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.     

The enteric neural receptor for 5-hydroxytryptamine

Summary An enteric neural receptor for serotonin (5-HT) has been characterized. This receptor was assayed, using³H-5-HT as a radiologand, 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 of³H-5-HT was demonstrated both to membranes of the dissected longitudinal muscle with adherent myenteric plexus and the mucosa-submucosa. Radioautographs showed these³H-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 of³H-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 of³H-5-HT from its binding sites on enteric membranes. It is concluded that the sites responsible for specific binding of³H-5-HT are enteric M or neural 5-HT receptors. These receptors differ from those now known to be present in the CNS.     

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.     

Histone deacetylases: Focus on the nervous system

Neurodegenerative disease strikes millions worldwide and there is mounting evidence suggesting that underlying the onset and progression of these debilitating diseases is inappropriate neuronal apoptosis. Recent reports have implicated a family of proteins known as histone deacetylases (HDACs) in various neuronal processes including the neuronal death program. Initial headway in this field has been made largely through the use of broad-spectrum HDAC inhibitors. In fact, pharmacological inhibition of HDAC activity has been shown to protect neurons in several models of neurodegeneration. The observation that HDAC inhibitors can have opposing effects in different paradigms of neurodegeneration suggests that individual members of the HDAC protein family may play distinct roles that could depend on the specific cell type under study. The purpose of this review is to detail work involving the use of HDAC inhibitors within the context of neurodegeneration and examine the roles of individual HDAC members in the nervous system with specific focus on neuronal cell death. Received 25 January 2007; received after revision 3 April 2007; accepted 26 April 2007     

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     

The role of the autonomic nervous system in mediating pancreatic endocrine responses to arginine in the calf

Summary The release of insulin which occurred in response to arginine, in the conscious calf, differed from that which occurs in response to glucose in that it was not significantly affected by either adrenergic or muscarinic blocking agents. Release of pancreatic glucagon was reduced by pretreatment with phentolamine.This work was supported by the British Diabetic Association. It is a particular pleasure to acknowledge the skilled assistance provided by Messrs P. M. M. Bircham and G. P. McGregor.     

Ecdysteroid receptors located in the central nervous system of an insect

Summary Using thaw-mount autoradiography for steroid hormones, we obtained direct evidence for a nuclear localization of ecdysteroid binding sites in target organs of blowfly (Calliphora vicina) larvae. The binding sites revealed properties of ecdysteroid receptors. Endocrine cells of the ring gland were found to be target tissues of ecydysteroids. This observation provides morphological evidence for a network of complex interendocrine regulation. In the central nervous system receptorcontaining neurons were identified which include many, if not all, neurosecretory cells of the brain. A map of ecdysteroid sensitive cells of the larval brain is presented.     

Local and target-derived actions of neurotrophins during peripheral nervous system development

Neurotrophic factors are present in limiting quantities, and neurons that obtain an adequate supply of the required neurotrophic factor survive whereas those that compete unsuccessfully die. Analysis of null mutant mice for neurotrophins and Trk receptors as well as in vivo experiments in ovo in the chick applying exogenous neurotrophins or neutralising antisera have significantly increased knowledge of the roles they play during development. This review focuses on recent advances in understanding the various roles of neurotrophins in dorsal root ganglion sensory neuron development at different times in embryonic development - an early local role for differentiation of the sensory precursor cells and a later survival-promoting target-derived role for the mature neurons. Neurotrophic factors are present in limiting quantities, and neurons that obtain an adequate supply of the required neurotrophic factor survive whereas those that compete unsuccessfully die. Analysis of null mutant mice for neurotrophins and Trk receptors as well as in vivo experiments in ovo in the chick applying exogenous neurotrophins or neutralising antisera have significantly increased knowledge of the roles they play during development. This review focuses on recent advances in understanding the various roles of neurotrophins in dorsal root ganglion sensory neuron development at different times in embryonic development - an early local role for differentiation of the sensory precursor cells and a later survival-promoting target-derived role for the mature neurons.     

The innate immunity of the central nervous system in chronic pain: The role of Toll-like receptors

Toll-like receptors (TLRs) are a family of pattern recognition receptors that mediate innate immune responses to stimuli from pathogens or endogenous signals. Under various pathological conditions, the central nervous system (CNS) mounts a well-organized innate immune response, in which glial cells, in particular microglia, are activated. Further, the innate immune system has emerged as a promising target for therapeutic control of development and persistence of chronic pain. Especially, microglial cells respond to peripheral and central infection, injury, and other stressor signals arriving at the CNS and initiate a CNS immune activation that might contribute to chronic pain facilitation. In the orchestration of this limited immune reaction, TLRs on microglia appear to be most relevant in triggering and tailoring microglial activation, which might be a driving force of chronic pain. New therapeutic approaches targeting the CNS innate immune system may achieve the essential pharmacological control of chronic pain. Received 21 November 2006; received after revision 8 January 2007; accepted 7 February 2007     

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     

Stereological analysis of lipofuscin in the central nervous system ofTorpedo marmorata: correlation with superoxide dismutase distribution

Summary It was observed that superoxide dismutase activity was inversely proportional to the amount of lipofuscin present in the various anatomotopographical areas of theTorpedo marmorata central nervous system. These results support the theory that age pigments are a product of free lipoperoxidation induced by free radicals.Part of the present work was presented at XIIth Int. Pigment Cell Conference, Giessen (FRG), 17–19 September 1983.     

Tachykinins and their functions in the gastrointestinal tract

In the gastrointestinal tract, tachykinins are peptide neurotransmitters in nerve circuits that regulate intestinal motility, secretion, and vascular functions. Tachykinins also contribute to transmission from spinal afferents that innervate the gastrointestinal tract and have roles in the responses of the intestine to inflammation. Tachykinins coexist with acetylcholine, the primary transmitter of excitatory neurons innervating the muscle, and act as a co-neurotransmitter of excitatory neurons. Excitatory transmission is mediated through NK1 receptors (primarily on interstitial cells of Cajal) and NK2 receptors on the muscle. Tachykinins participate in slow excitatory transmission at neuro-neuronal synapses, through NK1 and NK3 receptors, in both ascending and descending pathways affecting motility. Activation of receptors (NK1 and NK2) on the epithelium causes fluid secretion. Tachykinin receptors on immune cells are activated during inflammation of the gut. Finally, tachykinins are released from the central terminals of gastrointestinal afferent neurons in the spinal cord, particularly in nociceptive pathways. Received 24 March 2007; received after revision 30 August 2007; accepted 14 September 2007     

Suboesophageal DUM neurones are part of the antennal motor system of locusts and crickets

Summary The muscles which move the antennae of locusts and crickets are innervated by motoneurones of the deutocerebral part of the brain. In addition, these muscles receive axon collaterals of two dorsal, unpaired, median (DUM) neurones which are located in the suboesophageal ganglion. These DUM neurones also send axons towards the retrocerebral glandular complex.     

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.     

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.     

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.     

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.