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S Y Felten

Publications and source records attributed to S Y Felten.

At least 73 records · Page 4Linked to original sources

Noradrenergic sympathetic innervation of the spleen: V. Acute drug-induced depletion of lymphocytes in the target fields of innervation results in redistribution of noradrenergic fibers but maintenance of compartmentation.

Sympathetic noradrenergic fibers follow the vasculature into the white pulp of the spleen and branch from the periarteriolar plexuses into T lymphocyte zones. These lymphocytes, reported to express adrenergic receptors, are contacted directly by norepinephrine (NE) terminals and are putative targets of the locally released NE. Although this splenic innervation has been studied extensively, the functional interdependence of the lymphocytes and the sympathetic innervation is not well understood. To assess the effect of acute lymphocyte loss on the splenic innervation, T and B lymphocytes were depleted through treatment with cyclophosphamide (CY) or hydrocortisone acetate (HC). Despite reductions in spleen weight and cellularity, the total NE content (pmol) per spleen did not change. However, the NE concentration increased in the treated spleens. Although the general compartmental organization of the noradrenergic fibers in the treated spleens was similar to that of controls, the NE fibers redistributed and increased in density around the smaller central arteries in lymphocyte depleted spleens. The accommodation of these NE fibers to the changing environment of the white pulp suggests that the innervation to the spleen remains chemically stable despite a large disruption to the normal splenic milieu, but is capable of plasticity in the face of a shrinking white pulp.

Animals↗

Regulation of the immune system by sympathetic neural mechanisms.

The immune system is made up of primary and secondary lymphoid organs, containing lymphocytes and several accessory cell types, which are the key agents of immunological reactivity. Some of the basic features of immune responses are reviewed. Several pathways from the CNS to the immune system are of potential importance in physiological regulation. The sympathetic nervous system innervates all lymphoid organs with noradrenergic fibers. Furthermore, lymphocytes have receptors for sympathetic neurotransmitters, e.g., beta adrenoceptors. Sympathetic denervation by pharmacologic treatment with 6-hydroxydopamine has a marked affect on several immune responses, including antibody production, delayed hypersensitivity, and generation of cytotoxic T lymphocytes. Norepinephrine, epinephrine, and synthetic adrenergic agonists potentiate cytotoxic T lymphocyte responses in vitro. This appears to be mediated via beta 2 adrenoceptors. Studies with adrenoceptor blockers also indicate a possible role for alpha receptors. In sum, our studies indicate that intact noradrenergic innervation is required for normal immune function. Sympathetic neural influence, via norepinephrine release, may be exerted at the cellular (activation, proliferation, secretion of products) as well as the physiologic (antigen localization, lymphocyte migration) levels.

Animals↗

Alterations of monoamines in specific central autonomic nuclei following immunization in mice.

At the peak of an immune response (Day 4 following immunization) in mice, norepinephrine (NE) was selectively decreased in the paraventricular nucleus (PVN) of the hypothalamus. At times before (Day 2) and after (Day 8) the peak immune response, no changes in NE were found in this nucleus. Decreases in NE were not seen in other hypothalamic sites or in the A1 cell group of the medulla, which sends noradrenergic projections to the hypothalamus, suggesting that the effect is selective and regional. Morphometric evaluation of varicosities revealed no alterations in density of catecholamine-containing varicosities in the PVN, further suggesting that the decrease in NE is a metabolic effect and not a loss or redistribution of fibers. NE also was decreased in the hippocampus on Day 2 at the rising phase of the immune response. In addition, alterations in serotonin levels were found in the brain during an immune response. Serotonin was decreased in the hippocampus on Day 2, was decreased in the PVN and supraoptic nucleus on Day 4, and was increased in the nucleus tractus solitarius (NTS) on Day 2. These results support the presence of a functional link from the activated immune system to central autonomic nuclei interconnecting the hypothalamus, the limbic system, and the autonomic nervous system. In view of the role of the PVN in corticotropin-releasing factor secretion and regulation of autonomic outflow, evidence from lesion studies for hippocampal involvement in immune regulation, and a key role for NTS in regulation of autonomic outflow, the present findings reinforce the potential importance of these brain regions in reciprocal communication between the nervous and immune systems.

Animals↗

Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves.

Inflammatory or allergic conditions, as well as situations where healing and repair processes occur, are characterized by the presence of increased numbers of mast cells. Previous work on the effect of neuropeptides on mast cell mediator release showed that only substance P caused such release from intestinal mucosal mast cells [Shanahan, F., Denburg, J. A., Fox, J., Bienenstock, J. & Befus, A. D. (1985) J. Immunol. 135, 1331-1337]. Accordingly, we investigated the microanatomical relationship between mast cells and enteric nerves in normal rat intestine and parasite-infected rat intestine, in which mucosal mast cell hyperplasia occurs. Combined immunohistochemistry for neuron-specific enolase and staining with alcian blue at pH 0.5 was employed on paraffin-embedded sections of normal and Nippostrongylus brasiliensis-infected rat jejunum. Sixty-seven percent of intestinal mucosal mast cells were touching subepithelial nerves, and an additional 20% were within 2 micron of nerves. Assessment of the proportion of the lamina propria occupied by mast cells (12.5%), the average mast cell area (121 +/- 28 microns 2), and the density of enteric nerves (one per 788 +/- 151 microns 2) suggested that the association was 5 times greater than would be expected by chance alone (P less than 0.0001). In consecutive sections, the nerves in contact with mast cells were also shown to contain substance P and/or calcitonin-gene-related peptide. Electron microscopy confirmed this association: 8% of the mast cells in infected rats exhibited membrane-membrane contact with unmyelinated axons containing 70- to 170-nm dense-core vesicles, and an additional 31% were situated less than 250 nm from nerves. Other mast cells appeared to embrace nerve bundles through the projection of lamellopodia. These data provide systematic quantitative evidence that a structural foundation for communication between the immune and nervous systems exists in the rat gastrointestinal tract.

Animals↗

Noradrenergic innervation of the cerebellar cortex in normal and in Purkinje cell degeneration mutant mice: evidence for long term survival following loss of the two major cerebellar cortical neuronal populations.

Purkinje cell degeneration mutant mice were examined during the course of Purkinje cell death (26 and 35 days old) and at 3, 5, 9 and 12 months of age. Glyoxylic acid fluorescence histochemistry for catecholamines was used to investigate possible alterations or reorganization of the noradrenergic fibers from the coeruleo-cerebellar system in response to the degeneration of two major cell types in the cerebellar cortex, of which one, the Purkinje cell, is reported to be the major target neuron. In control mice, noradrenergic fibers traveled in linear and tortuous profiles through the granule cell layer, formed pericellular arrays alongside Purkinje cell somata, and branched profusely into both radially oriented and longitudinally oriented chains. The density of noradrenergic varicosities diminished in the molecular layer, there was with age. In the mutants, concomitant with the progressive shrinkage of the molecular layer, there was a progressive increase in the density of noradrenergic varicosities. This was most conspicuous at 9 and 12 months of age, at which time the molecular layer has been depleted not only of Purkinje cell dendrites, but also of parallel fibers. Noradrenergic fibers in these zones formed dense parallel bundles of varicose profiles whose density reached 621.3 +/- 122.8% (mean +/- SD, n = 4) at 9-12 months of age, compared with age-matched controls. Neurochemical measurement of norepinephrine content in whole cerebellum of the Purkinje cell degeneration mutants revealed no change compared with age-matched controls. We conclude that noradrenergic innervation persists in the cerebellar cortex despite the death of Purkinje cells and most of the granule cells. Although we found an increased density of varicosities in the molecular layer of mutant mice, progressing with age, we believe that this can be explained on the basis of the resultant geometry of the altered cerebellar cortex. It appears that the health of the environment surrounding the noradrenergic fibers in cerebellar cortex has little influence on their anatomical integrity.

Adrenergic Fibers↗

Involvement of peripheral and central catecholamine systems in neural-immune interactions.

In this review, we have attempted to delineate the current state of knowledge of the relationships between the immune system and one chemically specific component of the nervous system, the noradrenergic system, both in the brain and the periphery. We have discussed recent work describing the presence of noradrenergic innervation in lymphoid tissues in the major lymphatic organs. Our findings demonstrate clearly that the regions in which lymphocytes (mainly T cells) reside, and through which they recirculate, receive direct sympathetic neural input. The immune system can, therefore, be considered 'hard-wired' to the brain. The evidence for receptors on cells of the immune system capable of receiving signals from the brain is discussed. The significance of this 'hard-wiring' to the function of the immune system is considered, both with regard to the effect of its disruption on immune responses, and to the direct and indirect effects of sympathetic neurotransmitter substances on lymphocytes and their behavior in vitro and in vivo. Finally, our detailed analysis of changes occurring in central noradrenergic pathways as a result of stimulation of the immune system leads to an emerging picture of feedback loops from the immune system to the brain. Such circuits employ endocrine, and probably autonomic, outflow to modulate and regulate immune responses.

Adrenergic Fibers↗

Noradrenergic and peptidergic innervation of lymphoid tissue.

Sympathetic noradrenergic nerve fibers innervate both the vasculature and parenchymal fields of lymphocytes and associated cells in several lymphoid organs, including the thymus, spleen, lymph nodes, gut-associated lymphoid tissue (GALT), and bone marrow, in a variety of mammalian species. This innervation is both regional and specific, and generally is directed into zones of T lymphocytes and plasma cells rather than into nodular regions or B lymphocyte regions. In the thymus, noradrenergic fibers enter with nerve bundles and plexuses around blood vessels, travel into the cortex from subcapsular plexuses and with the vasculature, and branch into the parenchyma of the thymic cortex. The vasculature and parenchymal regions of both the outer and deep cortex are innervated by these fibers. In the spleen, noradrenergic fibers enter with the vasculature, travel along the trabeculae and along the branching vasculature, and are distributed mainly in the white pulp along the central artery and associated periarterial lymphatic sheath. Fibers branch from a dense plexus around the central artery and travel into the parenchyma, where they end among fields of lymphocytes and other cell types. In lymph nodes, noradrenergic fibers enter at the hilus, travel along the vasculature and in a subcapsular plexus, and branch into the parenchyma in paracortical and cortical regions, where they end among lymphocytes. In the GALT, represented in these studies by rabbit appendix, sacculus rotundus, and Peyer's patches, noradrenergic fibers enter at the serosal surface, travel longitudinally with the muscularis interna, turn radially into internodular plexuses, plunge directly through the thymus-dependent zones, and ramify profusely among lymphocytes, enterochromaffin cells, and plasma cells in the interdomal regions. In the bone marrow, noradrenergic fibers enter with blood vessels, distribute deeply into the marrow on those vessels, and branch sparsely into the substance of the marrow. Immunocytochemical observations revealed the presence of neuro-peptide-like immunoreactivity in the thymus and spleen. Vasoactive intestinal peptide (VIP)-like immunoreactivity is found in varicose profiles in the thymus within the cortex. In the spleen, immunoreactive profiles showing neuropeptide Y-like, Met-enkephalin-like, cholecystokinin-8 (CCK)-like, and neurotensin-like immunoreactivity are present along the central artery of the white pulp and its smaller branches, with only sparse fibers of most of these peptides entering the parenchyma. CCK-like profiles are present in abundance in the white pulp among parenchymal elements.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic Fibers↗

Anatomical alterations in locus coeruleus neurons in the adult spontaneously hypertensive rat.

A golgi-Cox examination of the locus coeruleus in the spontaneously hypertensive rat (SHR) has shown an increase in the number of primary dendritic branches, in the number of secondary branch points, in the mean length of the dendritic branches from the soma to the outer extent of the secondary branches, and in the longest extent of the dendritic domain in comparison with the locus coeruleus in the Wistar-Kyoto normotensive rats at sixteen weeks of age. We suggest that the anatomical changes may provide a substrate for altered afferent relationships in the neurochemical regulation of neurons of the locus coeruleus, although it remains to be shown whether such alterations are related in any way to blood pressure. It appears evident that the altered mechanisms resulting in hypertension in this genetic model are more complex than an anatomical or neurochemical modification in one of the central autonomic nuclei. However, the present finding that anatomical alterations in the dendritic arborizations of a key nucleus such as the locus coeruleus occur, points towards a need for further examination of the interrelationships of specific neurotransmitter systems in this nucleus.

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Norepinephrine and serotonin in central autonomic nuclei in the spontaneously hypertensive rat and two normotensive control rats.

Neurochemical analysis of norepinephrine and serotonin with high performance liquid chromatography with electrochemical detection (LCEC) in several microdissected central autonomic nuclei of 4 week old and 16 week old spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and control normotensive Wistar rats (WIS), revealed some differences among these strains, but only one change that correlated with the hypertensive state. Norepinephrine levels in the 4 week old SHR were greater in the parabrachial nuclei and the dorsal motor nucleus of X than in the WKY, but levels in the WIS normotensive also were greater than in the WKY, and equalled levels in the SHR. In the 16 week old rats, no difference was noted between NE levels in the SHR and WKY strains, but levels in the locus coeruleus and parabrachial nuclei of the WIS were greater than in both the SHR and WKY. Serotonin levels in the 4 week old SHR and WKY rats did not differ, while levels in the paraventricular nucleus, locus coeruleus, parabrachial nuclei, and medullary raphe nuclei of the WIS rat were greater than one or both of these inbred strains. In the dorsal motor nucleus of X in 16 week old rats, serotonin levels were greater in the SHR than in either the WKY or WIS controls, suggesting one possible transmitter action that should be explored further for its potential relationship to the hypertensive state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Sympathetic innervation of lymph nodes in mice.

Noradrenergic innervation of popliteal and mesenteric lymph nodes in mice was examined with fluorescence histochemistry. Dense varicose plexuses entered the nodes with the vasculature in the hilar region and continued with the vasculature into the medullary region. Fine, delicate varicosities and small vascular plexuses continued into the cortical and paracortical regions surrounding the germinal centers; some varicosities ended among lymphocytes. A subcapsular plexus contributed fibers into the cortical and paracortical regions. Chemical measurements revealed the presence of norepinephrine in lymph nodes that was depletable with 6-hydroxydopamine. Depletion of norepinephrine from lymph nodes with this agent resulted in a diminished primary immune response in draining lymph nodes following subcutaneous injection of an antigen in two mouse strains, but had no effect in two other strains. These findings suggest that noradrenergic fibers innervate both the vasculature and parenchymal regions of lymph nodes, and may participate in the modulation of immune responses in these organs.

Adrenergic Fibers↗

Noradrenergic innervation of the penis in control and streptozotocin-diabetic rats: evidence of autonomic neuropathy.

The noradrenergic sympathetic innervation of the penis of control and 4-month streptozotocin-diabetic rats was examined with the glyoxylic acid histofluorescence method. Noradrenergic varicosities were found in the corpora cavernosa in a dense subtunical plexus and in the perisinusoidal and trabecular regions of the erectile tissue, in the corpus spongiosum in perisinusoidal tissue, around large arteries and veins, and around small tortuous arterioles and small draining veins of the corpora cavernosa and spongiosum. Noradrenergic varicosities were diminished in number and fluorescent intensity in all regions of the penis of diabetic rats compared with controls. The subtunical plexus was absent, perisinusoidal and trabecular varicosities were sparse, and only occasional intermittent, discontinuous, dull fluorescent fibers or plexuses were found around the vessels. Quantitation with high-performance liquid chromatography revealed a significant reduction of norepinephrine in the penis of diabetic rats compared with controls. The present study suggests that long-term streptozotocin diabetes in the rat is accompanied by sympathetic autonomic neuropathy of the penis that seems to parallel changes in the noradrenergic content of penile corpora of men with diabetes and erectile impotence. The streptozotocin-diabetic rat merits further study to explore the relationship between noradrenergic innervation of the penis and erectile tissue.

Animals↗

Effects of streptozotocin diabetes on the noradrenergic innervation of the rat heart: a longitudinal histofluorescence and neurochemical study.

The effects of the age of induction and total duration of streptozotocin diabetes on the sympathetic noradrenergic innervation of the rat heart was examined with glyoxylic acid induced histofluorescence to demonstrate the distribution of noradrenergic fibers within the heart, and with high performance liquid chromatography with electrochemical detection to measure tissue levels of the neurotransmitter norepinephrine. Diabetes was induced in male Sprague-Dawley rats at 1, 2, and 4 months of age. Within each of these groups, diabetic rats survived for periods of 1, 2, and 4 months. Additional groups of diabetic rats survived to a chronological age of 8 months. Norepinephrine levels in the hearts of diabetic rats were increased over those of control rats in all groups at 1 month duration of diabetes. Ventricles were generally affected to a greater extent than atria. At 2 months duration of diabetes, ventricular levels remained elevated while atrial norepinephrine levels were at or below control levels. At 4 months duration of diabetes, and in all groups at 8 months of age, the norepinephrine levels were at or below control levels, except in the ventricles of rats induced at 4 months of age, which remained elevated. Histofluorescence studies demonstrated the presence of axon bundles and varicose noradrenergic profiles in the diabetic rat hearts, distributed in a pattern similar to that seen in controls. However, at 1 month duration of diabetes in all groups, the density of noradrenergic varicosities in diabetic rat hearts appeared increased with abundant branched profiles. These results are surprising, since studies on genetic models of diabetes have suggested decreased norepinephrine levels in the heart. The present study suggests that during the early phases of streptozotocin induced diabetes, noradrenergic nerves are still intact and may be susceptible to pharmacologic manipulation. The later fall of norepinephrine levels back to or below control levels may indicate actual neuronal damage, suggesting that early intervention may be necessary to protect these nerves from degeneration. This issue is potentially important in view of the reported toxic effects of high NE levels on the heart, and the high incidence of death from myocardial infarct in diabetic humans with autonomic neuropathy.

Animals↗

Comparison of the metabolic and toxic effects of 2-chloropropionate and dichloroacetate.

The metabolic and toxic effects of 2-chloropropionate and dichloroacetate, activators of the pyruvate dehydrogenase complex, were compared. In 4-hr fasted mice, the oral LD50 values for 2-chloropropionate and dichloroacetate were 15.4 +/- 0.1 and 32.1 +/- 1.1 mmol/kg, respectively. In suckling rats, both compounds effectively lowered blood lactate and glucose levels and increased blood ketone bodies. Although comparable effects were brought about by both compounds on other metabolites, dichloroacetate caused a greater increase in blood ketone bodies. In a prolonged oral toxicity study using male rats, both compounds decreased growth rate and food consumption and caused neurotoxic effects. Both compounds brought about hind limb weakness, slower nerve conduction velocities and decreased diameter of tibial nerves. 2-Chloropropionate treatment caused testicular abnormalities manifested by testicular maturation arrest and degeneration of germ cells. 2-Chloropropionate-treated rats had significantly lower plasma triacylglycerol levels than control or dichloroacetate-treated rats. In mature rats, total serum ketone bodies were increased by dichloroacetate but not significantly elevated by 2-chloropropionate. Although 2-chloropropionate may lack sufficient safety to warrant chronic use in humans, it is a useful research tool for studying the metabolic effects of activation of the pyruvate dehydrogenase complex. Since 2-chloropropionate is not converted to oxalate and is not as ketogenic as dichloroacetate, 2-chloropropionate may be useful clinically in situations requiring only short-term therapy.

Acetates↗

Noradrenergic sympathetic innervation of lymphoid tissue in the rabbit appendix: further evidence for a link between the nervous and immune systems.

The rabbit appendix, a region of gut with well organized zones of lymphoid tissue, was examined with the glyoxylic acid histofluorescence technique for the localization of noradrenergic fibers, with high performance liquid chromatography with electrochemical detection (LCEC) for the quantitation of norepinephrine and serotonin, with Bielshowski and Giemsa stains for additional information about neural supply, and with acetylcholinesterase histochemistry for the localization of this hydrolytic enzyme. Fluorescent plexuses entered the serosal surface of the appendix associated with blood vessels, traveled longitudinally inside the muscularis interna, mainly in association with blood vessels but adjacent to enteric smooth muscle, and branched into long, linear, varicose plexuses that ran inward in a radial orientation towards the lumen in the internodular septa. As these fibers approached the interdomal regions near the epithelial surface, they passed through thymus-dependent cell zones, and arborized extensively throughout the interdomal region. A high density of varicosities was found in the subepithelial region where immunoglobulin-secreting plasma cells are found. These varicosities were sparse at 21 days of age, but were increased in number at 42 days of age. They were even further increased in number and density in adults. These fibers were further identified with a Bielshowski silver stain, and also demonstrated acetylcholinesterase activity. The noradrenergic varicosities in the interdomal regions of the adult rabbit appendix were closely associated with numerous yellow fluorescent cells of 25-40 microns diameter, which sometimes demonstrated fine varicose processes. The adult rabbit appendix contained a moderate concentration of norepinephrine (163.0 +/- 22.9 ng/g wet weight) and a very high concentration of serotonin (3981 +/- 283 ng/g wet weight). Levels in neonates were considerably lower, suggesting that the yellow fluorescent cells may contain serotonin. Acetylcholinesterase was associated with neural fibers and with non-neural regions of the lymph nodules and the domes, perhaps playing a protective role for these regions of the cellular immune system. The rabbit appendix is a well organized region of lymphoid tissue with specific zones of noradrenergic innervation and possible "paraneuronal" activity, with a readily accessible lumen for the isolation and collections of secretions. We propose this model as an excellent structure for further exploration of interactions between the nervous and immune systems.

Acetylcholinesterase↗