bluuebunny/crossref_metadata_2025 huggingface dataset:
How Do We Approach the Locomotor Network in the Mammalian Spinal Cord?a
Authors: HULTBORN H. , CONWAY B. A. , GOSSARD J.‐P. , BROWNSTONE R. , FEDIRCHUK B. , SCHOMBURG E. D. , ENRÍQUEZ‐DENTON M. , PERREAULT M.‐C.
Published: February 2006

Abstract: For a large number of vertebrate species it is now indisputable that spinal networks have the capability of generating the basic locomotor rhythm. However, because of technical difficulties, the rate of progress in defining the intrinsic properties of mammalian locomotor rhythm generators has been slow in comparison to that made in the study of such networks in lower vertebrates. Investigations on afferent and descending control of locomotor activity in mammals have demonstrated that many of these pathways interact with the rhythm generator. In this review we discuss how these interactions (resetting) can be used for outlining relevant spinal circuits as a basis for a future identification of individual neurons of the spinal locomotor networks. In this overview we have given particular emphasis to selected afferent systems to illustrate the possibilities and problems with this approach.
Initiation of Locomotion in Mammals
Authors: JORDAN LARRY M.
Published: February 2006

Abstract: Several “locomotor regions” of the mammalian brain stem can be stimulated, either electrically or chemically, to induce locomotion. Active cells labeled with c‐fos within the mesencephalic locomotor region (MLR) have been found in the periaqueductal gray, the cuneiform nucleus, the pedunculopontine nucleus, and the locus coeruleus. Different subsets of these nuclei appear to be activated during locomotion produced in different behavioral contexts. The locomotor nuclei can be classified into areas associated with exploratory, appetitive, and defensive locomotion, in accordance with the proposal of Sinnamon (1993, Prog. Neurobiol. 41: 323‐344). The interpretation of lesion studies designed to reveal areas of the brain essential for locomotion must be based on knowledge of the nuclei which become active in the specific locomotor task being tested. An argument is put forward in favor of the continued use of the term “mesencephalic locomotor region.”
Cerebellar‐induced Locomotion: Reticulospinal Control of Spinal Rhythm Generating Mechanism in Catsa
Authors: MORI SHIGEMI , MATSUI TOSHIHIRO , KUZE BUNYA , ASANOME MITSURU , NAKAJIMA KATSUMI , MATSUYAMA KIYOJI
Published: February 2006

Abstract: In a decerebrate cat (locomotor preparation), stimulation of a restricted region along the midline cerebellar white matter has been found to evoke generalized augmentation of postural muscle tone on a stationary surface (Asanome et al. 1998. Neurosci. Res. 30: 257‐269) and “controlled” locomotion on the surface of a moving treadmill. Characteristics of cerebellar‐evoked locomotion were similar to those of mesencephalic locomotor region‐evoked “controlled” locomotion on the same animal. Microinjection of a neural tracer (CTb‐HRP) into the lesioned stimulus site of the cerebellar white matter resulted in both retrograde labeling of cells in the fastigial nuclei, bilaterally, and anterograde labeling of fibers descending to the brain stem. These results indicated that the effective cerebellar stimulus site (cerebellar locomotor region) corresponded to the midline region of the hook bundle of Russell (Rasmussen, A. T., 1933. J. Comp. Neurol. 57: 165‐197), through which crossed fastigioreticular, fastigiovestibular, and fastigiospinal fibers pass. In this study, contribution of reticulospinal systems to the control of cerebellar‐evoked locomotion was extensively studied. By stimulating the cerebellar locomotor region and the MLR in the same animal, a majority of antidromically identified pontomedullary reticulospinal cells were synaptically activated. The results of the present study demonstrated that fastigial cells with crossed fastigioreticular fibers and reticulospinal fibers play a crucial role in the control of posture and locomotion in the locomotor preparation.
Modulation of Information Forwarded to Feline Cerebellum by Monoaminesa
Authors: JANKOWSKA E. , SIMONSBERG I. HAMMAR , CHOJNICKA B.
Published: February 2006

The reported results demonstrate that monoamines modulate activity of three populations of spinocerebellar tract neurons that are rhythmically active during locomotion. However, information on dynamic changes in muscle length and tension (signaled by muscle spindle primary afferents and tendon organs) and on the absolute length of muscles (signaled by muscle spindle secondary afferents) is differently modulated. The transfer of the former is facilitated but that of the latter is either facilitated or depressed; it is facilitated via Clarke's column dorsal spinocerebellar tract neurons and depressed via dorsal horn dorsal spinocerebellar tract neurons. The effects of noradrenaline and serotonin are similar.
Mechanisms of Spontaneous Activity in the Developing Spinal Cord and Their Relevance to Locomotion
Authors: DONOVAN M. J. , WENNER P. , CHUB N. , TABAK J. , RINZEL J.
Published: February 2006

Abstract: The isolated lumbosacral cord of the chick embryo generates spontaneous episodes of rhythmic activity. Muscle nerve recordings show that the discharge of sartorius (flexor) and femorotibialis (extensor) motoneurons alternates even though the motoneurons are depolarized simultaneously during each cycle. The alternation occurs because sartorius motoneuron firing is shunted or voltage‐clamped by its synaptic drive at the time of peak femorotibialis discharge. Ablation experiments have identified a region dorsomedial to the lateral motor column that may be required for the alternation of sartorius and femorotibialis motoneurons. This region overlaps the location of interneurons activated by ventral root stimulation. Whole‐cell recordings from interneurons receiving short latency ventral root input indicate that they fire at an appropriate time to contribute to the cyclical pause in firing of sartorius motoneurons. Spontaneous activity was modeled by the interaction of three variables: network activity and two activity‐dependent forms of network depression. A “slow” depression which regulates the occurrence of episodes and a “fast” depression that controls cycling during an episode. The model successfully predicts several aspects of spinal network behavior including spontaneous rhythmic activity and the recovery of network activity following blockade of excitatory synaptic transmission.
Spinal Motor Patterns in the Turtlea
Authors: STEIN PAUL S. G. , McCULLOUGH MARGARET L. , CURRIE SCOTT N.
Published: February 2006

Abstract: Rhythmic alternation between ipsilateral hip flexors and extensors occurs during the normal pattern of fictive rostral scratching in response to unilateral midbody stimulation in D3‐end turtles (complete spinal transection posterior to the forelimb enlargement). Unilateral midbody stimulation evokes rhythmic bursts of ipsilateral hip flexor activity with no hip extensor activity in D3‐end turtles with D6‐D7 contralateral hemisection (transverse hemisection anterior to the hindlimb enlargement). Bilateral midbody stimulation in these turtles evokes reconstruction of rhythmic alternation between intact side hip flexors and extensors. These normal motor patterns in response to two‐site stimulation are reconstructed because one‐site stimulation in this preparation activates only hip flexor rhythms (J. Neurosci. 18: 467).

Hip flexor rhythms can therefore occur without hip extensor activation. This supports the concept that reciprocal inhibition between flexor and extensor interneurons is not required for flexor motor rhythm generation. Reciprocal inhibition, when present, also contributes to rhythmicity (J. Neurophysiol. 78: 3479; see also Currie and Gonsalves, this volume). Both mechanisms for rhythmicity are included in the Grillner unit burst generator model: hip flexor unit burst generators may be rhythmogenic in the absence of hip extensor activity and reciprocal inhibition contributes to rhythmogenesis.

Contralateral midbody stimulation assisted in the activation of ipsilateral hip extensor rhythmicity during reconstructed rostral scratching. This result provides additional support for the hypothesis that a bilateral shared core of hip interneuronal circuitry plays a critical role in the generation of the normal pattern of fictive rostral scratching (J. Neurosci. 15: 4343).
Distributed Effects of Dopamine Modulation in the Crustacean Pyloric Networka
Authors: HARRIS‐WARRICK RONALD M. , JOHNSON BRUCE R. , PECK JACK H. , KLOPPENBURG PETER , AYALI AMIR , SKARBINSKI JACK
Published: February 2006

Abstract: It is now clear that neuromodulators can reconfigure a single motor network to allow the generation of a family of related movements. Using dopamine modulation of the 14‐neuron pyloric network from the crustacean stomatogastric ganglion as an example, we describe two major mechanisms by which network output is modulated. First, the baseline electrophysiological properties of the network neurons can be altered. Dopamine can affect the activity of each neuron independently. For example, DA modulates IA in nearly every neuron in the pyloric network, but in opposite directions in different cells. Furthermore, DA usually modulates combinations of ionic currents. In some cases, currents with opposing actions on cell excitability are simultaneously affected, and the net response reflects the sum of these opposing effects. Second, neuromodulators can alter the strength of synaptic interactions within the network, quantitatively “rewiring” the network. Every synapse in the network is affected by DA, with some increased and others decreased in strength. DA acts both pre‐ and postsynaptically to affect transmission: these actions are frequently opposing in sign, and the net response arises as the sum of these opposing actions. Finally, spike‐evoked and graded transmission at the same synapse can be oppositely affected by DA. These results emphasize the distributed nature of modulation in motor networks.
Gabaergic Control of Spinal Locomotor Networks in the Neonatal Rat
Authors: CAZALETS JEAN‐REN , BERTRAND SANDRINE , SQALLI‐HOUSSAINI YOUSSEF , CLARAC FRANÇOIS
Published: February 2006

Abstract: We studied the GABAergic control of the spinal locomotor network using an isolated brain stem/spinal cord from newborn rats, in which locomotor‐like activity was recorded. We demonstrate that endogenously released GABA controls the locomotor network, by decreasing or completely abolishing all locomotor‐like activity. At first, we investigated the role played by GABA in the control of the locomotor period. By separately superfusing various compartments of the lumbar cord, we identified the targets of GABA. When bath‐applied on the upper lumbar segments (L1/L2), GABA or its agonists (muscimol, baclofen) modulated the locomotor period, whereas it had no effects when bath‐applied on the caudal lumbar cord (L3/L6). In the second step we studied how GABA may presynaptically control the locomotor drive arising from the locomotor network located in L1/L2. By use of the partitioned spinal cord, intracellular recordings from the caudal pool motoneurons (L4/L5) were performed, while initiating locomotor‐like activity in L1/L2. We found that GABA or its agonists decreased the monosynaptic locomotor drive that the motoneurons received from the L1/L2 network, and we found a presynaptic effect exerted through the activation of GABAB receptors. In conclusion, this study emphasizes the role played by GABA at various levels in the control of the locomotor network in mammals.
NMDA Receptor‐mediated Oscillatory Properties: Potential Role in Rhythm Generation in the Mammalian Spinal Cord
Authors: SCHMIDT BRIAN J. , HOCHMAN SHAWN , MacLEAN JASON N.
Published: February 2006

Abstract: Previous studies have demonstrated that (1) NMDA receptor activation occurs during locomotor network operation in lower and higher vertebrates and (2) NMDA induces active membrane properties that can be expressed as intrinsic voltage fluctuations in cells located in the spinal cord of lower vertebrates, as well as in neurons located in supraspinal regions of the mammalian nervous system. This paper reviews recent data showing that NMDA can induce similiar inherent membrane potential behavior in synaptically isolated motoneurons and interneurons in the mammalian (in vitro neonatal rat) spinal cord. These TTX‐resistant voltage fluctuations include rhythmic oscillations and plateau potentials, as well as low‐frequency long‐lasting voltage shifts (LLVSs). 5‐HT facilitates the transformation of LLVSs into oscillatory events, and 5‐HT receptor antagonists have the reverse effect. In the absence of TTX, locomotor‐related rhythmic drive potentials in spinal cord neurons can display nonlinear voltage behavior compatible with NMDA receptor activation, although other voltage‐activated conductances are not excluded. Suppression of the nonlinear voltage response associated with NMDA receptor activation, via removal of Mg2+, disrupts locomotor patterns of network activity. The potential role of NMDA receptor activation in the operation of mammalian locomotor networks is discussed in the context of these recent observations.
Enhancement and Resetting of Locomotor Activity by Muscle Afferentsa
Authors: PEARSON K. G. , MISIASZEK J. E. , FOUAD K.
Published: February 2006

Abstract:The generation of the normal motor pattern for walking in mammals requires feedback from muscle proprioceptors. Two characteristics of the motor pattern particularly dependent on proprioceptive signals are (1) the magnitude of activity in knee and ankle extensor muscles and (2) the duration of extensor bursts during stance. Sensory regulation of these characteristics ensures that the level of activity in extensor muscles during stance is appropriate for the load carried by the leg and that the swing phase is not initiated when a leg is loaded. Many different groups of afferents from flexor and extensor muscles can influence the locomotor pattern. Most attention has focused on the action of group I afferents from ankle extensors. Electrical stimulation of these afferents during extension increases the duration and the magnitude of extensor activity. The prolongation of extensor activity depends in part on excitation of the extensor half‐center by group Ib afferents from Golgi tendon organs. The enhancement of the magnitude of extensor bursts is produced primarily via disynaptic and polysynaptic pathways opened only during locomotion. The involvement of the proprioceptive signals in the generation of locomotor activity means that the gains in reflex pathways must be constantly calibrated according to the biomechanical properties of the locomotor system. Alteration of these properties by weakening ankle extensor muscles has recently been found to produce compensatory changes in proprioceptive influences on the locomotor pattern.
Frequency Control of a Slow Oscillatory Network by a Fast Rhythmic Input: Pyloric to Gastric Mill Interactions in the Crab Stomatogastric Nervous Systema
Authors: MARDER EVE , MANOR YAIR , NADIM FARZAN , BARTOS MARLENE , NUSBAUM MICHAEL P.
Published: February 2006

Abstract: The stomatogastic nervous system of the crab, Cancer borealis, produces a slow gastric mill rhythm and a fast pyloric rhythm. When the gastric mill rhythm is not active, stimulation of the modulatory commissural ganglion neuron 1 (MCN1) activates a gastric mill rhythm in which the lateral gastric (LG) neuron fires in antiphase with interneuron 1 (Int1). We present theoretical and experimental data that indicate that the period of the MCN1 activated gastric mill rhythm depends on the strength and time course of the MCN1 evoked slow excitatory synaptic potential (EPSP) in the LG neuron, and on the strength of inhibition of Int 1 by the pacemaker of the pyloric network. This work demonstrates a new mechansim by which a slow network oscillator can be controlled by a much faster oscillatory neuron or network and suggests that modulation of the slow oscillator can occur by direct actions on the neurons and synapses of the slow oscillator, or indirectly by actions on the fast oscillator and its synaptic connection with the slow oscillator.
Modeling of the Spinal Neuronal Circuitry Underlying Locomotion in a Lower Vertebratea
Authors: LANSNER ANDERS , HELLGREN KOTALESKI JEANETTE , GRILLNER STEN
Published: February 2006

Abstract: The neural circuitry generating lamprey undulatory swimming is among the most accessible and best known of the vertebrate neuronal locomotor systems. It therefore serves as an experimental model for such systems. Modeling and computer simulation of this system was initiated at a point when a significant part of the network had been identified, although much detail was still lacking. The model has been further developed over 10 years in close interaction with experiments. The local burst generating circuitry is formed by ipsilateral excitatory neurons and crossed reciprocal inhibitory neurons. Early models also incorporated an off‐switch lateral interneuron (L), the connectivity of which suggested it could contribute to burst termination at moderate to high bursting frequencies. Later examination of this model suggested, however, that the L interneuron was not of primary importance for burst termination, and this was later verified experimentally. Further, early models explained the effects of 5‐HT on bursting frequency, spike frequency, and burst duration as being due to its modulatory action on the spike frequency adaptation of lamprey premotor interneurons. In current network models, accumulated adaptation is in addition the main burst terminating factor. Drive‐related modulation of adaptation is explored as a mechanism for control of burst duration. This produces an adequate burst frequency range and a constant burst proportion within each cycle. It further allows for hemisegmental bursting, which has been observed experimentally. The local burst generator forms the basis of a network model of the distributed pattern generator that extends along the spinal cord. Phase constancy and flexibility of intersegmental coordination has been studied in such a simulated network. Current modeling work focuses on neuromodulator circuitry and action, network responses to input transients, how to model the intact versus an isolated piece of spinal cord, as well as on improving an earlier neuromechanical model of lamprey swimming.
Analysis and Modeling of the Locomotor Central Pattern Generator as a Network of Coupled Oscillators
Authors: SIGVARDT KAREN A. , MILLER WILLIAM L.
Published: February 2006

Abstract: The primary functions of spinal locomotor central pattern generators (CPGs) are to provide oscillatory motor commands to individual joints or segments and to control the precise timing of those commands across all joints or segments for efficient, coordinated locomotor behavior. Our ability to understand the neuronal mechanisms underlying intersegmental coordination has been hampered by the complexity of propriospinal interconnectivity and the paucity of quantitative data on the magnitude and timing of those connections. Theoretical approaches have therefore been employed to discover general roles by which CPG‐like oscillator systems must be constructed to produce appropriate coordinated locomotor behavior; the locomotor CPG is represented as a network of oscillators, where each oscillator generates local motor output and interoscillator coupling provides intersegmental coordination. Mathematical analysis of such coupled oscillator systems has provided a number of experimentally testable predictions regarding the link between coupling and coordination. Application of these network‐level predictions to the results of electrophysiological experiments has required data analysis methods that can relate the behavior of the in vitro spinal cord to the variables employed by the mathematical model. Hence, our most recent work has focused on developing analytic tools for quantifying the changes in locomotor output that result form experimental manipulations of the propriospinal system in terms of frequency, intersegmental phase, and intersegmental correlation. Results of recent experiments can now be used to put further constraints on the allowable kinds of intersegmental coupling provided by mathematical modeling of the system.
Zebrafish as a Model System for Studying Neuronal Circuits and Behaviora
Authors: FETCHO JOSEPH R. , LIU KATHARINE S.
Published: February 2006

Abstract: Zebrafish are best known as a model system for studies of the genetics of development. They do, however, also offer many advantages for the study of neuronal circuitry because the larvae are transparent, allowing optical studies of neuronal activity and noninvasive photoablations of individual neurons. The combination of these optical methods with genetics through the use of mutant and transgenic lines of fish should make the zebrafish model a unique and powerful one among vertebrates. Here we review the strengths of the model and the possibilities it offers for studies of the neural basis of behavior.
Engines, Accelerators, and Brakes on Functional Spinal Cord Repaira
Authors: STEEVES JOHN D. , TETZLAFF WOLFRAM
Published: February 2006

Abstract: It is proposed that four essential goals should be met for functional repair after traumatic injury of the adult spinal cord. These include protecting neural tissue after injury and limiting secondary cell damage; replacing lost tissue with transplanted cell “bridges”; blocking the expression of intrinsic factors within the adult CNS that inhibit neural repair; and providing appropriate sensorimotor activity to enhance plasticity within surviving circuits, as well as consolidate any anatomical repair/regeneration. Included is a brief discussion on the approaches and limitations in the evaluation of functional spinal cord repair.
Infection and Xenotransplantation: Developing Strategies to Minimize Risk
Authors: FISHMAN JAY A.
Published: February 2006

ABSTRACT: Infection in transplantation results from interaction between the level of immune suppression and the epidemiologic exposures of the recipient. “Xenosis,” infection in xenotransplantation, may be increased beyond that of allotransplantation because: (1) the xenograaft may serve as a permissive focus of infection for donor‐derived organisms; (2) these organisms may be unknown or xenotropic; (3) microbiologic assays may be unavailable; (4) clinical syndromes due to such novel pathogens may not be recognized; (5) the necessary level of immune suppression may be greater than for allotransplantation; (6) donor‐derived organisms may acquire new (e.g., genetic) characteristics in the human host; (7) the presence of immune suppression and the high, intrinsic rate of infection may mask the presence of xenosis; and (8) MHC‐incompatibility may reduce the efficacy of the immune response within the xenograft. Because immunocompromised individuals are sentinels for infection by many types of novel infectious agents, and because there is some unknown level of risk that such pathogens will spread to the general population, microbiologic studies must be initiated in tandem with preclinical and clinical studies of xenotransplantation.
Developing Guidelines on the Care and Use of Animals
Authors: BAYNE KATHRYN
Published: February 2006

ABSTRACT: Oversight of laboratory animal care and use in the research environment is multilayered. Federal and state regulations apply to many laboratory animal species; funding agencies frequently require adherence to additional guidelines; institutions may develop in‐house policies; and an institution may choose to voluntarily participate in an accreditation program, indicating a commitment by the institution to apply the most rigorous standards to the animal care and use program. In general, regulations follow a prescriptive “engineering” approach, while guidelines applied to the care and use of research animals follow a “performance” approach, which defines the desired outcome in detail, but acknowledges that multiple methods may achieve that outcome. The performance approach relies on sound professional judgment, thereby allowing flexibility based on an institution's unique circumstances. Further, this approach should facilitate the international harmonization of animal care and use standards. The performance, or outcome, approach to developing guidelines is described, using the Guide for the Care and Use of Laboratory Animals (NRC, 1996) as the model.
Defining Appropriate Health Status and Management Programs for Specific‐Pathogen‐Free Swine for Xenotransplantation
Authors: SWINDLE M. MICHAEL
Published: February 2006

ABSTRACT:Swine are expected to be utilized as xenograft donors for both whole‐organ and cellular transplantation. In order to meet the criteria for regulatory guidelines, donor animals are going to have to be free of potential zoonoses and other complicating diseases. Screening of animals will have to include tests for viruses, bacteria, parasites, congenital defects, and other inapparent diseases such as neoplasia or metabolic dysfunctions. The term Specific‐Pathogen‐Free (SPF) swine is a proprietary designation in the U.S. that does not include screening for all appropriate organisms for xenotransplantation. A program for breeding animals as xenograft donors will have to be conducted in a biomedical research facility rather than a conventional farm setting. The research programs at such a facility should include serology, microbiology, necropsy, histology and parasitology. The use of sentinel animal monitoring in a research facility is one method to ensure compliance. It will be impossible to provide complete individual animal screening in a timely fashion prior to performing a xenograft transplant. Quality control measures need to ensure that there is a reasonable confidence that the donor tissue is appropriate for the procedure to be performed. It is suggested that a term such asxenograft‐defined florabe used to designate the appropriate health status of donor animals rather than SPF in order to avoid confusion with existing standards.
Researcher‐Driven Versus Policy‐Driven Economic Appraisal: The Case of Xenotransplantation
Authors: MOATTI JEAN‐PAUL
Published: February 2006

ABSTRACT:Worldwide ethical considerations have led to banning markets for human organs and to promoting supply of organs for transplantation strictly on a donor noncommercial basis. In most industrialized countries, including France, there is a shortage of organs available for transplantation. Following on the earlier debate between Titmuss and Arrow over banning the market for blood supply, this presentation first challenges the conventional economic view that the ban is necessarily responsible for these critical shortages. It will argue that it is the obstacles to adequate exhortation (i.e., the efforts to inform and persuade participants in the donor system who cannot be paid for what they supply) rather than the inefficiency per se of appeals to donor altruism that are the cause of a shortage. The paper will then discuss the way a market for non‐human organs may be an efficient alternative to a donor system by supplying a substitute good. Data from a survey in a random sample of the French general population (≥18 years of age in June 1997; response rate = 62.0%;n= 1,011) show that less than half of the respondents (42.4%) agreed that xenotransplantations should be developed. Support for xenotransplantation was higher (50.6% vs. 38.2% in the rest of the sample,p< 0.001) among respondents who declare that in case of an accidental death of a family member, they would accept the use of his organs for transplantation, among those with the highest level of knowledge about transplantation (48.6% vs. 39.4%,p< 0.005), and among blood donors (45.9% vs. 38.3%,p< 0.02). Supply of non‐human organs should remain under the control of the public sector in order to be consonant with current donor systems for human organs. Recommendations for adequate regulation of the R&D process of non‐human alternatives for organ transplantations will be made.
Stress, Adaptation, and Disease: Allostasis and Allostatic Load
Authors: McEWEN BRUCE S.
Published: February 2006

Abstract: Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine‐immune mechanisms. This has been called “allostasis” or “stability through change” by Sterling and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component of maintaining homeostasis. When these adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed “allostatic load” or the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993; 153:2093.). Allostatic load can lead to disease over long periods. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter‐regulated allostatic systems after stress. Examples will be given for each type of allostatic load from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity. The relationship of allostatic load to genetic and developmental predispositions to disease is also considered.
Hormones, Pregnancy, and Autoimmune Diseases
Authors: WILDER RONALD L.
Published: February 2006

Abstract: Hormonal factors linked to age, gender, and reproductive status are undoubtedly involved in regulating the onset of numerous autoimmune diseases. For example, systemic lupus erythematosus (SLE), a disease characterized by immune complex‐mediated pathology linked to excess Th2 cytokine production (e.g., IL‐10) primarily affects women in the reproductive years. Rheumatoid arthritis (RA), a disease characterized primarily by cell‐mediated joint immunopathology linked to deficient Th2 cytokine production, is also more common in women, but, in contrast to SLE, the highest incidence is at menopause. Pregnancy‐associated changes in these diseases, however, provide the most compelling evidence that hormonal factors play a major role in modulating the expression of these diseases. SLE often flares during pregnancy, whereas RA commonly remits during pregnancy and flares or initially develops in the postpartum period, These observations appear to be explained by the accumulating data indicating that during pregnancy cell‐mediated immune function and Th1 cytokine production (e.g., IL‐12, interferon‐γ) are suppressed, and humoral immunity and Th2 cytokine production (e.g., IL‐4, IL‐10) are enhanced. These patterns reverse in the postpartum period. In other words, antithetical Th1/Th2 cytokine profiles appear to characterize pregnancy and the postpartum period. Strong evidence now indicates that changes in the production of cortisol, progesterone, and estrogen play a major role in modulating Th1/Th2 cytokine balance.
Contribution of the ICE Family to Neurodegeneration
Authors: SHIVERS BRENDA D. , BOXER PETER A. , KEANE KAREN M. , KUPINA NANCY C. , LYNCH TONI , SCHIELKE GERALD P. , VARTANIAN MARK G. , VASILAKOS JOHN P.
Published: February 2006

Abstract: The ICE family of cysteine proteases mediates necrotic or apoptotic events in the nervous system as well as in other tissues. This suggests that inhibitors may be of therapeutic value in acute and, perhaps, chronic neurode‐generative disease. In addition, some members of this family may respond to intercellular signals controling proliferation or differentiation. This possibility should be kept in mind as therapeutics are pursued.
Interleukin‐1‐Induced Plasticity of Hypothalamic CRH Neurons and Long‐Term Stress Hyperresponsivenessa
Authors: TILDERS FRED J. H. , SCHMIDT E. DONNE
Published: February 2006

Abstract: Infections and endotoxin (LPS) can affect hypothalamic CRH neurons and activate the HPA system. This can be prevented by IL‐1 receptor antagonist and mimicked by IL‐1. Chronic activation of the HPA system by repeated or chronic administration of IL‐1 (1 week) to rats is associated with plastic changes in hypothalamic CRH neurons. Single administration IL‐1β (5 μg/kg i.p.) to male Wistar or Lewis rats induced a similar form of neuroplasticity 1‐3 weeks later. This is characterized by a selective increase in coproduction, costorage, and cosecretion of AVP in hypothalamic CRH neurons. Exposure of IL‐1‐primed rats 1‐2 weeks later to foot shocks or IL‐1 resulted in exaggerated ACTH and CORT responses as compared to vehicle‐primed controls. Thus, rats are hyperresponsive to stressors weeks after IL‐1 exposure. In IL‐1‐primed animals, CRH binding and CRH‐ and V1b receptor mRNA levels in the pituitary glands are not altered by IL‐1 exposure 2 weeks earlier. We conclude that IL‐1‐induced, long‐lasting hyperresponsiveness to stressors is primarily caused by functional alterations in the brain that may be directly related to observed plasticity of hypothalamic CRH neurons.
Leukemia Inhibitory Factor Regulates Proopiomelanocortin Transcriptiona
Authors: RAY DAVID W. , REN SONG‐GUANG , MELMED SHLOMO
Published: February 2006

Abstract: Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in both fetal and adult pituitary tissue, and LIF immunoreactivity is found in functional human pituitary tumors. LIF induces basal, and augments CRH‐induced, POMC mRNA and ACTH secretion from AtT20 cells. Therefore, we examined LIF signaling and LIF regulation of POMC expression in AtT20 cells. Immunoneutralization studies demonstrated the dependence of LIF action on both the specific LIF receptor (35% inhibition; p < 0.05) and also the gpl30 affinity converter (41% inhibition; p < 0.05). These antisera also attenuate basal ACTH secretion without added LIF. LIF rapidly induced tyrosyl phosphorylation of both STAT lα, and STATβ and also induced phosphorylation of a novel STAT lα related protein p115. LIF induced POMC transcription (−706/+64) and strikingly potentiated CRH action (up to 18‐fold induction). This synergy involved cAMP‐dependent pathways, as forskolin action was also potentiated by LIF. Deletion of the major CRH‐responsive region in POMC (‐323/‐166) abolished both CRH and LIF action on POMC transcription. Thus LIF action in pituitary corticotrophs is dependent on LIF receptor heterodimerisation with gpl30 and involves STAT protein tyrosyl phosphorylation. LIF enhances POMC transcription and strongly potentiates the well‐documented action of CRH on the POMC gene. These results define a subcellular mechanism for an immuno‐neuroendocrine interface between peripheral afferent signals and the HPA axis.
The Role of IL‐6 Type Cytokines and Their Receptors in Boneaa
Authors: MANOLAGAS STAVROS C.
Published: February 2006

Abstract:Substantial evidence indicates that the IL‐6 type of cytokines have profound effects on bone metabolism by regulating osteoclast and osteoblast development and function. In addition, there is evidence that the gp130 signal transduction pathway may be a critical site for the regulation of the rate of bone remodeling, and probably the coupling of bone resorption to bone formation. Sex steroids inhibit the expression of the genes encoding IL‐6, gp80, and gp130, most likely by repressing the activity of transcription factors such as NFκB and NF‐IL‐6. Considering this and the evidence that IL‐6 autoregulates its own production and can upregulate the components of its receptor, removal of the direct inhibitory effects of sex steroids on IL‐6, gp80, and gp130 could unleash a self‐amplifying cascade of events responsible for increasing not only the production of IL‐6, but also the responsiveness of osteoclast progenitors, osteoblast progenitors, and stromal/osteoblastic cells that support osteoclastogenesis, or combinations of these cells, to IL‐6 type cytokines. Such a scenario could explain both the increased osteoclastogenesis and osteoblastogenesis that follows loss of gonadal function and thereby the effect of such loss on the rate of bone remodeling and skeletal homeostasis. Manipulation of the effects of IL‐6 type cytokines, by selectively targeting to specific bone cell precursors, may allow means of altering the balance between bone resorption and formation in favor of the latter.
Luteinizing Hormone‐Releasing Hormone Is a Primary Signaling Molecule in the Neuroimmune Network
Authors: MARCHETTI BIANCA , GALLO FRANCESCO , FARINELLA ZELINDA , TIROLO CATALDO , TESTA NUCCIO , ROMEO CARMELA , MORALE MARIA C.
Published: February 2006

Abstract: The brain‐pituitary‐reproductive axis and the brain thymus‐lymphoid axis are linked by an array of internal mechanisms of communication that use similar signals (neurotransmitters, peptides, growth factors, hormones) acting on similar recognition targets. Moreover, such communication networks form the basis and control each step and every level of reproductive physiology. This presentation highlights the extent to which endocrine, neural, glial, or immunologically competent cells may achieve their specific functions using common mechanisms, but employing them to different degrees. In particular, this work will focus on LHRH, the chief hormone orchestrating reproductive events. Within the thymus LHRH plays a unique role of immunomodulator, contributing to the sex‐dependent changes in immune responsiveness during the estrous‐menstrual cycle as well as pregnancy. From the recent cloning and sequencing of lymphocyte LHRH, the expression of LHRH receptor mRNA in lymphocyte, the transduction mechanisms involved, and the steroidogenic sensitivity of the intralymphocyte LHRH system. it would appear that this peptide may act as an immunological response modifier in the brain‐pituitary‐lymphoid‐gonadal axis. The interplay between neuronal, endocrine, and immune compartments is further emphasized in the study of LHRH‐astroglial interactions. Astrocytes are able to manufacture a wide variety of signaling agents and can secrete immunoregulatory molecules that influence immune cells, as well as the glial cells themselves. Astroglia and the immortalized hypothalamic LHRH (GT1‐1) neurons communicate with an array of mechanisms, via soluble mediators as well as cell‐to‐cell contacts. Manipulation of astroglial‐derived cytokines and nitric oxide (NO) in GT1‐1 neuron‐astroglia cocultures, underscores a potential cross‐talk between different intra/inter‐cellular mediators in the dynamic control of LHRH release. Further studies aimed to disclose at a biochemical and a molecular level such bidirectional, informative network will give us new insights into more general issues concerned with the malfunction of the neuroendocrine‐immune axis.
Alterations in Sympathetic Noradrenergic Innervation in Lymphoid Organs with Age
Authors: MADDEN KELLEY S. , THYAGARAJAN S. , FELTEN DAVID L.
Published: February 2006

Abstract: Previous work in our laboratories has shown a selective age‐related loss of sympathetic noradrenergic (NA) nerves from the spleen and lymph nodes of rats. In contrast, NA nerve fiber density is dramatically increased in the thymus of aged mice and rats. We hypothesize that the diminished splenic NA innervation in old rats is due to cumulative oxidative metabolic autodestruction of NA nerve terminals by high concentrations of norepinephrine released during specific time periods of immunologic reactivity. These old animals show a loss of NK cell activity, diminished T‐cell proliferation, and diminished cell‐mediated immunity. To assess the plasticity of NA nerve fibers in the aged rat spleen, male Fischer 344 rats at 24 months of age were treated for 2 months with daily injections of 0.25 or 1.0 mg/kg/day of l‐deprenyl, followed by a 10‐day drug washout period. The l‐deprenyl‐treated rats showed a remarkable sprouting of NA nerves into the splenic white pulp, with regrowth into appropriate vascular and parenchymal compartments. Rats with enhanced NA nerve regrowth showed increased IL‐2 and IFN‐γ production and NK cell activity compared with vehicle injected or uninjected age‐matched control rats. We proposed that l‐deprenyl stimulates NA nerve regrowth into secondary lymphoid organs, which leads to partial recovery of measures of immunosenescence.
The Role of the Vagus Nerve in Cytokine‐to‐Brain Communication
Authors: MAIER STEVEN F. , GOEHLER LISA E. , FLESHNER MONIKA , WATKINS LINDA R.
Published: February 2006

Abstract: Peripheral interleukin‐1β (IL‐β) and inflammatory stimuli that induce the synthesis and release of IL‐1β produce a variety of central nervous system responses. Most proposals designed to explain how peripheral IL‐1β influences the CNS have focused on blood‐borne routes of communication. We will review data that indicate that at least some of the CNS response to peripheral IL‐1β are instead mediated by a neural route of communication between the periphery and the CNS. IL‐1β activates afferent vagal fibers that terminate in the nucleus tractus solitarius, and communication via the vagus is responsible for much of the hyperalgesia, fever, anorexia, taste aversions, increased levels of plasma corticosteroid, and brain norepinephrine changes produced by intraperitoneal injections of IL‐1β and LPS. Data extending this analysis to TNF‐α and intravenous routes will be described.
Alternative Pathways of Neural Control of the Immune Process
Authors: REICHLIN SEYMOUR
Published: February 2006

Abstract: Less well established alternative neuromodulatory pathways are neuropeptide‐mediated axon reflexes of sensory neurons, gut immunotrafficing, gut transmucosal transport of endogenous bacterial toxin, and the direct secretion of immunoregulatory cytokines by the brain. TNF‐α and IL‐1ra enter peripheral blood after their intracerebroventricular (i.c.v.) injection. Closed head injury or stroke increases blood IL‐6 and the acute phase response; neuroblastomas immunosuppress by secreting TGF‐β. The IL‐6 that appears in the blood after i.c.v. IL‐1 in the rat is partly derived by secretion from the brain into the superior sagital sinus (Romero et al.; 1996. Am. J. Physiol. 270: R518) and is not dependent on peripheral sympathetic activation. Central endothelium and choroid plexus are potential sources of sagital sinus IL‐6. TNF‐α, which appears in blood after i.c.v. LPS, but not IL‐1β, is due largely to toxin leaving the brain compartment and activating peripheral immunoreactive tissues. Antigens and cytokine immunoregulators drain into cervical lymph. Changes in glial milieu induced by intrinsic neuronal activity could by secretion from brain to blood modulate peripheral immunoreactivity.
A Positive Role for Thymus‐Derived Steroids in Formation of the T‐Cell Repertoire
Authors: VACCHIO MELANIE S. , ASHWELL JONATHAN D. , KING LESLIE B.
Published: February 2006

Abstract: T cells undergo rigorous selection processes in the thymus that are necessary to prevent T cells with either autoreactive or nonfunctional T‐cell receptors (TCRs) from entering the periphery. Although both positive and negative selection depend on TCR‐mediated signals, the means by which a thymocyte interprets these signals to result in survival or death is not understood. Glucocorticoids are known to induce thymocyte apoptosis at high concentrations, but at lower concentrations glucocorticoids can antagonize TCR‐mediated deletional signals and allow survival of thymocytes and T cell hybridomas. Interestingly, transgenic mice in which the expression of the glucocorticoid receptor has been downmodulated specifically in thymocytes have abnormal thymocyte differentiation, indicating that glucocorticoids play a significant role in T‐cell development. Furthermore, we have demonstrated the presence of steroidogenic enzymes in the thymic epithelium and can show that, in vitro, these cells readily synthesize pregnenolone, the first product in the steroidogenic pathway, and deoxycorticosterone. Inhibition of local glucocorticoid biosynthesis in thymi from TCR transgenic mice during fetal thymic organ culture (FTOC) revealed significant alterations in the process of thymocyte selection. These data suggest that glucocorticoids do not simply suppress the immune system but rather are necessary for thymocyte survival and differentiation.
Cellular and Molecular Aspects of Thymic T‐Cell Education in Neuroendocrine Self Principles: Implications for Autoimmunitya
Authors: GEENEN VINCENT , MARTENS HENRI , VANDERSMISSEN ERIC , ACHOUR IMANE , KECHA OUAFAE , FRANCHIMONT DENIS
Published: February 2006

Abstract: Thymic epithelial and nurse cells from different species express a repertoire of neuroendocrine polypeptide precursors. This repertoire exerts a dual role in T‐lymphocyte selection according to their status either as cryptocrine signals or as neuroendocrine self‐antigens of the peptide sequences that are processed from those precursors then presented to pre‐T cells. Thymic neuroendocrine self‐antigens correspond to peptide sequences highly conserved throughout evolution of their family. Though thymic MHC class I molecules are involved in the processing of thymic neuroendocrine self‐antigens, preliminary data show that their presentation to pre‐T cells is not allelically restricted. Thymic T‐cell education in neuroendocrine families also implies that the structure of a given family may be presented to pre‐T cells. Our studies have evidenced the homology between thymic neuroendocrine‐related self‐antigens and dominant T‐cell epitopes of peripheral neuroendocrine signals (neuroendocrine autoantigens). The biochemical difference between neuroendocrine autoantigens and homologous thymic self‐antigens might explain the opposite immune responses evoked by those two types of antigens (activation and memory induction vs. tolerogenic effect). Altogether, these studies support the therapeutic use of thymic neuroendocrine self‐antigens in reprogramming the immunological self‐tolerance that is broken in autoimmune endocrine diseases like insulin‐dependent diabetes type I. As recently stated by P. M. Allen in an important review, the fate of developing T lymphocytes in the thymus is influenced by the numerous types of peptidic interactions within the thymic cellular environment. 1 To define the precise nature of thymic cells and naturally occurring biochemical peptide signals involved in positive and negative selection of immature T cells has become a prominent objective for the future research efforts in thymic physiology. This paper will try to show how thymic neuroendocrine‐related peptides synthesized and processed within the thymic microenvironment indeed can play a role both in the development of the peripheral T‐cell repertoire and in the death of randomly rearranged, self‐reactive T cells.
Regulation of Inhibitory Pathways of the Interleukin‐1 System
Authors: MANTOVANI A. , MUZIO M. , GHEZZI P. , COLOTTA C. , INTRONA M.
Published: February 2006

Abstract: The IL‐1 system includes two agonists, converting enzymes, antagonists, and two receptors (R). New elements and functions in the system will be discussed, including (a) cloning of a new isoform of the receptor antagonist; (b) further analysis of the type II IL‐1‐binding molecule as a decoy R. The modulation of IL‐1R by chemotactic signals was recently investigated. It was found that chemoattractants cause rapid release of the type II decoy R from myelomonocytic cells with a t1/2 of 30 sec. Induction of decoy R release represents an early event in the multistep process of recruitment. It may serve to block the systemic action of IL‐1 leaking from sites of inflammation, while preserving responsiveness in situ. We recently cloned the first long pentraxin, PTX3 (human and mouse, cDNA and genomic) as an IL‐1‐inducible gene. The structural and functional features of this molecule as well as initial evidence of involvement in human pathology will be discussed.