Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System.

Comprised of the sympathetic nervous system, parasympathetic nervous system, and enteric nervous system, the autonomic nervous system (ANS) provides the neural control of all parts of the body except for skeletal muscles. The ANS has the major responsibility to ensure that the physiological integrity of cells, tissues, and organs throughout the entire body is maintained (homeostasis) in the face of perturbations exerted by both the external and internal environments. Many commonly prescribed drugs, over-the-counter drugs, toxins, and toxicants function by altering transmission within the ANS. Autonomic dysfunction is a signature of many neurological diseases or disorders. Despite the physiological relevance of the ANS, most neuroscience textbooks offer very limited coverage of this portion of the nervous system. This review article provides both historical and current information about the anatomy, physiology, and pharmacology of the sympathetic and parasympathetic divisions of the ANS. The ultimate aim is for this article to be a valuable resource for those interested in learning the basics of these two components of the ANS and to appreciate its importance in both health and disease. Other resources should be consulted for a thorough understanding of the third division of the ANS, the enteric nervous system. © 2016 American Physiological Society. Compr Physiol 6:1239-1278, 2016.

[Horseradish peroxidase retrograde labeling of primary sensory axons in rats: a comparison between three different intraspinal injections methods]. / Marquage rétrograde des axones sensitifs primaires par la peroxydase du raifort chez le rat: mise au point de la technique d'injection intramédullaire.

STUDY AIM: In order to improve the results of intraspinal retrograde labeling of post-ganglionic primary sensory axons by horseradish peroxidase (HRP), the authors compared three different intraspinal injection methods of this tracer into the inferior thoracic spinal cord in the rat. MATERIAL AND METHOD: 'Open field' method (group 1, N = 8); stereotactic injection, needle tip diameter = 0.72 mm (group 2, N = 8); stereotactic injection, needle tip diameter = 0.24 mm (group 3, N = 8). Histological features of the spinal injection site showed that tissue damages due to injection was more extensive and deeper than expected. HRP transported in retrograde fashion from injection site to sensory body cells located in dorsal root ganglia (DRG) was revealed by the Mesulam histochemical technique. RESULTS: The mean number of labeled neurons per DRG was 652 in group 3, 116 in group 2, and 77 in group 1. Differences were statistically significant, especially between groups 1 and 3 (P = 4.10(-16)) and groups 2 and 3 (P = 2.10(-17)). CONCLUSION: Retrograde labeling of primary sensory axons by HRP (or another axonal tracer) with fine needle stereotactic intraspinal injection may represent an alternative to anterograde labeling. This reliable and reproducible method may be useful in studies dealing with regeneration of post-ganglionic primary sensory axons.

Ultrastructure of the ganglion on human internal laryngeal nerve.

There is now definite evidence for the presence of a macroscopic ganglion on the human internal laryngeal nerve, with the distribution of its post-ganglionic fibres to the glands in the saccule and to the glands at the root of epiglottis in the vicinity of the opening of the saccule. This ganglion could be identified as early as 14 weeks in human foetal larynx, which contains immature neurons. Seven ganglia, dissected from human laryngectomy specimens and resected for carcinoma larynx, were studied by electron microscopy. Ultrastructurally, the neurons and the synaptic terminals had both small, round, luscent vesicles and dense core vesicles. Symmetrical, asymmetrical and electrical synaptic complexes were noted. A few neurons revealed degenerative changes suggestive of axotomy. The location of the ganglion on the internal laryngeal nerve, a branch of nervus vagus, and ultrastructural demonstration of large and small dense core vesicles and small luscent vesicles in the neurons of this ganglion, lead us to believe that the ganglion is parasympathetic in nature.

Localization of NADPH diaphorase in bladder afferent and postganglionic efferent neurons of the rat.

NADPH diaphorase histochemistry was used in combination with axonal labelling techniques to determine if NADPH diaphorase is present in afferent and postganglionic efferent pathways to the urinary bladder of the rat. In the L6 and S1 dorsal root ganglia, 80.9 and 78.5%, respectively, of bladder afferent neurons labelled with fluorescent dyes were NADPH diaphorase positive. In the major pelvic ganglion (MPG), many non-labelled neurons and fibers were intensely stained for NADPH diaphorase. Intensely stained cells were clustered near the exit of the penile nerve although stained cells were also scattered throughout the ganglion. Only a small percentage (3.5%) of bladder postganglionic neurons in the MPG were NADPH diaphorase positive. Since NADPH diaphorase activity commonly reflects the presence of nitric oxide synthase, the present findings raise the possibility that nitric oxide may have a role as a neurotransmitter or neuromodulator in afferent pathways from the urinary bladder.

Proportions of renal and splenic postganglionic sympathetic populations containing galanin and dopamine beta hydroxylase.

Galanin is a 29-amino acid neuropeptide found in rat spinal cord, autonomic ganglia and gastrointestinal tract, as well as in other areas of the nervous system in rats and other species. As part of an overall objective to determine if peptides contribute to target-specific control of visceral function, this study was designed to determine the percentages of populations of renal and splenic postganglionic neurons that contain galanin, and to determine if these neurons were likely to be adrenergic. Retrogradely transported fluorescent dyes were placed on renal and splenic nerves in male Wistar rats anaesthetized with sodium pento-barbital. Four days post-operatively, rats were perfused transcardially with fixative, and T12-L1 thoracolumbar chain ganglia, splanchnic ganglia and the solar plexus were removed. Immunocytochemical methods were then used to determine the proportions of the retrogradely labelled renal and splenic neurons containing galanin-like immunoreactivity and dopamine beta hydroxylase-like immunoreactivity. In seven rats, 24 +/- 3% of 2838 renal neurons were found to contain galanin-like immunoreactivity; in six rats, 32 +/- 5% of 5102 splenic neurons were found to contain galanin-like immunoreactivity. These proportions of the two populations were not significantly different from one another. In three rats, 94 +/- 2% of 684 renal neurons were found to contain dopamine beta hydroxylase-like immunoreactivity, and 95 +/- 2% of 2597 splenic neurons in three rats also showed dopamine beta hydroxylase-like immunoreactivity. These experiments indicate that subpopulations of both renal and splenic postganglionic sympathetic neurons contain the neuropeptide galanin and that these neurons are likely to be adrenergic in function. These findings suggest a role for galanin in control of the kidney and the spleen by the sympathetic nervous system.

Central nervous system innervation of the penis as revealed by the transneuronal transport of pseudorabies virus.

Transneuronal tracing techniques were used in order to identify putative spinal interneurons and brainstem sites involved in the control of penile function. Pseudorabies virus was injected into the corpus cavernosus tissue of the penis in rats. After a four day survival period, rats were perfused with fixative and virus-labelled neurons were identified by immunohistochemistry. Postganglionic neurons were retrogradely labelled in the major pelvic ganglia. In the spinal cord, sympathetic and parasympathetic preganglionic neurons were labelled transneuronally. Presumptive interneurons were also labelled in the lower thoracic and lumbosacral spinal cord in locations consistent with what is currently known about such interneurons. In the brainstem, transneuronally labelled neurons were found in the medulla, pons and hypothalamus. Regions consistently labelled included the nucleus paragigantocellularis, parapyramidal reticular formation of the medulla, raphe pallidus, raphe magnus, A5 noradrenergic cell group, Barrington's nucleus and the paraventricular nucleus of the hypothalamus. This study confirmed previous studies from our lab and others concerning the preganglionic and postganglionic neurons innervating the penis. The number, morphology and location of these neurons were consistent with labelling seen following injection of conventional tracers into the penis. The brainstem nuclei labelled in this study were also consistent with what is currently known about the brainstem control of penile function. The labelling appeared to be highly specific, in that descending systems involved in other functions were not labelled. These results provide further evidence that the pseudorabies virus transneuronal tracing technique is a valuable method for identifying neural circuits mediating specific functions.

Localization of sympathetic postganglionic neurons innervating the femoral-saphenous vein in cats.

Physiological and histochemical studies have suggested that the limb veins are innervated by sympathetic adrenergic fibers. In the present experiment, horseradish peroxidase (HRP) was used as a retrograde tracer to identify and localize the sympathetic postganglionic neurons that innervate the femoral-saphenous vein in cats. In anesthetized cats, HRP was applied perivascularly on a femoral and a saphenous vein segment (4-8 mm in length for each segment) to allow uptake into the nerve endings. The sympathetic chains on both sides were dissected after the animal was sacrificed and fixed 60 h following the HRP application. Histological examination on serial section was done to count the HRP-labeled neurons in each sympathetic ganglion from L1 to S1. In 10 cats, the total number of HRP neurons amounted to 8569. Most neurons arose from L3 (47%) and then L4 (31%). The number of neurons became progressively decreasing towards both ends of the sympathetic chain. Few neurons (less than 2% of the total) were discovered in the contralateral sympathetic ganglia. In each ganglion, the distribution of HRP neurons appeared to be scattering. Our findings provide anatomical evidence to support that the femoral-saphenous vein of the cat was innervated by the sympathetic efferent fibers. The main origins of these neurons are the third and fourth lumbar sympathetic ganglia.

Distribution of otic postganglionic and recurrent mandibular nerve fibres to the cavernous sinus plexus in monkeys.

The distribution of dorsal rami of the otic ganglion was traced on one or both sides of 1 rhesus and 15 cynomolgus monkeys using interrupted serial sections. From 15 to 24 fine rami containing unmyelinated and small myelinated nerve fibres entered the cranial cavity with the mandibular nerve through the foramen ovale. Most rami contributed to a plexus positioned in the crotch of the mandibular and maxillary nerves adjacent to the trigeminal ganglion. The plexus was augmented by an accessory otic ganglion. Rami then continued dorsally on each side of or through the maxillary nerve and joined the cavernous sinus plexus. The pathway described probably gives otic parasympathetic fibres access to the cerebral arteries and may share a wider distribution in common with other nerves contributing to the cavernous sinus plexus.

Effects of unilateral pelvic ganglionectomy on urinary bladder function in the male rat.

Micturition interval and micturition volume were measured in water loaded male rats before and up to 6 weeks after unilateral pelvic ganglionectomy. There was no effect on micturition interval until 7 days after the ganglionectomy. Micturition interval then remained increased. Maximal micturition volume was higher than in the control group from 4 to 14 days after surgery. Cystometrograms were recorded 12 days or 6 weeks after surgery. At 12 days the micturition pressure was lower in the unilaterally ganglionectomized than in the controls. After 6 weeks there was no significant difference in micturition pressure. A reduction of micturition pressure by about 50% was observed after i.v. injection of atropine, but no residual urine developed. Electron microscope investigation showed a considerable decrease in number of nerve terminals on the ganglionectomized side 3 days after surgery. Most of them were devoid of synaptic vesicles. On the contralateral side the majority of nerve terminals appeared normal, but many had a decreased number of vesicles. After 14 days the number of terminals was still lower than normal on the ganglionectomized side. They generally contained only a small number of vesicles. Also, on the contralateral side some nerve endings with the reduced complement of vesicles were found. We suggest that the effects of unilateral ganglionectomy on micturition volume and interval can be explained by a decreased sensory input from the bladder and that the effect on micturition pressure is due to a transient decrease in number and function of motor nerve terminals in the detrusor muscle.

Vasomotor, pilomotor and secretomotor neurons distinguished by size and neuropeptide content in superior cervical ganglia of mice.

Populations of postganglionic sympathetic neurons projecting to cranial targets from the superior cervical ganglia of mice were identified by retrograde axonal tracing with Fast blue combined with double-labelling immunofluorescence to detect immunoreactivity to tyrosine hydroxylase and neuropeptide Y. Nearly all neurons in the ganglion contained tyrosine hydroxylase immunoreactivity, but only about 50% of them also contained immunoreactivity to neuropeptide Y. The maximum diameter of cells with immunoreactivity to neuropeptide Y was significantly smaller than that of cells without it. Terminal axons containing immunoreactivity to both neuropeptide Y and tyrosine hydroxylase occurred around blood vessels supplying most cranial tissues, including the skin. Axons with immunoreactivity to tyrosine hydroxylase but not to neuropeptide Y innervated the piloerector muscles and the acini of the salivary glands. After injection of Fast blue into the skin or the submandibular salivary gland, populations of vasomotor, pilomotor and secretomotor neurons could be distinguished by soma size and by neuropeptide Y immunoreactivity. Neurons projecting to the salivary glands were the largest (mean diameter: 32 microns) and lacked immunoreactivity to neuropeptide Y; neurons projecting to cutaneous blood vessels were the smallest (mean diameter: 19 microns) and contained immunoreactivity to neuropeptide Y; neurons projecting to piloerector muscles were intermediate in size (mean diameter: 23 microns) and lacked neuropeptide Y immunoreactivity. A cluster analysis procedure confirmed that soma size and peptide content together identify major functional populations of neurons in the superior cervical ganglia of mice.

Innervation of the zona fasciculata of the adult human adrenal cortex: a light and electron microscopic study.

Autonomic innervation of the adrenal cortex has been demonstrated in several species. Detailed ultrastructural studies on the innervation of the zona fasciculata of the normal human adrenal cortex are lacking. We report herein our observations on the pattern of innervation of the cells of the zona fasciculata of the normal adult human cortex at both the light and electron microscope levels. Postganglionic unmyelinated fibers were observed to descend from a dense capsular meshwork and to be distributed as delicate branches among the columns of endocrine cells. Immunoperoxidase staining confirmed the presence of nerve fibers in the zona fasciculata in a distribution similar to that observed after staining with silver impregnation methods. Ultrastructural findings lent further support to these observations by the demonstration of bundles of unmyelinated fibers with focal enlargements containing terminal boutons with both clear and dense core vesicles in close approximation with the endocrine cells.

The innervation of the adrenal gland. IV. The source of pre- and postganglionic nerve fibres to the guinea-pig adrenal gland.

The pre- and postganglionic sympathetic innervation of the guinea-pig adrenal medulla was investigated using the retrograde neuronal tracers Fast Blue and WGA-HRP. Labelled preganglionic cell bodies were located in the intermediolateral horn of spinal segments T3-L2, the majority (73.9%) were found between T6-T12 representing 70.2% of the total number of labelled cells; the segment T10 contained the largest number of labelled neurons. Labelled postganglionic cell bodies were found in the paravertebral ganglia between vertebral levels T3-T12 (representing 22.6% of the total labelled neurons), the maximum number was found at T10. In addition, labelled neurons were found in the suprarenal ganglion (representing 7.2%). No labelled cells were found in the coeliac ganglia. The labelled neurons were found ipsilateral to the site of injection into the left adrenal gland. It is concluded that the guinea-pig adrenal gland receives both a pre- and a significant postganglionic sympathetic innervation. The destination of these nerve fibres within the adrenal gland has yet to be determined.

Sympathetic neural outflow directly recorded in patients with primary autonomic failure: clinical observations, microneurography, and histopathology.

We evaluated 2 patients with primary autonomic failure, without clinical peripheral neuropathy. One had primary autonomic failure alone (PAF), and the other had autonomic failure and multiple system atrophy (MSA). Direct intraneural recordings demonstrated a marked reduction of sympathetic efferent nerve impulse activity in the PAF patient. The patient with MSA had spontaneous bursts of sympathetic nerve impulses that confirmed the functional integrity of post-ganglionic sympathetic efferent neurons. Neurosecretory activity of these neurons correlated with the electrophysiologic findings. The PAF patient had markedly reduced supine norepinephrine (NE) levels that did not rise upon standing. The supine NE level in the MSA patient was normal. Morphometric study of biopsied sural nerve in the MSA patient showed that unmyelinated fibers were normal, whereas the nerve of the PAF patient showed clear evidence of past degeneration. We suggest that the primary preganglionic sympathetic defect in MSA releases viable postganglionic sympathetic efferents from central control. Decentralized postganglionic elements may fire spontaneously, thus activating peripheral effectors and providing potentially useful signs and symptoms for differential diagnosis.

[An ultrastructural study of the neuromuscular junctions of the cat intrinsic laryngeal muscles. II. Synapse formation by autonomic nerves].

The purpose of this study is to identify the origin of the nerve terminals of unknown origin observed at the previously denervated neuromuscular junctions in the cat intrinsic laryngeal muscles. The results were as follows: 1. Until 3 weeks after the transection of the recurrent laryngeal nerve, no nerve terminals were found at the neuromuscular junctions of the intrinsic laryngeal muscles except for the cricothyroid muscle, and no nerve fibres were detected in the Schwann tubes formed by Schwann cells and perineural cells. In addition, autonomic nerves around the vessels in the muscles were markedly decreased. 2. At 6 weeks, accompanied by an increase of autonomic nerves around the vessels, nerve fibres and nerve varicosities containing a number of large granular vesicles were observed in the Schwann tubes. 3. From 9 to 30 weeks, nerve terminals containing large granular vesicles were found at the neuromuscular junctions in all cases, even though the superior laryngeal nerve or the vagal nerve was transected on the ipsilateral side. 4. A spontaneous discharge was recognized in 6/8 cases after 6 weeks, but an evoked electromyogram could not be recognized. 5. The synaptic vesicles of the nerve terminals were labelled by 5-hydroxydopamine (5-OHDA), which was used as a marker for the sympathetic nerve. From these results, it was indicated that if the transected recurrent laryngeal nerve was prevented from regenerating, the autonomic nerves around the vessels entered into the Schwann tubes and reached the denervated neuromuscular junctions, instead of the motor nerve. The effect of autonomic nerves on muscle fibres was discussed.

Autonomic nerve terminals in relation to contractile and non-contractile structures in the conduit coronary artery of the dog.

The ramus interventricularis anterior (RIA), its first- and second-order branch were prepared for EM (perfused with glutaraldehyde under pressure, or simply fixed with KMnO4). No nerve fibres were found in the tunica media of either of the three consecutive segments. In the tunica adventitia axons with varicosities were found at a distance from the tunica media of 0.5-15 microns (about 50% 0.5-4.5 microns) in the RIA, 0.4-12 microns (about 50% 0.5-3.4 microns) in the first-order branch and 0.3-6.0 microns (about 50% 0.3-2.3 microns) in the second-order branch. Varicosities contain small, dense-cored vesicles (35-60 nm) and large, dense-cored vesicles (70-90 nm, exceptionally up to 120 nm); the other type contains small, clear vesicles (35-60 nm) and few large, dense-cored vesicles (70-90 nm). The remarkably large distance between the nerve terminals and smooth muscle cells fits well with the small range of sympathetic control of the conduit coronary artery. Close apposition of nerve terminals to fibroblasts (30-200 nm) was revealed in all three consecutive coronary portions. Moreover, terminal axons often lose the Schwann cell cover on the abluminal site and face the fibroblast.

The components of the hypogastric nerve in male and female guinea pigs.

A quantitative study has been made of the neural components of the hypogastric nerves of male and female guinea pigs using retrograde transport of horseradish peroxidase (HRP) to identify the population of neurones projecting in the nerve trunk, and electronmicroscopic analysis of the myelinated and unmyelinated axons present. Application of HRP to the transected axons of the hypogastric nerve labelled the cell bodies of sensory neurones in lumbar and sacral dorsal root ganglia, preganglionic neurones in the lumbar and sacral spinal cord, and postganglionic neurones in the inferior mesenteric ganglion and in the lumbar paravertebral chain; some ganglion cells of the pelvic plexus were also labelled. The number and distribution of each type of neurone with axons in the hypogastric nerve differed between the sexes: in particular, about twice as many preganglionic axons were present in the male as in the female.

Ultrastructure of vesicourethral innervation. III. Axoaxonal synapses between postganglionic cholinergic axons and probably SIF-cell derived processes in the feline lissosphincter.

Ultrastructurally nonspecialized axoaxonal-type synapses between postganglionic cholinergic axons innervating the lissosphincter and apposed probably SIF-cell derived neuronal processes are described. These processes were considered as the peripheral extraganglionic counterparts of those belonging to type I SIF cell interneurons, described in many mammalian peripheral autonomic ganglia. On this basis, the herein reported cholinergic/probably SIF-cell derived axoaxonal-type synapses are proposed as an auxiliary mechanism of prejunctional catecholaminergic inhibition of the normally excitatory cholinergic (postganglionic parasympathetic) neuroeffector transmission in the feline lissosphincter.

Distribution of sympathetic nerve endings within the rabbit carotid body: a histochemical and ultrastructural study.

The distribution of sympathetic (noradrenergic) nerves within the rabbit carotid body was investigated by fluorescence microscopy and electron microscopy. With the Falck-Hillarp method, fluorescent nerve fibres were found associated with blood vessels and type I/type II cell groups. After the injection of 6-hydroxydopamine, degenerating nerve profiles were found near blood vessels, near type I/type II cell groups and in contact with type II cells. Following the administration of [3H]noradrenaline, labelled nerve profiles were observed in close association with blood vessels and around cell groups; a few labelled nerve profiles were observed in contact with type II cells. With a modified chromaffin method, chromaffin nerve profiles were found around blood vessels, around type I/type II cell groups and their sensory nerve supply and in contact with type II cells. It was shown that for about one-third of the chromaffin nerve profiles, the nearest structure (in the plane of section) was a type I/type II cell group. Furthermore, the mean distance between chromaffin nerve profiles and blood vessels and between chromaffin nerve profiles and type I/type II cell groups was about the same (2.2 microns and 2.7 microns respectively). These results suggest that the carotid body sympathetic innervation might have, in addition to its vasomotor function, a direct action on the chemosensory structures. This hypothesis is discussed in the light of currently available physiological data and a comparison is made with the role of the sympathetic innervation in other sensory systems.