Imaging of the autonomic nervous system: focus on cardiac sympathetic innervation

Symptoms or signs of abnormal autonomic nervous system function occur commonly in several neurological disorders. Clinical evaluations have depended on physiological, pharmacological, and neurochemical approaches. Recently, imaging of sympathetic noradrenergic innervation has been introduced and applied especially in the heart. Most studies have used the radiolabeled sympathomimetic amine, (123)I-metaiodobenzylguanidine. Decreased uptake or increased "washout" of (123)I-metaiodobenzylguanidine-derived radioactivity is associated with worse prognosis or more severe disease in hypertension, congestive heart failure, arrhythmias, and diabetes mellitus. This pattern may reflect a high rate of postganglionic sympathetic nerve traffic to the heart. Many recent studies have agreed on the remarkable finding that all patients with Parkinson's disease and orthostatic hypotension have a loss of cardiac sympathetic innervation, whereas all patients with multiple system atrophy, often difficult to distinguish clinically from Parkinson's disease, have intact cardiac sympathetic innervation. Because Parkinson's disease entails a postganglionic sympathetic noradrenergic lesion, the disease appears to be not only a movement disorder, with dopamine loss in the nigrostriatal system of the brain, but also a dysautonomia, with noradrenaline loss in the sympathetic nervous system of the heart. As new ligands are developed, one may predict further discoveries of involvement of components of the autonomic nervous system in neurological diseases.     

The peripheral sympathetic nervous system. Its role in normal and pathologic anxiety

Acute emotional arousal, regardless of the emotional state, increases sympathetic activity. The sympathetic response, however, does not lead to a uniform change in all sympathetically innervated systems. The response magnitude of specific systems, such as the cardiovascular system, depends to a large extent on constitutional and hereditary factors. The subjective awareness of bodily changes accompanying heightened sympathetic activity is inaccurate; people often recognize the direction but not the degree of change. The level of body awareness depends on various psychologic factors, of which anxiety plays an important role. Acute stress produces sympathetic activation in nonanxious as well as anxious persons. Nonanxious persons tend to have more flexible autonomic responses. They show stronger responses to novel situations but return to lower autonomic levels earlier and habituate faster than do anxious persons. That is, nonanxious persons possess a greater autonomic flexibility than anxious persons. It is important to know the physiologic state of anxiety disorder patients during periods when they do not feel anxious, during times of heightened tension, during the performance of standardized stress tasks, during exposure to psychopathology-specific stressors, and during "spontaneously" occurring surges of anxiety, such as panic attacks. At present only limited information concerning these conditions is available. There is little evidence that anxiety disorder patients, perhaps with the exception of very severe cases, have an increased sympathetic tone when they do not feel anxious. However, all anxiety disorders, with the exception of simple phobia, show some sort of physiologic activation in threatening situations, including the recording of physiologic baseline values in laboratories. The type of activation differs among anxiety disorders. During periods of rest, social phobics and panic disorder patients tend to show sympathetic activation, generalized anxiety disorder patients show increased muscular tension without sympathetic activation, and obsessive-compulsive patients show increased muscular tension along with sympathetic inhibition. Under laboratory stress, both normals and anxiety disorder patients react with sympathetic arousal. However, in generalized anxiety and obsessive-compulsive patients the response is weaker than in normals, suggesting the presence of an inhibitory process. Thus, the autonomic flexibility of anxiety disorder patients is reduced.(ABSTRACT TRUNCATED AT 400 WORDS)     

Degeneration of peripheral nervous system in rats experimentally induced by methylmercury intoxication

The objective of this study is to elucidate the primary action of methylmercury chloride (MMC) intoxication on peripheral nervous system. We chronologically observed the pathological changes of sciatic nerve, dorsal root ganglion (DRG) neurons, ventral and dorsal roots in rats given 4 mg/kg/day of MMC on consecutive days and killed on days 11, 15, 18 and 21. On day 11, an initial axonal degeneration of type B neuron occurred, predominantly in the distal portions of sciatic nerve. The DRG type A neuron was infiltrated by MRF-1-positive macrophages on day 11. Electron microscopy also demonstrated degenerated mitochondria in type A neuron. On day 21, most of type A neurons seemed to have disappeared. However, type B neurons were well preserved. Immunoblotting with monoclonal antibodies, P0 and neurofilament, demonstrated that both of proteins significantly decreases from day 15. In conclusion, these results indicate that the primary action on type A neuron is the neuron body that consequently results in an anterograde degeneration of nerve fibers, while the type B neuron degeneration occurs in a dying-back process in this subacute model. These findings suggest that the mechanisms involved in the degeneration induced by MMC vary and may depend on certain intrinsic factors peculiar to these neurons.     

Functional plasticity in the sympathetic nervous system of the neonatal rat

The age-dependent effects of sympathetic superior cervical ganglionectomy on smooth muscle alpha-adrenoceptor contractile responses were investigated in Müller's muscle in the superior eyelid of the Sprague-Dawley rat. Ganglionectomies in juvenile (32 days) and adult (70 days) rats produced sustained sympathetic denervation, determined by absence of contractile responses to electrical stimulation of ipsilateral and contralateral sympathetic chains and reduced responses to indirect release of nerve terminal norepinephrine by tyramine. Denervation was associated with diminished contractile responses and postjunctional supersensitivity to alpha-adrenoceptor stimulation by methoxamine. In contrast, contractile responses in rats ganglionectomized as neonates (day 3) were greater than those of other groups and sensitivity to methoxamine was comparable to control values. Responses to tyramine suggested that noradrenergic reinnervation had occurred. Electrical stimulation of the ipsilateral chain did not elicit contractions; however, stimulation of the contralateral chain evoked contractions in all neonatally ganglionectomized preparations and responses were present by 20 days of age. Contralateral reinnervation was derived from postganglionic sympathetic neurons with axons in the internal carotid nerve. This pathway is probably not formed by collateral sprouting of neurons with bilateral projections at the time of surgery for contralateral stimulation did not evoke contractions in the neonate. It is concluded that Müller's muscle is reinnervated by sympathetic neurons in the contralateral chain after denervation in neonates but not in older animals, and it is suggested that the higher potential for plasticity is attributable to the immaturity of the neonatal sympathetic nervous system.     

GABA receptor-mediated effects in the peripheral nervous system

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult mammalian central nervous system (CNS), exerts its action via an interaction with specific receptors (e.g., GABAA and GABAB). These receptors are expressed not only in neurons but also on glial cells of the CNS, which might represent a target for the allosteric action of neuroactive steroids. Herein, we have demonstrated first that in the peripheral nervous system (PNS), the sciatic nerve and myelin-producing Schwann cells express both GABAA and GABAB receptors. Specific ligands, muscimol and baclofen, respectively, control Schwann-cell proliferation and expression of some specific myelin proteins (i.e., glycoprotein P0 and peripheral myelin protein 22 [PMP22]). Moreover, the progesterone (P) metabolite allopregnanolone, acting via the GABAA receptor, can influence PMP22 synthesis. In addition, we demonstrate that P, dihydroprogesterone, and allopregnanolone influence the expression of GABAB subunits in Schwann cells. The results suggest, at least in the myelinating cells of the PNS, a cross-interaction within the GABAergic receptor system, via GABAA and GABAB receptors and neuroactive steroids.     

Neuronal expression of caspase-1 immunoreactivity in the rat central nervous system

Caspase-1/interleukin-1beta (IL-1beta)-converting enzyme (ICE) cleaves IL-1beta and IL-18 precursor proteins to the active forms of these proinflammatory cytokines. Since both cytokines are constitutively expressed in the brain, we investigated whether this is also the case for caspase-1. Using an antibody raised against the p10-subunit of the active enzyme, constitutive expression of caspase-1 immunoreactivity was found in nerve cells in the arcuate nucleus and in nerve fibres throughout the brain. Co-localisation with alpha-melanocyte stimulating hormone was demonstrated. The distribution pattern of caspase-1 immunoreactive structures is consistent with a role to produce mature IL-1beta in regions where IL-1beta mediates fever and sleep.     

Neuronal localization of the mitochondrial protein NIPSNAP1 in rat nervous system

The NIPSNAP (4‐nitrophenylphosphatase domain and non‐neuronal SNAP25‐like protein homolog 1) proteins belong to a highly conserved family of proteins of unknown function. We found that NIPSNAP1 binds to the branched‐chain α‐keto acid (BCKA) dehydrogenase enzyme complex, which is disrupted in maple syrup urine disease, a disease of branched‐chain amino acid catabolism that results in neurological dysfunction. Phenylketonuric (PKU) and epileptic mice show altered expression of NIPSNAP1 in the brain. Therefore, the distribution and localization of NIPSNAP1 in rat brain was determined. Results show that NIPSNAP1 is expressed exclusively in neurons including pyramidal neurons in the cerebral cortex, Purkinje neurons in the cerebellum and motor neurons in the spinal cord. Dopaminergic neurons in midbrain and noradrenergic neurons in the brainstem, which are affected in PKU, also express NIPSNAP1. NIPSNAP1 is found to be localized in the mitochondrial matrix and can bind dihydrolipoyl‐transacylase and ‐transacetylase components of the BCKA and pyruvate dehydrogenase complexes in vitro. Our data provide the first experimental evidence for a strictly neuronal expression of this mitochondrial protein in the rat nervous system.     

Immunization of adult rats against 2.5 S NGF: Effects on the peripheral sympathetic nervous system

The biochemical and morphological changes effected by immunization of adult rats with 2.5 S mouse nerve growth factor (NGF) were studied in sympathetic ganglia and in representative target organs. This immunization procedure maintains high levels of circulating anti NGF-antibody for periods of months. Morphological analysis revealed a general reduction in the size of the adrenergic neurons in the superior cervical ganglion (SCG) which was also reflected at the biochemical level by a 30% decrease in total protein content and a 50--60% reduction in the total activities of all norepinephrine-synthesizing enzymes. However, there was no change in total choline acetyltransferase activity. The biochemical and morphological changes observed in the SCG seem to be confined to the neuronal cell body, since at any stage of immunization target organs (the submandibular and the pineal gland) remained unaffected. All sympathetic ganglia investigated--except the superior mesenteric ganglion--responded in a similar way to the immunization against 2.5 S NGF. These changes in the adrenergic cell bodies were largely reversible. The recovery of normal enzyme activities followed closely the decrease of the antibody titer after cessation of immunization boosting. This indicates that cell death is not caused by anti NGF-antibodies in ganglia of adult animals. Thus, in contrast to adrenergic neurons from newborn animals, which depend on NGF or a crossreacting NGF-like material for survival, differentiated adrenergic neurons need this factor for the maintenance of their normal function but not for survival.     

Unmyelinated axon subpopulations in the rat peripheral nervous system

Using the neurotoxin capsaicin, we examined subpopulations of unmyelinated axons in mixed (sciatic), cutaneous (sural), and muscular (nerve to soleus) nerves. Administration of capsaicin to neonatal rats caused reduction of the sciatic nerve immunoreactive (IR)-substance P (by 45%) and IR-somatostatin (by 84%) contents. This correlated with a substantial reduction in unmyelinated axons in the sciatic and sural nerves (45% and 65%, respectively), although there was no significant decrease in unmyelinated axons in the nerve to soleus. In a parallel study, we have shown that sympathetic ganglia-derived unmyelinated axons account for about 20 to 25% of the total unmyelinated axon population in both the sural nerve and the nerve to soleus. Thus, in the sural nerve, the majority of unmyelinated axons are dorsal root ganglia-derived, contain either substance P or somatostatin, and are capsaicin-sensitive; whereas in the nerve to soleus, the majority of unmyelinated axons are dorsal root ganglia-derived but are insensitive to capsaicin and do not contain substance P or somatostatin. These latter unmyelinated axons presumably contain a yet to be defined neurotransmitter and may be the axons connecting with muscular ergoreceptors, a subpopulation of unmyelinated axons that are biochemically and functionally distinct from the unmyelinated axons of cutaneous nerves.     

Short- and long-term effects of nerve growth factor on the sympathetic nervous system in the adult mouse.

Nerve growth factor (NGF) induced a marked increase in the adrenergic nerve terminal networks of several peripheral organs in intact adult and young adult mice. The animals were investigated at 3 days and at 2 months after 6 daily subcutaneous injections of the 7S species of NGF (1 mug/g body weight each dose). At 3 days after the end of the treatment an increased fluorescence intensity, as well as an increased density of the adrenergic terminal plexuses was observed by fluorescence histochemical techniques in iris, salivary glands, heart, intestine, spleen and pancreas. These changes were paralleled by significant increases (up to 55%) in the endogenous NA levels. Increased NA levels were also detected in the brain of the NGF-treated animals. At 2 months after treatment the effects had almost totally disappeared, demonstrating that the NGF-induced overgrowth of the sympathetic axons was only temporary. The increased adrenergic innervation probably resulted from a stimulatory effect of NGF on collateral sprouting from the intact adrenergic axons. In line with the idea that the terminals of peripheral axons are continuously renewed, it is suggested that endogenous NGF could play a regulatory role in such a continuous growth process of the fully developed, adult sympathetic nervous system, directed at the maintenance of an adequate adrenergic terminal network.     

A model for investigating the effect of drugs on the peripheral sympathetic nervous system in man

A model for assessing the effect of sympatholytic drugs on the peripheral sympathetic nervous system in man is described. Guanethidine, a sympatholytic drug, and the vehicle have been used to explore the model which is based on the Bier block. Sympathetic activity was assessed by measuring: (i) palmar sweating; (ii) skin temperature; (iii) radial/brachial pressure index; (iv) hand blood flow; and (v) vasoconstrictor ice response of hand blood flow. Neither the tourniquet nor the vehicle had any effect on sympathetic activity whereas guanethidine produced significant changes in skin temperature (P < 0.05), hand blood flow (P < 0.001) and the vasoconstrictor ice response (P < 0.002), illustrating the usefulness of the model.     

Passive-avoidance learning after medial septal lesions: Effect of experience and the peripheral sympathetic nervous system

Prior studies from our laboratory suggest that peripheral sympathetic ingrowth, which occurs in the hippocampus following medial septal lesions, is detrimental to the reaquisition of a spatial learning/memory task. To assess the generality of this finding we studied step-through passive-avoidance learning in animals with a medial septal lesion with or without superior cervical ganglionectomy under two experimental conditions. In the first condition, in which no prior experience with the task occurred, animals with a lesion demonstrated facilitation of learning. In the second condition, in which animals received pretraining with no shock prior to surgical manipulation, the behavior of animals with the lesion was similar to that of controls. No effect of ganglionectomy or initial sympathetic ingrowth was found in either condition. The results suggest that the effects of medial septal lesions on passive avoidance behavior are determined by the experimental condition and that early peripheral sympathetic ingrowth does not contribute either in a detrimental or beneficial fashion to passive avoidance learning.     

Schwann cells and peripheral nervous system myelin in the rat retina

Summary Within the retinal nerve fiber layer of a 6-week-old Sprague-Dawley rat, scattered aggregates of PNS myelinated axons have been found and described. We believe this is likely to represent a normal but rare phenomenon in the rat.     

Side effects of anticonvulsants on the peripheral nervous system and vestibulo-ocular functions

Clinical findings of patients with polyneuropathy during treatment with anticonvulsant drugs are referred and cases are demonstrated concerning differential diagnosis of subclinical polyneuropathy as well as phenytoinophthalmoplegia.     

Sympathetic postganglionic unmyelinated axons in the rat peripheral nervous system

We determined the contribution made to the unmyelinated axon population of the rat peripheral nervous system by sympathetic paravertebral ganglion cells. Sympathectomy, achieved by administration of guanethidine to neonatal rats, led to atrophy of the sympathetic paravertebral ganglion chain, a 95% decrease in peripheral nerve norepinephrine, and loss of 20 to 26% of the unmyelinated axons in a cutaneous nerve (sural), a muscular nerve (nerve to soleus), and a mixed nerve (sciatic). These data indicate that up to a quarter of the total population of peripheral nerve unmyelinated axons are sympathetic ganglia-derived.     

Early development of the peripheral nervous system in a lancelet species

The developmental pattern of the lancelet (amphioxus) peripheral nervous system from embryos to larvae has been studied by using wholemount immunostaining and transmission electron microscopy. The peripheral nerves first appeared on the anterior dorsal surface of the medulla at the middle neurula stage, when the anterior nerve cord was just closing. A single axon with a large growth cone was the progenitor of each nerve. The nerve roots adopted an asymmetric arrangement soon after. The first nerve, likely a pair of pure sensory nerves, sprouted from the anterior tip of the nerve cord. This nerve may be comparable topographically to the preoptic nerve (the posterior branch of the terminal nerve) in lungfishes. However, the neuron that first extends its axon was located in the medulla, as in the other posterior nerves. One of the extramedullary primary sensory neurons, the corpuscles of de Quatrefages, appeared in larvae with the mouth and two anterior gill pores. Their axons were seemingly fasciculated with the efferent axon of the first nerve. The second nerve, the most complex one to appear during embryonic and early larval development, innervated the preoral pit and the buccal region. The third and fourth nerves on the left side also innervated the buccal region. The larval innervation patterns in the anterior region differed from the adult organization, suggesting a segmental rearrangement of the nerve supply during development. There was no evidence to dichotomize the peripheral nerves into cranial and spinal nerves, as exist in vertebrates. These characteristics of the peripheral nervous system in the lancelet indicate that this animal has a rather derived or primitive developmental system of peripheral nerves, making the analysis of homology with vertebrates difficult. J. Comp. Neurol. 393:415–425, 1998. © 1998 Wiley-Liss, Inc.     

Deficiency of sympathetic nervous system function in myasthenia.

The norepinephrine (NE) and epinephrine (E) responses to forearm ischemia were studied in 24 myasthenic patients and 22 subjects with lumbar disc disease (control group). In some of these myasthenic (11 cases) and control (11 cases) subjects the NE and E responses to orthostasis were also investigated. In controls both stimuli induced a rise in NE urinary excretion without significantly changing the E excretion. On the other hand, in myasthenic patients forearm ischemia and orthostasis were followed by an augmentation in E excretion, the NE excretion remaining unchanged or even undergoing a depression. In other myasthenic patients (10 cases) and subjects with lumbar disc disease (10 cases) NE and E responses to exercise were tested. The results were similar to those presented above: controls reacted to exercise by a rise in NE excretion, while myasthenic patients, by an augmentation in E excretion; the NE excretion underwent no change or even decreased after exercise in myasthenia. The obliteration of NE response to all three testing stimuli found in myasthenic patients may be considered as a sign of their sympathetic deficiency. In such patients the normal E discharge produced by forearm ischemia, orthostasis or exercise may be interpreted as a compensatory reaction, being probably the consequence of sympathetic deficiency. The noradrenergic deficit of myasthenic patients is ascribable to their cholinergic hyperactivity.     

Electrophysiological effects of diphenylhydantoin and carbamazepine on the peripheral and central nervous system

This article reviews the electrophysiological effects of diphenylhydantoin and carbamazepine on peripheral nerve conduction velocity and EEG activity. Guidelines are provided to test the hypothesis that anticonvulsants affect simultaneously parameters of peripheral nerve and brain functions.     

Expression of presenilin 1 in nervous system during rat development.

Alzheimer's disease (AD) is a polygenic disorder involving at least four different genes. Among them, missense mutations in the presenilins segregate with the vast majority of early onset cases of familial AD. To elucidate possible function(s) of presenilin 1 (PS1), we have studied its expression during the development of the rat nervous system. Analysis by in situ hybridization showed expression of PS1 in a variety of cell types and tissues during development, with prominent expression in the nervous system. During late embryogenesis, the ventricular zone presented the highest levels of expression, paralleling the pattern previously reported for Notch. Later, during postnatal development, we observed a peak of PS1 expression at postnatal day 10, particularly in the cerebellum and hippocampus, a time when proliferation and migration are still ongoing and synapse formation is being completed. We propose that presenilins participate in at least two different developmental processes: (1) one involved in neurogenesis and skeleton formation during embryonic development, probably involving coordinate expression with Notch, and (2) a second one in the postnatal central nervous system, perhaps involved in neuritogenic and/or synaptogenic stages, most likely playing a role in amyloid precursor protein processing and amyloid beta production.