Showing papers in "The Neuroscientist in 2002"

Electrodermal responses: what happens in the brain.

Abstract: Electrodermal activity (EDA) is now the preferred term for changes in electrical conductance of the skin, including phasic changes that have been referred to as galvanic skin responses (GSR), that result from sympathetic neuronal activity. EDA is a sensitive psychophysiological index of changes in autonomic sympathetic arousal that are integrated with emotional and cognitive states. Until recently there was little direct knowledge of brain mechanisms governing generation and control of EDA in humans. However, studies of patients with discrete brain lesions and, more recently, functional imaging techniques have clarified the contribution of brain regions implicated in emotion, attention, and cognition to peripheral EDA responses. Moreover, such studies enable an understanding of mechanisms by which states of bodily arousal, indexed by EDA, influence cognition and bias motivational behavior.

GABA and glutamate in the human brain.

Abstract: Cortical excitability reflects a balance between excitation and inhibition. Glutamate is the main excitatory and GABA the main inhibitory neurotransmitter in the mammalian cortex. Changes in glutamate and GABA metabolism may play important roles in the control of cortical excitability. Glutamate is the metabolic precursor of GABA, which can be recycled through the tricarboxylic acid cycle to synthesize glutamate. GABA synthesis is unique among neurotransmitters, having two separate isoforms of the rate-controlling enzyme, glutamic acid decarboxylase. The need for two separate genes on two chromosomes to control GABA synthesis is unexplained. Two metabolites of GABA are present in uniquely high concentrations in the human brain. Homocarnosine and pyrrolidinone have a major impact on GABA metabolism in the human brain. Both of these GABA metabolites have anticonvulsant properties and can have a major impact on cortical excitability.

Ion Regulation in the Brain: Implications for Pathophysiology

Abstract: Ions in the brain are regulated independently from plasma levels by active transport across choroid plexus epithelium and cerebral capillary endothelium, assisted by astrocytes. In "resting" brain tissue, extracellular potassium ([K+]o) is lower and [H]o is higher (i.e., pHo is lower) than elsewhere in the body. This difference probably helps to maintain the stability of cerebral function because both high [K]o and low [H+]o enhance neuron excitability. Decrease in osmolarity enhances synaptic transmission and neuronal excitability whereas increased osmolarity has the opposite effect. Iso-osmotic low Na+ concentration also enhances voltage-dependent Ca2+ currents and synaptic transmission. Hypertonicity is the main cause of diabetic coma. In normally functioning brain tissue, the fluctuations in ion levels are limited, but intense neuronal excitation causes [K+]o to rise and [Na+]o, [Ca2+]o to fall. When excessive excitation, defective inhibition, energy failure, mechanical trauma, or blood-brain barrier defects drive ion levels beyond normal limits, positive feedback can develop as abnormal ion distributions influence neuron function, which in turn aggravates ion maldistribution. Computer simulation confirmed that elevation of [K+]o can lead to such a vicious circle and ignite seizures, spreading depression (SD), or hypoxic SD-like depolarization (anoxic depolarization).

Role of superoxide dismutases in oxidative damage and neurodegenerative disorders.

Abstract: In recent years, oxidative stress has been implicated in a variety of degenerative processes, diseases, and syndromes. Some of these include atherosclerosis, myocardial infarction, stroke, and ischemia/reperfusion injury; chronic and acute inflammatory conditions such as wound healing; central nervous system disorders such as forms of familial amyotrophic lateral sclerosis (ALS) and glutathione peroxidase-linked adolescent seizures; Parkinson's disease and Alzheimer's dementia; and a variety of other age-related disorders. Among the various biochemical events associated with these conditions, emerging evidence suggests the formation of superoxide anion and expression/activity of its endogenous scavenger, superoxide dismutase (SOD), as a common denominator. This review summarizes the function of SOD under normal physiological conditions as well as its role in the cellular and molecular mechanisms underlying oxidative tissue damage and neurological abnormalities. Experimental evidence from laboratory animals that either overexpress (transgenics) or are deficient (knockouts) in antioxidant enzyme/protein levels and the genetic SOD mutations observed in some familial cases of ALS are also discussed.

Genealogy of the “Grandmother Cell”

Abstract: A “grandmother cell” is a hypothetical neuron that responds only to a highly complex, specific, and meaningful stimulus, such as the image of one’s grandmother. The term originated in a parable Jerry Lettvin told in 1967. A similar concept had been systematically developed a few years earlier by Jerzy Konorski who called such cells “gnostic” units. This essay discusses the origin, influence, and current status of these terms and of the alternative view that complex stimuli are represented by the pattern of firing across ensembles of neurons.

Environment, Mitochondria, and Parkinson's Disease

Abstract: Parkinson's disease (PD) is a common and disabling neurodegenerative disease marked by progressive motor dysfunction, which results from selective degeneration of the nigrostriatal pathway. Epidemiological studies indicate that exposure to pesticides, rural living, farming, and drinking well water are associated with an increased risk of developing PD. Rare cases of PD are caused by mutations in nuclear genes, and there is increasing evidence for susceptibility genes that alter disease risk. Parkinson's disease is also associated with a systemic defect in mitochondrial complex I activity. Animal models indicate that exposure to inhibitors of mitochondrial complex I, including pesticides, is sufficient to reproduce the features of PD, but genetic factors clearly modulate susceptibility. Complex I defects may result in oxidative stress and increase the susceptibility of neurons to excitotoxic death. In this way, environmental exposures and mitochondrial dysfunction may interact and result in neurodegeneration.

How do we tell time

Abstract: Animals time events on scales that range more than 10 orders of magnitude-from microseconds to days. This review focuses on timing that occurs in the range of tens to hundreds of milliseconds. It is within this range that virtually all the temporal cues for speech discrimination, and haptic and visual processing, occur. Additionally, on the motor side, it is on this scale that timing of fine motor movements takes place. To date, psychophysical data indicate that for many tasks there is a centralized timing mechanism, but that there are separate networks for different intervals. These data are supported by experiments that show that training to discriminate between two intervals generalizes to different modalities, but not different intervals. The mechanistic underpinnings of timing are not known. However various models have been proposed, they can be divided into labeled-line models and population clocks. In labeled-line models, different intervals are coded by activity in independent and discrete populations of neurons. In population models, time is coded by the population activity of a large group of neurons, and timing requires dynamic interaction between neurons. Population models are generally better suited for parallel processing of interval, duration, order, and sequence cues and are thus more likely to underlie timing in the range of tens to hundreds of milliseconds.

The Wnt Signaling Pathway in Bipolar Disorder

Abstract: The Wnt signaling pathway is a highly conserved pathway critical for proper embryonic development. However, recent evidence suggests that this pathway and one of its key enzymes, glycogen synthase kinase 3beta, may play important roles in regulating synaptic plasticity, cell survival, and circadian rhythms in the mature CNS-all of which have been implicated in the pathophysiology and treatment of bipolar disorder. Furthermore, two structurally highly dissimilar medications used to treat bipolar disorder, lithium and valproic acid, exert effects on components of the Wnt signaling pathway. Together, these data suggest that the Wnt signaling pathway may play an important role in the treatment of bipolar disorder. Here, the authors review the modulation of the Wnt/GSK-3beta signaling pathway by mood-stabilizing agents, focusing on two therapeutically relevant aspects: neuroprotection and modulation of circadian rhythms. The future development of selective GSK-3beta inhibitors may have considerable utility not only for the treatment of bipolar disorder but also for a variety of classical neurodegenerative disorders.

Two phylogenetic specializations in the human brain.

Abstract: In this study, two anatomical specializations of the brain in apes and humans are considered. One of these is a whole cortical area located in the frontal polar cortex (Brodmann’s area 10), and the other is a morphologically distinctive cell type, the spindle neuron of the anterior cingulate cortex. The authors suggest that the spindle cells may relay to other parts of the brain—especially to area 10, the outcome of processing within the anterior cingulate cortex. This relay conveys the motivation to act. It particularly concerns the recognition of having committed an error that leads to the initiation of adaptive responses to these adverse events so as to reduce error commission. This capacity is related to the development of self-control as an individual matures and gains social insight. Although the anterior cingulate deals with the individual’s immediate response to changing conditions, area 10 is involved in the retrieval of memories from the individual’s past experience and the capacity to plan adap...

Neural coding and the basic law of psychophysics.

Abstract: There have been three main ideas about the basic law of psychophysics. In 1860, Fechner used Weber's law to infer that the subjective sense of intensity is related to the physical intensity of a stimulus by a logarithmic function (the Weber-Fechner law). A hundred years later, Stevens refuted Fechner's law by showing that direct reports of subjective intensity are related to the physical intensity of stimuli by a power law. MacKay soon showed, however, that the logarithmic and power laws are indistinguishable without examining the underlying neural mechanisms. Mountcastle and his colleagues did so, and, on the basis of transducer functions obeying power laws, inferred that subjective intensity must be related linearly to the neural coding measure on which it is based. In this review, we discuss these issues and we review a series of studies aimed at the neural mechanisms of a very complex form of subjective experience-the experience of roughness produced by a textured surface. The results, which are independent of any assumptions about the form of the psychophysical law, support the idea that the basic law of psychophysics is linearity between subjective experience and the neural activity on which it is based.

Calcium Dysregulation in the Aging Brain

Abstract: The idea that age-related cognitive decline is associated with disruption of calcium (Ca2+) homeostasis has been investigated over the past two decades. Much of this work has focused on the hippocampus because hippocampal-dependent memory is age sensitive. It is now well established that Ca(2+)-dependent processes such as susceptibility to neurotoxicity, the afterhyperpolarization amplitude, induction of synaptic plasticity, and long-term potentiation and long-term depression are altered with age. Recent work has identified changes in Ca2+ signaling pathways that may underlie the development of these biological markers of aging. This review considers recent findings concerning interactions between the various Ca(2+)-dependent processes, with special emphasis on the role of altered Ca2+ regulation and disruption of Ca2+ signaling pathways in mediating the expression of biological and behavioral markers of brain aging.

Interleukin-6 (IL-6): A Possible Neuromodulator Induced by Neuronal Activity

Abstract: IL-6 and its receptor(s) are found in the CNS in health and disease. Cellular sources are glial cells and neurons. Glial production of IL-6 has intensively been studied, but comparatively little is known about the induction of IL-6 in neurons. Emerging evidence suggests that IL-6 possesses neurotrophic properties. Recent data show that neuronal IL-6 expression is induced by excitatory amino acids or membrane depolarization. This implicates that IL-6 is produced not only under pathological conditions but may play a critical role as a physiological neuromodulator that is induced by neuronal activity and regulates brain functions. In the following article, the authors review the current data on IL-6 expression in neurons, with special reference to the induction of IL-6 by neuronal activity. They discuss its direct and indirect effects as a neuromodulator and speculate about the possible function of IL-6 as a physiological regulatory molecule and as a neuroprotective agent in brain pathology.

Mechanisms of hypoxic neurodegeneration in the developing brain.

Abstract: Asphyxia and other insults to the developing brain are responsible for several human neurodevelopmental disorders. The pattern of neonatal brain injury differs from that seen in the adult nervous system, and there are wide differences in regional vulnerability. Recent evidence suggests that two events that contribute to this pattern of selective vulnerability are developmental changes in excitatory glutamate-containing neurotransmitter circuits and the propensity for immature neurons to die by apoptosis rather than necrosis. Developmental up-regulation of NMDA receptors with enhanced function and increased expression of caspase-3 at critical periods in development are linked to these mechanisms. Although these molecular changes enhance the developing brain's capacity for plasticity by helping to prune redundant synapses and neurons, they can become "Achilles heels" in the face of a brain energy crisis.

The Role of Neurotrophins in Neurotransmitter Release

Abstract: The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling o...

Matrix Metalloproteinases and Neuroinflammation in Multiple Sclerosis

Abstract: Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes. Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barre, and multiple sclerosis (MS). The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB). They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin. During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons. Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect. Agents that block the action of the MMPs have been shown to reduce the damage to the BBB and lead to symptomatic improvement in several animal models of neuroinflammatory diseases, including experimental allergic encephalomyelitis. Such agents may eventually be useful in the control of excessive proteolysis that contributes to the pathology of MS and other neuroinflammatory conditions.

Inflammation, apoptosis, and Alzheimer's disease.

Abstract: The pathophysiology of Alzheimer's disease (AD) involves the deposition of amyloid in the brain and the extensive loss of neurons. The mechanisms subserving neuronal death in the disease remain unclear, although it has been postulated that this is due to apoptosis. There is compelling evidence that inflammatory processes play a role in disease progression and pathology. Amyloid plaque deposition is accompanied by the association of microglia with the senile plaque, and this interaction stimulates these cells to undergo phenotypic activation and the subsequent elaboration of proinflammatory and neurotoxic products. This review focuses on the mechanisms by which neurons are lost in AD and the role microglial proinflammatory products play in neuronal death.

Book Review: Metabotropic Glutamate Receptors: Electrical and Chemical Signaling Properties

Abstract: Over the last two decades, glutamate has been established as the main excitatory neurotransmitter in the mammalian brain. Glutamate released from synapses activates ion channel-forming receptors at postsynaptic cells and consequently mediates fast postsynaptic potentials. These receptors are termed ionotropic glutamate receptors (iGluRs). The subsequent discovery of metabotropic glutamate receptors (mGluRs) revealed that glutamate can also mediate slow synaptic potentials, modulate ion channels, and directly couple to GTP binding proteins. In contrast to the iGluRs, the mGluRs possess seven transmembrane domains and a large intracellular C-terminus that involves interactions with a variety of other intracellular signaling systems. Eight functionally distinct mGluR subtypes are known to be localized to specific neuron types at presynaptic and/or postsynaptic membranes. Their physiological functions involve the generation of slow excitatory and inhibitory synaptic potentials, modulation of synaptic transmis...

Modular organization of spinal motor systems.

Abstract: The vertebrate nervous system produces a wide range of movement flexibly and efficiently, even though the simplest of these movements is potentially highly complex. The strategies by which the nervous system overcomes these complexities have therefore been of interest to motor physiologists for decades. In this review, the authors present a number of recent experiments that propose one strategy by which the nervous system might simplify the production of movement. These experiments suggest that spinal motor systems are organized in terms of a small number of distinct motor responses, or "modules." These distinct modules can be combined together simply to produce a wide range of different movements. Such a modular organization of spinal motor systems can potentially allow the nervous system to produce a wide range of natural behaviors in a simple and flexible manner.

Epilepsy as an Example of Neural Plasticity

Abstract: Epilepsy is a devastating disease affecting more than 1% of the population. Yet, if one considers the neurobiological substrates of this disease, what is revealed is an array of phenomenon that exemplify the remarkable capacity for the brain to change its basic structure and function, that is, neural plasticity. Some of these alterations are transient and merely impressive for their extent, or for their robust nature across animal models and human epilepsy. Others are notable for their persistence, often enduring for months or years. As an example, the dentate gyrus, and specifically the principal cell of the dentate gyrus, the granule cell, is highlighted. This area of the brain and this particular cell type, for reasons that are currently unclear, hold an uncanny capacity to change after seizures. For those interested in plasticity, it is suggested that perhaps the best examples for studying plasticity lie in the field of epilepsy.

Prostaglandin D2 in Sleep-Wake Regulation: Recent Progress and Perspectives:

Abstract: Prostaglandin (PG) D2 is one of the most active endogenous sleep-promoting substances, which induces physiological sleep in rodents, primates, and most probably in humans as well. In this update article, we review recent experimental results concerning the molecular mechanisms underlying sleep-wake regulation by PGD2, the link between the humoral regulation by the PGD2 system, and the neural network involved in the promotion of non-rapid eye movement (NREM) sleep and the abnormality of NREM sleep regulation found in gene-manipulated mice for PGD synthase.

Do You Know Your Brain? A Survey on Public Neuroscience Literacy at the Closing of the Decade of the Brain

Abstract: What does the public know about the developments offered by brain research? What factors influence public neuroscience literacy? What issues need to be emphasized to the public? To address these questions, a survey was conducted using a questionnaire with 95 assertions, answered by indicating yes, no, or I don't know. The opinions of 35 senior neuroscientists and 2158 members of the public of Rio de Janeiro were heard on issues such as the mind-brain relationship, the senses, learning, and memory. The incidence of "correct" answers among the public improved the most with schooling, followed by reading of popular science magazines and of newspapers. An analysis of the responses to each assertion revealed which themes are well- or poorly known to the public. The results attest for the importance of popular scientific communication and indicate issues on which communication efforts should be concentrated in order to increase public awareness about the brain.

Book Review: Protein Kinase Signal Transduction Cascades in Mammalian Associative Conditioning

Abstract: One of the most intriguing and intensely studied questions facing contemporary neuroscientists involves the elucidation of the physiological mechanisms that underlie learning and memory. Recent advances have given us a much more detailed understanding of the signal transduction mechanisms subserving learning in the intact animal. One fact that has become clear is that activation of protein kinases and phosphorylation of their downstream effectors play a critical role. Four protein kinase cascades have garnered considerable attention in the study of information storage at both the synaptic and behavioral levels: Ca++/phospholipid-dependent protein kinase (PKC), Ca++/calmodulin-dependent protein kinase II (CaMKII), cAMP-dependent protein kinase (PKA), and extracellular signal-regulated kinase (ERK). This review will concentrate on studies of two behavioral tasks, conditioned fear and conditioned taste aversion, that provide evidence for the involvement of these kinase systems in associative learning. The authors will also examine a number of potential kinase substrates and how each could participate in the formation of long-term memories.

Iron and Parkinson's disease.

Abstract: Multiple studies implicate iron in the pathophysiology of Parkinson's disease (PD). In the brains of patients with PD, iron levels are elevated and the levels of iron-binding proteins are abnormal. Iron has been suspected to contribute to PD because Fe(II) is known to promote oxidative damage. Recent studies suggest that an additional mechanism by which iron might contribute to PD is by inducing aggregation of the alpha-synuclein, which is a protein that accumulates in Lewy bodies in PD.

Cellular replacement therapy for Parkinson's disease--where we are today?

Abstract: The concept of replacing lost dopamine neurons in Parkinson's disease using mesencephalic brain cells from fetal cadavers has been supported by over 20 years of research in animals and over a decade of clinical studies. The ambitious goal of these studies was no less than a molecular and cellular "cure" for Parkinson's disease, other neurodegenerative diseases, and spinal cord injury. Much research has been done in rodents, and a few studies have been done in nonhuman primate models. Early uncontrolled clinical reports were enthusiastic, but the outcome of the first randomized, double blind, controlled study challenged the idea that dopamine replacement cells can cure Parkinson's disease, although there were some significant positive findings. Were the earlier animal studies and clinical reports wrong? Should we give up on the goal? Some aspects of the trial design and implantation methods may have led to lack of effects and to some side effects such as dyskinesias. But a detailed review of clinical neural transplants published to date still suggests that neural transplantation variably reverses some aspects of Parkinson's disease, although differing methods make exact comparisons difficult. While the randomized clinical studies have been in progress, new methods have shown promise for increasing transplant survival and distribution, reconstructing the circuits to provide dopamine to the appropriate targets and with normal regulation. Selected promising new strategies are reviewed that block apoptosis induced by tissue dissection, promote vascularization of grafts, reduce oxidant stress, provide key growth factors, and counteract adverse effects of increased age. New sources of replacement cells and stem cells may provide additional advantages for the future. Full recovery from parkinsonism appears not only to be possible, but a reliable cell replacement treatment may finally be near.

Cortex governs multisensory integration in the midbrain.

Abstract: Neurons in the superior colliculus (SC), a prominent midbrain structure, are able to synthesize information from different senses. This synthesis plays an important role in determining whether SC-mediated orientation behaviors will be initiated. In some circumstances, multisensory integration in the SC is evident as a response that is significantly enhanced above that evoked by the most effective single-modality stimulus. It can sometimes even exceed the arithmetic sum of the single-modality responses. In other circumstances, multisensory integration is evident as response depression, an effect sometimes powerful enough to eliminate even robust single-modality responses. The conditions that produce multisensory enhancement also increase the probability of orientation responses, and those that produce multisensory response depression decrease the probability of orientation responses. Although one might posit that the capability to integrate cross-modal cues (and, in this case, alter overt behavior) would be evident in all neurons capable of responding to stimuli from two or more sensory modalities, this turns out to be incorrect. When descending influences from the cortex are temporarily inactivated, SC neurons are rendered unable to synthesize their multiple sensory inputs, and animals no longer show enhanced orientation responses. Nevertheless, the ability to respond to cues from multiple sensory modalities is retained at both the single neuron and behavioral levels. Two cortical areas have been implicated in controlling these midbrain processes: the anterior ectosylvian sulcus and the rostral lateral suprasylvian sulcus.

The Cadherin Family of Cell Adhesion Molecules: Multiple Roles in Synaptic Plasticity

Abstract: Cadherins are cell adhesion molecules that are critically important for establishing brain structure and connectivity during early development. They are enriched at synapses and, by virtue of a number of properties including homophilic recognition and molecular diversity, have been implicated in the generation of synaptic specificity. Cadherins also participate in remodeling synaptic architecture and modifying the strength of the synaptic signal, thereby retaining an active role in synaptic structure, function, and plasticity, which extends beyond initial development. Cadherins have been implicated in the induction of long-term potentiation (LTP) of hippocampal synaptic strength, a cellular model for learning and memory. LTP is associated with the synthesis and recruitment of N-cadherin to newly forming synaptic junctions, induces molecular changes to N-cadherin indicative of augmented adhesive force, and can be prevented when cadherin adhesion is blocked. NMDA receptor activation, which is critically required for synaptic plasticity, may provide a signal that regulates the molecular configuration of synaptic N-cadherin, and therefore the strength of adhesion across the synaptic cleft. Additionally, there exists at the synapse a pool of surface cadherins that is untethered to the actin cytoskeleton and capable of a rapid and reversible dispersion along the plasmalemma under conditions of strong activity. These observations suggest that synaptic activity dynamically regulates both the strength and the localization of cadherin-cadherin bonds across the synaptic junctional interface, changes that may be crucial for regulating synaptic plasticity.

Brain specialization for music.

Abstract: Music, like language, is a universal and specific trait to humans. Similarly, music appreciation, like language comprehension, appears to be the product of a dedicated brain organization. Support for the existence of music-specific neural networks is found in various pathological conditions that isolate musical abilities from the rest of the cognitive system. Cerebrovascular accidents, traumatic brain damage, and congenital brain anomalies can lead to selective disorders of music processing. Conversely, autism and epilepsy can reveal the autonomous functioning and the selectivity, respectively, of the neural networks that subserve music. However, brain specialization for music should not be equated with the presence of a singular "musical center" in the brain. Rather, multiple interconnected neural networks are engaged, of which some may capture the essence of brain specialization for music. The encoding of pitch along musical scales is likely such an essential component. The implications of the existence of such special-purpose cortical processes are that the human brain might be hardwired for music.

The Thalamic Reticular Nucleus: More Than a Sensory Nucleus?

Abstract: Sensory information is routed to the cortex via the thalamus, but despite this sensory bombardment, animals must attend selectively to stimuli that signal danger or opportunity. Sensory input must be filtered, allowing only behaviorally relevant information to capture limited attentional resources. Located between the thalamus and cortex is a thin lamina of neurons called the thalamic reticular nucleus (Rt). The thalamic reticular nucleus projects exclusively to thalamus, thus forming an essential component of the circuitry mediating sensory transmission. This article presents evidence supporting a role for Rt beyond the mere relay of sensory information. Rather than operating as a component of the sensory relay, the authors suggest that Rt represents an inhibitory interface or "attentional gate," which regulates the flow of information between the thalamus and cortex. Recent findings have also implicated Rt in higher cognitive functions, including learning, memory, and spatial cognition. Drawing from recent insights into the dynamic nature of the thalamic relay in awake, behaving animals, the authors present a speculative account of how Rt might regulate thalamocortical transmission and ultimately the contents of consciousness.

Multiple Sclerosis as a By-Product of the Failure to Sustain Protective Autoimmunity: A Paradigm Shift

Abstract: Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.

The Globus Pallidus, Deep Brain Stimulation, and Parkinson's Disease

Abstract: Parkinson's disease (PD) is caused by the degeneration of the dopaminergic neurons in the substantia nigra Loss of dopaminergic innervation leads to hyperactivity in the internal segment of the globus pallidus (GPi), the main output nucleus of the basal ganglia and to a profound disturbance in the function of motor circuits Lesions of the GPi (or in its upstream modulator, the subthalamic nucleus) can greatly improve the motor symptoms of PD presumably by reducing this pathological activity Paradoxically, high-frequency electrical stimulation of the GPi (deep brain stimulation, DBS) mimics the effects of pallidotomy and has become an accepted therapeutic technique The mechanisms underlying the beneficial effects of pallidal DBS are not known Various mechanisms that might account for inhibiting or disrupting the pathological pallidal outflow by high-frequency DBS have been proposed ranging from depolarization block to stimulation-evoked release of GABA, and these are discussed