinal cord injury. Descending inputs from the brain that occur during normal development, as a result of supraspinal trauma, and during skill acquisition change the spinal cord. The early development of adult spinal cord reflex patterns is driven by descending activity; disorders that disrupt descending activity later in life gradually change spinal cord reflexes. Athletic training, such as that undertaken by ballet dancers, is associated with gradual alterations in spinal reflexes that appear to contribute to skill acquisition. Operant conditioning protocols in animals and humans can produce comparable reflex changes and are associated with functional and structural plasticity in the spinal cord, including changes in motoneuron firing threshold and axonal conduction velocity, and in synaptic terminals on motoneurons. The corticospinal tract has a key role in producing this plasticity. Behavioral changes produced by practice or injury reflect the combination of plasticity at multiple spinal cord and supraspinal sites. Plasticity at multiple sites is both necessary—to insure continued performance of previously acquired behaviors—and inevitable—due to the ubiquity of the capacity for activity-dependent plasticity in the central nervous system. Appropriate induction and guidance of activity-dependent plasticity in the spinal cord is an essential component of new therapeutic approaches aimed at maximizing function after spinal cord injury or restoring function to a newly regenerated spinal cord. Because plasticity in the spinal cord contributes to skill acquisition and because the spinal cord is relatively simple and accessible, this plasticity is a logical and practical starting point for studying the acquisition and maintenance of skilled behaviors.
-
-
-
Quantitative Genetics and Mouse Behavior
Vol. 24 (2001), pp. 845–867More Less▪ AbstractQuantitative differences are observed for most complex behavioral and pharmacological traits within any population. Both environmental and genetic influences regulate such individual differences. The mouse has proven to be a superb model in which to investigate the genetic basis for quantitative differences in complex behaviors. Genetically defined populations of mice, including inbred strains, heterogeneous stocks, and selected lines, have been used effectively to document these genetic differences. Recently, quantitative trait loci methods have been applied to map the chromosomal regions that regulate variation with the goal of eventually identifying the gene polymorphisms that reside in these regions.
-
-
-
Early Anterior/Posterior Patterning of the Midbrain and Cerebellum
Vol. 24 (2001), pp. 869–896More Less▪ AbstractTransplantation studies performed in chicken embryos indicated that early anterior/posterior patterning of the vertebrate midbrain and cerebellum might be regulated by an organizing center at the junction between the midbrain and hindbrain. More than a decade of molecular and genetic studies have shown that such an organizer is indeed central to development of the midbrain and anterior hindbrain. Furthermore, a complicated molecular network that includes multiple positive and negative feedback loops underlies the establishment and refinement of a mid/hindbrain organizer, as well as the subsequent function of the organizer. In this review, we first introduce the expression patterns of the genes known to be involved in this patterning process and the quail-chick transplantation experiments that have provided the foundation for understanding the genetic pathways regulating mid/hindbrain patterning. Subsequently, we discuss the molecular genetic studies that have revealed the roles for many genes in normal early patterning of this region. Finally, some of the remaining questions and future directions are discussed.
-
-
-
Neurobiology of Pavlovian Fear Conditioning
Vol. 24 (2001), pp. 897–931More Less▪ AbstractLearning the relationships between aversive events and the environmental stimuli that predict such events is essential to the survival of organisms throughout the animal kingdom. Pavlovian fear conditioning is an exemplar of this form of learning that is exhibited by both rats and humans. Recent years have seen an incredible surge in interest in the neurobiology of fear conditioning. Neural circuits underlying fear conditioning have been mapped, synaptic plasticity in these circuits has been identified, and biochemical and genetic manipulations are beginning to unravel the molecular machinery responsible for the storage of fear memories. These advances represent an important step in understanding the neural substrates of a rapidly acquired and adaptive form of associative learning and memory in mammals.
-
-
-
α-Latrotoxin and Its Receptors: Neurexins and CIRL/Latrophilins
Vol. 24 (2001), pp. 933–962More Less▪ Abstractα-Latrotoxin, a potent neurotoxin from black widow spider venom, triggers synaptic vesicle exocytosis from presynaptic nerve terminals. α-Latrotoxin is a large protein toxin (120 kDa) that contains 22 ankyrin repeats. In stimulating exocytosis, α-latrotoxin binds to two distinct families of neuronal cell-surface receptors, neurexins and CLs (Cirl/latrophilins), which probably have a physiological function in synaptic cell adhesion. Binding of α-latrotoxin to these receptors does not in itself trigger exocytosis but serves to recruit the toxin to the synapse. Receptor-bound α-latrotoxin then inserts into the presynaptic plasma membrane to stimulate exocytosis by two distinct transmitter-specific mechanisms. Exocytosis of classical neurotransmitters (glutamate, GABA, acetylcholine) is induced in a calcium-independent manner by a direct intracellular action of α-latrotoxin, while exocytosis of catecholamines requires extracellular calcium. Elucidation of precisely how α-latrotoxin works is likely to provide major insight into how synaptic vesicle exocytosis is regulated, and how the release machineries of classical and catecholaminergic neurotransmitters differ.
-
-
-
Imaging and Coding in the Olfactory System
John S Kauer, and Joel WhiteVol. 24 (2001), pp. 963–979More Less▪ AbstractFunctional imaging methods permit analysis of neuronal systems in which activity is broadly distributed in time and space. In the olfactory system the dimensions that describe odorant stimuli in “odorant space” are still poorly defined. One way of trying to characterize the attributes of this space is to examine the ways in which its dimensions are encoded by the neurons and circuits making up the system and to compare these responses with physical-chemical attributes of the stimuli and with the output behavior of the animal. For documenting distributed events as they occur, imaging methods are among the few tools available. We are still in the early stages of this analysis; however, a number of recent studies have contributed new information to our understanding of the odorant coding problem. This paper describes imaging results in the context of other data that have contributed to our understanding of how odors are encoded by the peripheral olfactory pathway.
-
-
-
The Role of the Cerebellum in Voluntary Eye Movements
Vol. 24 (2001), pp. 981–1004More Less▪ AbstractIn general the cerebellum is crucial for the control but not the initiation of movement. Voluntary eye movements are particularly useful for investigating the specific mechanisms underlying cerebellar control because they are precise and their brain-stem circuitry is already well understood. Here we describe single-unit and inactivation data showing that the posterior vermis and the caudal fastigial nucleus, to which it projects, provide a signal during horizontal saccades to make them fast, accurate, and consistent. The caudal fastigial nucleus also is necessary for the recovery of saccadic accuracy after actual or simulated neural or muscular damage causes horizontal saccades to be dysmetric. Saccade-related activity in the interpositus nucleus is related to vertical saccades. Both the caudal fastigial nucleus and the flocculus/paraflocculus are necessary for the normal smooth eye movements that pursue a small moving spot. By using eye movements, we have begun to uncover basic principles that give us insight into how the cerebellum may control movement in general.
-
-
-
Role of the Reelin Signaling Pathway in Central Nervous System Development
Dennis S Rice, and Tom CurranVol. 24 (2001), pp. 1005–1039More Less▪ AbstractThe neurological mutant mouse reeler has played a critical role in the evolution of our understanding of normal brain development. From the earliest neuroanatomic studies of reeler, it was anticipated that the characterization of the gene responsible would elucidate important molecular and cellular principles governing cell positioning and the formation of synaptic circuits in the developing brain. Indeed, the identification of reelin has challenged many of our previous notions and has led to a new vision of the events involved in the migration of neurons. Several neuronal populations throughout the brain secrete Reelin, which binds to transmembrane receptors located on adjacent cells triggering a tyrosine kinase cascade. This allows neurons to complete migration and adopt their ultimate positions in laminar structures in the central nervous system. Recent studies have also suggested a role for the Reelin pathway in axonal branching, synaptogenesis, and pathology underlying neurodegeneration.
-
-
-
Human Brain Malformations and Their Lessons for Neuronal Migration
Vol. 24 (2001), pp. 1041–1070More Less▪ AbstractThe developmental steps required to build a brain have been recognized as a distinctive sequence since the turn of the twentieth century. As marking tools for experimental embryology emerged, the cellular events of cortical histogenesis have been intensively scrutinized. On this rich backdrop, molecular genetics provides the opportunity to play out the molecular programs that orchestrate these cellular events. Genetic studies of human brain malformation have proven a surprising source for finding the molecules that regulate CNS neuronal migration. These studies also serve to relate the significance of genes first identified in murine species to the more complex human brain. The known genetic repertoire that is special to neuronal migration in brain has rapidly expanded over the past five years, making this an appropriate time to take stock of the emerging picture. We do this from the perspective of human brain malformation syndromes, noting both what is now known of their genetic bases and what remains to be discovered.
-
-
-
Morphological Changes in Dendritic Spines Associated with Long-Term Synaptic Plasticity
Vol. 24 (2001), pp. 1071–1089More Less▪ AbstractDendritic spines are morphological specializations that receive synaptic inputs and compartmentalize calcium. In spite of a long history of research, the specific function of spines is still not well understood. Here we review the current status of the relation between morphological changes in spines and synaptic plasticity. Since Cajal and Tanzi proposed that changes in the structure of the brain might occur as a consequence of experience, the search for the morphological correlates of learning has constituted one of the central questions in neuroscience. Although there are scores of studies that encompass this wide field in many species, in this review we focus on experimental work that has analyzed the morphological consequences of hippocampal long-term potentiation (LTP) in rodents. Over the past two decades many studies have demonstrated changes in the morphology of spines after LTP, such as enlargements of the spine head and shortenings of the spine neck. Biophysically, these changes translate into an increase in the synaptic current injected at the spine, as well as shortening of the time constant for calcium compartmentalization. In addition, recent online studies using time-lapse imaging have reported increased spinogenesis. The currently available data show a strong correlation between synaptic plasticity and morphological changes in spines, although at the same time, there is no evidence that these morphological changes are necessary or sufficient for the induction or maintenance of LTP. Still, they highlight once more how form and function go hand in hand in the central nervous system.
-
-
-
Stopping Time: The Genetics of Fly and Mouse Circadian Clocks
Vol. 24 (2001), pp. 1091–1119More Less▪ AbstractForward genetic analyses in flies and mice have uncovered conserved transcriptional feedback loops at the heart of circadian pacemakers. Conserved mechanisms of posttranslational regulation, most notably phosphorylation, appear to be important for timing feedback. Transcript analyses have indicated that circadian clocks are not restricted to neurons but are found in several tissues. Comparisons between flies and mice highlight important differences in molecular circuitry and circadian organization. Future studies of pacemaker mechanisms and their control of physiology and behavior will likely continue to rely on forward genetics.
-
-
-
Neurodegenerative Tauopathies
Vol. 24 (2001), pp. 1121–1159More Less▪ AbstractThe defining neuropathological characteristics of Alzheimer's disease are abundant filamentous tau lesions and deposits of fibrillar amyloid β peptides. Prominent filamentous tau inclusions and brain degeneration in the absence of β-amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified by sporadic corticobasal degeneration, progressive supranuclear palsy, and Pick's disease, as well as by hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Because multiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are linked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed, emerging data support the hypothesis that different tau gene mutations are pathogenic because they impair tau functions, promote tau fibrillization, or perturb tau gene splicing, thereby leading to formation of biochemically and structurally distinct aggregates of tau. Nonetheless, different members of the same kindred often exhibit diverse FTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influence the phenotypic manifestations of neurodegenerative tauopathies. Although these and other hypothetical mechanisms of neurodegenerative tauopathies remain to be tested and validated, transgenic models are increasingly available for this purpose, and they will accelerate discovery of more effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer's disease.
-
-
-
Maternal Care, Gene Expression, and the Transmission of Individual Differences in Stress Reactivity Across Generations
Vol. 24 (2001), pp. 1161–1192More Less▪ AbstractNaturally occurring variations in maternal care alter the expression of genes that regulate behavioral and endocrine responses to stress, as well as hippocampal synaptic development. These effects form the basis for the development of stable, individual differences in stress reactivity and certain forms of cognition. Maternal care also influences the maternal behavior of female offspring, an effect that appears to be related to oxytocin receptor gene expression, and which forms the basis for the intergenerational transmission of individual differences in stress reactivity. Patterns of maternal care that increase stress reactivity in offspring are enhanced by stressors imposed on the mother. These findings provide evidence for the importance of parental care as a mediator of the effects of environmental adversity on neural development.
-
-
-
Natural Image Statistics and Neural Representation
Vol. 24 (2001), pp. 1193–1216More Less▪ AbstractIt has long been assumed that sensory neurons are adapted, through both evolutionary and developmental processes, to the statistical properties of the signals to which they are exposed. Attneave (1954), Barlow (1961) proposed that information theory could provide a link between environmental statistics and neural responses through the concept of coding efficiency. Recent developments in statistical modeling, along with powerful computational tools, have enabled researchers to study more sophisticated statistical models for visual images, to validate these models empirically against large sets of data, and to begin experimentally testing the efficient coding hypothesis for both individual neurons and populations of neurons.
-
-
-
Nerve Growth Factor Signaling, Neuroprotection, and Neural Repair
Vol. 24 (2001), pp. 1217–1281More Less▪ AbstractNerve growth factor (NGF) was discovered 50 years ago as a molecule that promoted the survival and differentiation of sensory and sympathetic neurons. Its roles in neural development have been characterized extensively, but recent findings point to an unexpected diversity of NGF actions and indicate that developmental effects are only one aspect of the biology of NGF. This article considers expanded roles for NGF that are associated with the dynamically regulated production of NGF and its receptors that begins in development, extends throughout adult life and aging, and involves a surprising variety of neurons, glia, and nonneural cells. Particular attention is given to a growing body of evidence that suggests that among other roles, endogenous NGF signaling subserves neuroprotective and repair functions. The analysis points to many interesting unanswered questions and to the potential for continuing research on NGF to substantially enhance our understanding of the mechanisms and treatment of neurological disorders.
-
-
-
Flies, Genes, and Learning
Vol. 24 (2001), pp. 1283–1309More Less▪ AbstractFlies can learn. For the past 25 years, researchers have isolated mutants, engineered mutants with transgenes, and tested likely suspect mutants from other screens for learning ability. There have been notable surprises—conventional second messenger systems co-opted for intricate associative learning tasks, two entirely separate forms of long-term memory, a cell-adhesion molecule that is necessary for short-term memory. The most recent surprise is the mechanistic kinship revealed between learning and addictive drug response behaviors in flies. The flow of new insight is likely to quicken with the completion of the fly genome and the arrival of more selective methods of gene expression.
-
Previous Volumes
-
Volume 46 (2023)
-
Volume 45 (2022)
-
Volume 44 (2021)
-
Volume 43 (2020)
-
Volume 42 (2019)
-
Volume 41 (2018)
-
Volume 40 (2017)
-
Volume 39 (2016)
-
Volume 38 (2015)
-
Volume 37 (2014)
-
Volume 36 (2013)
-
Volume 35 (2012)
-
Volume 34 (2011)
-
Volume 33 (2010)
-
Volume 32 (2009)
-
Volume 31 (2008)
-
Volume 30 (2007)
-
Volume 29 (2006)
-
Volume 28 (2005)
-
Volume 27 (2004)
-
Volume 26 (2003)
-
Volume 25 (2002)
-
Volume 24 (2001)
-
Volume 23 (2000)
-
Volume 22 (1999)
-
Volume 21 (1998)
-
Volume 20 (1997)
-
Volume 19 (1996)
-
Volume 18 (1995)
-
Volume 17 (1994)
-
Volume 16 (1993)
-
Volume 15 (1992)
-
Volume 14 (1991)
-
Volume 13 (1990)
-
Volume 12 (1989)
-
Volume 11 (1988)
-
Volume 10 (1987)
-
Volume 9 (1986)
-
Volume 8 (1985)
-
Volume 7 (1984)
-
Volume 6 (1983)
-
Volume 5 (1982)
-
Volume 4 (1981)
-
Volume 3 (1980)
-
Volume 2 (1979)
-
Volume 1 (1978)
-
Volume 0 (1932)