Neuropeptides and the microcircuitry of the enteric nervous system

The discovery of neuropeptides in enteric neurons has revolutionized the study of the microcircuitry of the enteric nervous system. From 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.     

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.     

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.

     

The presence of monoamines in the nervous system ofPeripatopsis (Onychophora)

Summary Preliminary observations of formaldehyde-induced fluorescence support the suggestion that monoamines such as noradrenaline, dopamine and 5-hydroxytryptamine are transmitter agents in the central nervous system of Onychophora.Acknowledgments. We wish to thank Dr M. Fillenz for valuable advice and for generously enabling this work to be carried out, and we are indebted to Dr V. van der Lande for material.     

The potential therapeutic role of statins in central nervous system autoimmune disorders

3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of mevalonate are also involved in posttranslational modification of specific proteins involved in cell proliferation and differentiation. Thus, statins have important biologic effects that may be independent of their cholesterol-reducing properties. Recent studies indicate that statins have antiinflammatory and neuroprotective properties which may be beneficial in the treatment of multiple sclerosis as well as other central nervous system (CNS) neurodegenerative diseases. This article will outline current experimental evidence that may suggest potential clinical benefits for patients with CNS autoimmune disorders. Ultimately, clinical trials will have to determine the safety and efficacy of statins in this patient population.Received 17 April 2003; received after revision 21 May 2003; accepted 22 May 2003     

The role of apolipoprotein E in lipid metabolism in the central nervous system

The critical roles of apolipoprotein E (apoE) in regulating plasma lipid and lipoprotein levels have been extensively studied for over 2 decades. However, an understanding of the roles of apoE in the central nervous system (CNS) is less certain. This review will summarize the available experimental results on the role of apoE in CNS lipid homeostasis with respect to its modulation of sulfatide trafficking, alteration of CNS cholesterol homeostasis and apoE-induced changes in phospholipid molecular species in specialized subcellular membrane fractions. The results indicate that apoE mediates sulfatide trafficking and metabolism in the CNS. Moreover, although apoE does not affect the cholesterol mass content or the phospholipid mass levels and composition in the CNS as a whole, apoE modulates cholesterol and phospholipid homeostasis in selective subcellular membrane compartments. Through elucidating the roles of apoE in CNS lipid metabolism, new insights into overall functions of apoE in neurobiology can be accrued ultimately, leading to an increased understanding of CNS lipid metabolism and the identification of novel therapeutic targets for CNS diseases.Received 9 January 2004; received after revision 28 February 2004; accepted 10 March 2004     

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     

Multitasking with neurotensin in the central nervous system

The 13-amino acid peptide neurotensin (NT) was discovered over 30 years ago and has been implicated in a wide variety of neurotransmitter and endocrine functions. This review focuses on four areas where there has been substantial recent progress in understanding NT signaling and several functions of the endogenous peptide. The first area concerns the functional activation of the high-affinity NT receptor, NTR-1, including the delineation of the NT binding pocket and receptor domains involved in functional coupling to intracellular signaling pathways. The development of NT receptor antagonists and the application of genetic and molecular genetic approaches have accelerated progress in understanding NT function in several areas, including the involvement of NT in antipsychotic drug actions, psychostimulant sensitization and the modulation of pain, and these are reviewed in that order. There is now substantial evidence indicating that NT is required for certain antipsychotic drug actions and that the peptide plays a key role in stress-induced analgesia.Received 18 March 2005; received after revision 9 May 2005; accepted 23 May 2005     

Heat shock response in the central nervous system

The heat shock response is induced in nervous tissue in a variety of clinically significant experimental models including ischemic brain injury (stroke), trauma, thermal stress and status epilepticus. Excessive excitatory neurotransmission or the inability to metabolically support normal levels of excitatory neurotransmission may contribute to neuronal death in the nervous system in many of the same pathophysiologic circumstances. We demonstrated that in vitro glutamate-neurotransmitter induced excitotoxicity is attenuated by the prior induction of the heat shock response. A short thermal stress induced a pattern of protein synthesis characteristic of the highly conserved heat shock response and increased the expression of heat shock protein (HSP) mRNA. Protein synthesis was necessary for the neuroprotective effect. The study of the mechanisms of heat shock mediated protection may lead to important clues as to the basic mechanisms underlying the molecular actions of the HSP and the factors important for excitotoxic neuronal injury. The clinical relevance of these findings in vitro is suggested by experiments performed by others in vivo demonstrating that pretreatment of animals with a submaximal thermal or ischemis stress confers protection from a subsequent ischemic insult.     

A central nervous system depressant-antidepressant.

A new tricyclic agent with an allenyl side chain experimentally shows antidepressant activity similar to amitriptyline and imipramine but also exerts marked CNS depression. Such dual activity should be of clinical interest for treatment of mixed anxiety and depression.     

The early effects of low DDT doses on the nervous system in animal experiments

Zusammenfassung Es wurde bei Verabreichung eines mit 40-0,5 mg DDT/kg Körpergewicht vermischten Futters an Ratten festgestellt, dass 40 und 20 mg DDT die Frequenz und Amplitude, 10 mg nur die Amplitude des spontanen EEG erhöht. Bei Verabreichung von 5 mg waren, bei stroboskoper Belastung, die Veränderungen noch sichtbar. Dosen zwischen 20 und 2,5 mg verminderten die Dauer und Tiefe der auf den Gehirnstamm als Angriffspunkt wirkenden Nembutalnarkose. Dosen von 2 bis 0,5 mg blieben wirkungslos. Die Vermutung wird ausgesprochen, dass sich durch DDT im Gehirnstamm ein Irritationsherd im Zusammenhang mit der Anhäufung von Acetylcholin bildet.     

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.     

The effect of central nervous system stimulation on plasma erythropoietin levels in rhesus monkeys

Zusammenfassung Elektrische Reizung der Nuclei supraoptici und preoptici hypothalami, ebenso der eminentia mediana hatte eine signifikante Erhöhung des Plasma Erythropoietins zur Folge, nicht aber bei Reizung der Nuclei mammillaria hypothalami und commissura anterior. Es wird der hypothalamische Einfluss auf die Erythropoiese kurz erörtert.     

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.     

The nature of the solitary active cells of the central nervous system

Résumé Les cellules actives isolées du système nerveux central démontrées par la méthode deHess-Pearse pour le TPN-H diaphorase, sont des neurones. Ceux-ci sont identifiés par une méthode de coloration argentine que l'on peut pratiquer directement sur les coupes enzymatiques. La recette de cette méthode est donnée.     

The enteric neural receptor for 5-hydroxytryptamine

An enteric neural receptor for serotonin (5-HT) has been characterized. This receptor was assayed, using 3H-5-HT as a radioligand, by rapid filtration of isolated enteric membranes and by radioautography. In addition, intracellular recordings were made from ganglion cells of the myenteric plexus. High affinity, saturable, reversible, and specific binding of 3H-5-HT was demonstrated both to membranes of the dissected longitudinal muscle with adherent myenteric plexus and the mucosa-submucosa. Radioautographs showed these 3H-5-HT binding sites to be in myenteric ganglia and in a broad unresolved band at the mucosal-submucosal interface. Antagonists active at receptors for other neurotransmitters than 5-HT, at either of the two known types of CNS 5-HT receptor, and at 5-HT uptake sites on serotonergic neurons failed to inhibit binding of 3H-5-HT. The structural requirements of analogues for binding to the enteric 5-HT receptor matched the known pharmacology of M or neural 5-HT receptors. A novel 5-HT antagonist was found. This compound, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP), antagonized the action of 5-HT on type II/AH cells of the myenteric plexus but did not affect the release or actions of acetylcholine (nicotinic or muscarinic) or substance P. 5-HTP-DP was also an equally potent displacer of 3H-5-HT from its binding sites on enteric membranes. It is concluded that the sites responsible for specific binding of 3H-5-HT are enteric M or neural 5-HT receptors. These receptors differ from those now known to be present in the CNS.