Noradrenergic sympathetic innervation of lymphoid organs.
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Adrenergic Fibers↗
Biomedical subjects
D L Felten
Publications and source records attributed to D L Felten.
Selective loss of monoaminergic neurons in weaver mutant mice--an immunocytochemical study.
Tyrosine hydroxylase (TH) immunocytochemistry and quantitative light microscopic analysis of neurons in the substantia nigra pars compacta, the ventral tegmental area, and the locus coeruleus of weaver mutant mice at 12 and 15 weeks of age and unaffected controls revealed a decrease in the number of TH-positive neurons in the substantia nigra of weaver mice, but no change in cell numbers in the ventral tegmental area and locus coeruleus. Furthermore, the 15-week-old mutants showed a significant cell loss in the substantia nigra pars compacta compared with the 12-week-old group. Thus, the weaver mutant may provide a good model for studying the mechanisms of selective dopaminergic cell loss.
Animals↗
Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp.
Sympathetic noradrenergic nerve fibers, stained with antiserum for tyrosine hydroxylase (TH), richly innervate the splenic white pulp. These fibers distribute with the vascular and trabecular systems, and associate mainly with the central artery and its branches, the periarteriolar lymphatic sheath (PALS), the marginal sinus, and the parafollicular zone, with occasional delicate fibers also present in the follicles. Simultaneous staining of TH-positive nerve fibers and markers for specific lymphoid cells has shown several regions of contact between nerves and lymphocytes or macrophages. The TH-positive nerve fibers in the plexuses around the central arterial system and in the PALS are present among T lymphocytes (OX-19-positive cells) including both T helper and T suppressor cells, and interdigitating cells. At the marginal sinus, TH-positive fibers run adjacent to macrophages (ED3-positive cells), B lymphocytes (IgM-positive), and intensely fluorescent IgM-positive cells. Along the parafollicular zone, TH-positive nerve fibers run adjacent to T lymphocytes, peripheral follicular B lymphocytes, and intensely fluorescent IgM-positive cells. Within some follicles, delicate fibers end adjacent to both T and B lymphocytes. These relationships suggest a direct interaction between norepinephrine release from the TH-positive nerve terminals and the lymphocytes and macrophages closely associated with them, and focuses attention on the potential neural modulation of related functions such as T and B lymphocyte entry into the spleen and antigen capture (marginal zone), antigen presentation and T cell activation (PALS), B cell activation (parafollicular zone and marginal zone), and lymphocyte egress (outer marginal zone).
Animals↗
Noradrenergic sympathetic innervation of the spleen: III. Development of innervation in the rat spleen.
The ontogeny of noradrenergic innervation and its compartmental development were studied in the rat spleen using glyoxylic acid histofluorescence and high-performance liquid chromatography (HPLC). Noradrenergic nerves were present at birth in bundles adjacent to the splenic artery and vein. On days 1-3, fluorescent profiles largely were associated with the vasculature and with the perivascular zone. By day 6, these fibers formed increasingly elaborate and tortuous plexuses around the central arteries and their branches. By day 10, fibers were present along the marginal sinus and extended into the developing marginal zone. Between day 10 and day 13 the largest increase in norepinephrine (NE) levels (per mg protein) were noted, and the periarteriolar lymphatic sheath (PALS) achieved its adult form, with increased innervation of the parenchyma. In contrast, the venous/trabecular system developed relatively late. The first trabecular fibers were evident at day 10, and the capsule was not innervated until day 13. From 13 days to adulthood, there was a gradual refinement and extension of existing patterns with no change in NE levels as measured by HPLC (per mg protein), suggesting that the innervation was keeping pace with rapid increases in spleen growth. The pattern of growth and development for noradrenergic nerves in the PALS remarkably parallels changes in T cell compartmentation during this period. We propose that norepinephrine is available for interaction with T cells at the earliest stages of development and could play a role in such processes as lymphocyte packing and the onset of immunocompetence.
Aging↗
Noradrenergic sympathetic innervation of the spleen: IV. Morphometric analysis in adult and aged F344 rats.
Noradrenergic postganglionic sympathetic innervation of the spleen in 8-month-old (adult) and 27-month-old (aged) Fischer 344 (F344) rats was examined using fluorescence histochemistry for catecholamines coupled with stereologic point-counting analysis for quantitation of noradrenergic varicosities. Noradrenergic varicosities in the spleen were evaluated in four compartments: (1) vascular-, (2) trabecular-, (3) capsular-, and (4) parenchymal-associated fibers. The 27-month-old rats were subdivided further into two groups based upon behavioral testing for gustatory neophobia, a condition reported to be associated with acute locus coeruleus lesions in young rats and with diminished norepinephrine (NE) levels in central noradrenergic neurons in aged rats. In the 8-month-old rats, spleens displayed abundant innervation. Noradrenergic plexuses entered the spleen with the splenic artery and its branches, distributed into capsular and trabecular compartments, and followed the vasculature and trabeculae into splenic white pulp. Noradrenergic fibers entered the white pulp mainly in association with the central artery and its branches; liner and punctate varicosities branched mainly from vascular plexuses into the large, well-defined parenchyma of the white pulp, ending primarily among fields of T lymphocytes. Some fibers extended along the inner edge of the marginal zone and the parafollicular zone. Few noradrenergic varicosities were found in the red pulp. In both groups of aged rats, sympathetic noradrenergic innervation was diminished markedly.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
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↗
Brain, behavior, and immunity.
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Homeostasis↗
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↗
Immune interactions with specific neural structures.
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Encephalitis↗
Noradrenergic sympathetic neural interactions with the immune system: structure and function.
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Animals↗
Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults.
Parkinson's disease is a neurodegenerative disorder characterized mainly by damage to the dopaminergic nigrostriatal system. Recently, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce damage in the nigrostriatal system, accompanied by Parkinson-like symptoms in humans. We present here evidence that MPTP treatment in aged 21-month-old mice produced a marked reduction in the presence and intensity of fluorescence in noradrenergic neurons of the locus coeruleus and in dopaminergic neurons of the ventral tegmental area in addition to extensive damage to the substantia nigra. Aged mice treated with MPTP also showed physical signs of movement disability characterized by marked akinesia, rigidity of the hind limbs, and an initial resting tremor of the entire body. Such symptoms were less evident in young mice treated with MPTP. These remarkable initial behavioral effects of MPTP treatment in aged mice and evidence of reduced catecholamine fluorescence in the locus coeruleus and ventral tegmental area suggest that aged mice are more sensitive to, and more severely affected by MPTP treatment than young mice. We suggest that these MPTP-treated aged mice provide a useful animal model for studying both anatomical and functional characteristics of Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
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↗
Ventral tegmental area of the rabbit brain: a developmental Golgi study.
The ventral tegmental area (VTA) of the rabbit mesencephalon was examined with Golgi-Cox impregnation at neonatal (days 3-21 of age) and young adult (6-12 months of age) stages of development. Neurons in the dorsal midline were small, with sparsely-branched, vertically-oriented dendrites. Neurons in the ventral midline were medium-sized, oval cells with sparse, vertically-oriented dendrites, and multipolar cells with more abundant diffusely-oriented dendrites. Neurons in the medial zone of the VTA, between the midline and the exiting III nerve fibers, were oval in shape, medium in size, and possessed vertical dendritic arborizations of greater size and extent of branching than those in the dorsal midline. Lateral neurons, found among III nerve fibers, were medium-sized and possessed dendritic trees that were specifically oriented in a vertical or horizontal plane, or were diffusely-branched with more abundant arborizations than their specifically oriented counterpart. Very small neurons with short, single branches were scattered among all regions of the VTA. The major cell types showed a similar pattern of dendritic maturation. At 3-9 days of age, the dendrites were generally short, spiny and poorly branched. From days 9-21, the branches increased in number and length, spines were lost, and these neurons rapidly approached adult size and form. The neurons of VTA appear isodendritic in form, and developed in a pattern consistent with other areas of reticular formation, suggesting that VTA may be part of the reticular core of the brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
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.
Animals↗
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↗