Neuropeptides and the microcircuitry of the enteric nervous system

Summary The discovery of neuropeptides in enteric neurons has revolutionized the study of the microcircuitry of the enteric nervous system. Form immunohistochemistry, it is now clear that some individual enteric neurons contain several different neuropeptides with or without other transmitter-specific markers and that these markers occur in various combinations. There is evidence from experiments in which nerve pathways are interrupted that populations of enteric neurons with different combinations of markers have different projection patterns, sending their processes to distinct targets using different routes. Correlations between the neurochemistry of enteric neurons and the types of synaptic inputs they receive are also beginning to emerge from electrophysiological studies. These findings imply that enteric neurons are chemically coded by the combinations of peptides and other transmitter-related substances they contain and that the coding of each population correlates with its role in the neuronal pathways that control gastrointestinal function.     

The enteric nervous system in gastrointestinal disease etiology

A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut–brain interaction, inflammatory bowel diseases, and colorectal cancer.

     

Kinesins in the nervous system

Both the development and the maintenance of neurons require a great deal of active cytoplasmic transport. Much of this transport is driven by microtubule motor proteins. Membranous organelles and other macromolecular assemblies bind motor proteins that then use cycles of adenosine 5'-triphosphate hydrolysis to move these 'cargoes' along microtubules. Different sets of cargoes are transported to distinct locations in the cell. The resulting differential distribution of materials almost certainly plays an important part in generating polarized neuronal morphologies and in maintaining their vectorial signalling activities. A number of different microtubule motor proteins function in neurons; presumably they are specialized for accomplishing different transport tasks. Questions about specific motor functions and the functional relationships between different motors present a great challenge. The answers will provide a much deeper understanding of fundamental transport mechanisms, as well as how these mechanisms are used to generate and sustain cellular asymmetries.     

Central nervous system and hibernation

Conclusions The role of the nervous system in the mechanism of hibernation is extremely important. The special properties of the brain of hibernators permits them wonderfully to resist to hypoxia and hypothermia, such as this state ofneural hibernation, a reversible hypothermia whichBullard, David andNichols ⁶⁰ have obtained in the thirteen-lined ground squirrel (Citellus tridecimlineatus) by hypoxia at a low temperature.The study of the glycolysis of the brain of hibernators has revealed that the brain of hibernators (European hamster) uses more glucose and produces more lactic acid than the brain of homoiotherms (albino rat). One finds, therefore, in hibernators two metabolic manifestations which are known to increase the resistance to hypoxia and hypothermia.The study of ATP synthesis by isolated mitochondriae of the brain of hibernators shows that this synthesis is more intense in them than in homiotherms.The recording of cerebral waves indicates that during hibernation the cortex of hibernators remains excitable and manifests, either after external disturbances or without any apparent cause, periods of electrogenesis.The role of the nervous system as an integrator of the arousal mechanism has clearly appeared in the researches on the electric activity of the various subcortical systems.Hibernation appears as a metabolic regulation at a minimum level (Wyss ⁶¹), a regulation in which the role of central nervous system is capital: its functional suppression, e.g. by anesthesia, leads to fatal hypothermias (Benedict andLee ⁶²,Kayser ⁶³,Strumwasser ⁴⁰).

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Résumé Le sommeil hivernal est une régulation métabolique à minimum (Wyss ⁶¹). Cette régulation exige une température optimale de l'ambiance audessus et au-dessous de laquelle les échanges respiratoires de l'hibernant sont augmentés.Le système nerveux central est responsable de cette régulation: si l'on supprime l'activité des centres nerveux de l'hibernant par des anesthésiques on supprime sa faculté de régler ses échanges et l'hibernant meurt en hypothermie (Benedict etLee ⁶²).Les centres nerveux de l'hibernant en sommeil hivernal restent excitables en dépit de la profonde hypothermie. L'hibernant partage cette faculté avec les homéothermes nouveau-nés, incomplètement développés. La résistance des centres nerveux à l'hypothermie se trouve associée dans les deux cas à une résistance accrue à l'hypoxie.L'étude du métabolisme cellulaire de la substance nerveuse des hibernants et des mammifères nouveaunés révèle une consommation de glucose et une production d'acide lactique accrues. Vu que le blocage de la consommation de glucose et de la glycolyse supprime la résistance à l'hypoxie, il est naturel d'attribuer la résistance spéciale du système nerveux des hibernants et des jeunes mammifères à cette particularité métabolique.L'intensité de la formation de l'acide adényl-triphosphorique par les mitochondries des cellules nerveuses des hibernants est aussi plus marquée que chez les homéothermes de même taille pris comme témoins. Cette seconde manifestation semble aussi correspondre à une adaptation particulière de l'activité des centres nerveux des hibernants à des conditions de fonctionnement spéciales.Le sommeil hivernal ne s'explique pas uniquement par les particularités fonctionnelles du système nerveux des hibernants. Le sommeil hivernal est une manifestation saisonnière liée à des facteurs externes (température, lumière, nourriture) et à des facteurs internes (cycle saisonnier des glandes endocrines;Kayser ⁵⁹). Mais seules les particularités fonct onnelles du système nerveux des hibernants autorisent une adaptation de l'hibernant aux conditions de vie en hypothermie. C'est la raison pour laquelleBullard et al.⁶⁰ ont pu réaliser chez un Spermophile américain ce qu'ils ont appelé le «Neural state of hibernation». C'est la même raison qui permet la survie de 30 jours en hypothermie du Lérot à jeun vivant à +5°C en été (Kayser ²³), avec une dépense d'énergie qui ne diffère à peu près pas de celle du Lérot en hibernation en plein hiver.

     

Collagens in the developing and diseased nervous system

Collagens are extracellular proteins characterized by a structure in triple helices. There are 28 collagen types which differ in size, structure and function. Their architectural and functional roles in connective tissues have been widely assessed. In the nervous system, collagens are rare in the vicinity of the neuronal soma, occupying mostly a “marginal” position, such as the meninges, the basement membranes and the sensory end organs. In neural development, however, where various ECM molecules are known to be determinant, recent studies indicate that collagens are no exception, participating in axonal guidance, synaptogenesis and Schwann cell differentiation. Insights on collagens function in the brain have also been derived from neural pathophysiological conditions. This review summarizes the significant advances which underscore the function and importance of collagens in the nervous system. Received 09 September 2008; received after revision 24 October 2008; accepted 28 October 2008     

Neuronal and glial markers of the central nervous system

This brief review evaluates the expression of cell-specific markers on differentiated neural cells and, where necessary, on their developing precursors. Within these limitations only the commonly used markers are discussed and those deemed unequivocal are only briefly appraised.     

Neuronal and glial markers of the central nervous system

Summary This brief review evaluates the expression of cell-specific markers on differentiated neural cells and, where necessary, on their developing precursors. Within these limitations only the commonly used markers are discussed and those deemed unequivocal are only briefly appraised.     

Developmental and pathological angiogenesis in the central nervous system

Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood–brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.     

Relaxin family peptide systems and the central nervous system

Since its discovery in the 1920s, relaxin has enjoyed a reputation as a peptide hormone of pregnancy. However, relaxin and other relaxin family peptides are now associated with numerous non-reproductive physiologies and disease states. The new millennium bought with it the sequence of the human genome and subsequently new directions for relaxin research. In 2002, the ancestral relaxin gene RLN3 was identified from genome databases. The relaxin-3 peptide is highly expressed in a small region of the brain and in species from teleost to primates and has both conserved sequence and sites of expression. Combined with the discovery of the relaxin family peptide receptors, interest in the role of the relaxin family peptides in the central nervous system has been reignited. This review explores the relaxin family peptides that are expressed in or act upon the brain, the receptors that mediate their actions, and what is currently known of their functions.     

Neurotrophins and neuronal differentiation in the central nervous system

The central nervous system requires the proper formation of exquisitely precise circuits to function properly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. For these circuits to form correctly, neurons must elaborate precisely patterned axonal and dendritic arbors. Although the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections remain mostly unknown, the neurotrophins have emerged recently as attractive candidates for regulating neuronal differentiation in the developing brain. The experiments reviewed here provide strong support for a bifunctional role for the neurotrophins in axonal and dendritic growth and are consistent with the exciting possibility that the neurotrophins might mediate activity-dependent synaptic plasticity.     

Neuropeptides of the silkworm,Bombyx mori

Six neuropeptides of the silkworm,Bombyx mori, have been isolated and chemically characterized during the past 10 years. They are bombyxin, prothoracicotropic hormone, pheromone-biosynthesis-activating neuropeptide/melanization-and-reddish-coloration hormone, diapause hormone, eclosion hormone, and adipokinetic hormone. Recent progress in research on these neuropeptides is described.     

Neuropeptides of the silkworm, Bombyx mori.

Six neuropeptides of the silkworm, Bombyx mori, have been isolated and chemically characterized during the past 10 years. They are bombyxin, prothoracicotropic hormone, pheromone-biosynthesis-activating neuropeptide/melanization-and-reddish-coloration hormone, diapause hormone, eclosion hormone, and adipokinetic hormone. Recent progress in research on these neuropeptides is described.     

Receptor and nonreceptor protein tyrosine phosphatases in the nervous system

Protein tyrosine phosphatases (PTPs) have emerged as a new class of signaling molecules that play important roles in the development and function of the central nervous system. They include both tyrosine-specific and dual-specific phosphatases. Based on their cellular localization they are also classified as receptor-like or intracellular PTP. However, the intracellular mechanisms by which these PTPs regulate cellular signaling pathways are not well understood. Evidence gathered to date provides some insight into the physiological function of these PTPs in the nervous system. In this review, we outline what is currently known about the functional role of PTPs expressed in the brain.Received 31 March 2003; received after revision 7 May 2003; accepted 22 May 2003     

Central nervous system stem cells in the embryo and adult

The central nervous system is generated from neural stem cells during embryonic development. These cells are multipotent and generate neurons, astrocytes and oligodendrocytes. The last few years it has been found that there are populations of stem cells also in the adult mammalian brain and spinal cord. In this paper, we review the recent development in the field of embryonic and adult neural stem cells. Received 26 March 1998; received after revision 27 April 1998; accepted 27 April 1998     

Axon guidance at the central nervous system midline

A key feature of the central nervous system of most higher organisms is their bilateral symmetry about the midline. The specialised cells that lie at the midline have an essential role in regulating the axon guidance decisions of both neurons that project axons across the midline and those that project on one side. The midline cells produce both attractive and repellent short- and long-range signals to guide axonal growth. The axons themselves express specific receptors that can be dynamically regulated in response to midline-derived signals. In this way, axons extend toward or away from the midline and those that do cross change their behaviour to respond to longitudinal signals on the contralateral side.