Activity Of Sympathetic Preganglionic Neurons Research Articles

Dominant mechanism in spinal cord injury-induced immunodeficiency syndrome (SCI-IDS): sympathetic hyperreflexia.

Clinical studies have shown that individuals with spinal cord injury (SCI) are particularly susceptible to infectious diseases, resulting in a syndrome called SCI-induced immunodeficiency syndrome (SCI-IDS), which is the leading cause of death after SCI. It is believed that SCI-IDS is associated with exaggerated activation of sympathetic preganglionic neurons (SPNs). After SCI, disruption of bulbospinal projections from the medulla oblongata C1 neurons to the SPNs results in the loss of sympathetic inhibitory modulation from the brain and brainstem and the occurrence of abnormally high levels of spinal sympathetic reflexes (SSR), named sympathetic hyperreflexia. As the post-injury survival time lengthens, mass recruitment and anomalous sprouting of excitatory interneurons within the spinal cord result in increased SSR excitability, resulting in an excess sympathetic output that disrupts the immune response. Therefore, we first analyze the structural underpinnings of the spinal cord-sympathetic nervous system-immune system after SCI, then demonstrate the progress in highlighting mechanisms of SCI-IDS focusing on norepinephrine (NE)/Beta 2-adrenergic receptor (β2-AR) signal pathways, and summarize recent preclinical studies examining potential means such as regulating SSR and inhibiting β2-AR signal pathways to improve immune function after SCI. Finally, we present research perspectives such as to promote the effective regeneration of C1 neurons to rebuild the connection of C1 neurons with SPNs, to regulate excitable or inhibitory interneurons, and specifically to target β2-AR signal pathways to re-establish neuroimmune balance. These will help us design effective strategies to reverse post-SCI sympathetic hyperreflexia and improve the overall quality of life for individuals with SCI.

How sympathetic are your spinal cord circuits?

What is the topic of this review? This review focuses on the role of gap junctions and interneurones in sympathetic control at the spinal cord level. What advances does it highlight? The review considers the importance of these local spinal circuits in contributing to rhythmic autonomic activity and enabling appropriate responses to homeostatic perturbations. Sympathetic control of end organs relies on the activity of sympathetic preganglionic neurones (SPNs) within the spinal cord. These SPNs exhibit heterogeneity with respect to function, neurochemistry, location, descending inputs and patterns of activity. Part of this heterogeneity is bestowed by local spinal circuitry. Our understanding of the role of these local circuits, including the significance of connections between the SPNs themselves through specialized gap junctions, is patchy. This report focuses on interneurones and gap junctions within these circuits. Gap junctions play a role in sympathetic control; they are located on SPNs in the intermediolateral cell column. Mefloquine, a chemical that blocks these gap junctions, reduces local rhythmic activity in the spinal cord slice and disrupts autonomic control in the working heart-brainstem preparation. The role that these gap junctions may play in health and disease in adult animals remains to be elucidated fully. Presympathetic interneurones are located in laminae V, VII and X and the intermediolateral cell column; those in laminaX are GABAergic and directly inhibit SPNs. The GABAergic inputs onto SPNs exert their effects through activation of synaptic and extrasynaptic receptors, which stabilize the membrane at negative potentials. The GABAergic interneurones contribute to rhythmic patterns of activity that can be generated in the spinal cord, because bicuculline reduces network oscillatory activity. These studies indicate that local spinal cord circuitry is critical in enabling appropriate levels and patterning of activity in sympathetic outflow. We need to understand how these circuits may be harnessed in the situation of spinal cord injury.

Sympathetic preganglionic neurons: properties and inputs.

The sympathetic nervous system comprises one half of the autonomic nervous system and participates in maintaining homeostasis and enabling organisms to respond in an appropriate manner to perturbations in their environment, either internal or external. The sympathetic preganglionic neurons (SPNs) lie within the spinal cord and their axons traverse the ventral horn to exit in ventral roots where they form synapses onto postganglionic neurons. Thus, these neurons are the last point at which the central nervous system can exert an effect to enable changes in sympathetic outflow. This review considers the degree of complexity of sympathetic control occurring at the level of the spinal cord. The morphology and targets of SPNs illustrate the diversity within this group, as do their diverse intrinsic properties which reveal some functional significance of these properties. SPNs show high degrees of coupled activity, mediated through gap junctions, that enables rapid and coordinated responses; these gap junctions contribute to the rhythmic activity so critical to sympathetic outflow. The main inputs onto SPNs are considered; these comprise afferent, descending, and interneuronal influences that themselves enable functionally appropriate changes in SPN activity. The complexity of inputs is further demonstrated by the plethora of receptors that mediate the different responses in SPNs; their origins and effects are plentiful and diverse. Together these different inputs and the intrinsic and coupled activity of SPNs result in the rhythmic nature of sympathetic outflow from the spinal cord, which has a variety of frequencies that can be altered in different conditions.

How sympathetic are your spinal cord circuits?

New findings What is the topic of this review? This review focuses on the role of gap junctions and interneurones in sympathetic control at the spinal cord level. What advances does it highlight? The review considers the importance of these local spinal circuits in contributing to rhythmic autonomic activity and enabling appropriate responses to homeostatic perturbations. Sympathetic control of end organs relies on the activity of sympathetic preganglionic neurones (SPNs) within the spinal cord. These SPNs exhibit heterogeneity with respect to function, neurochemistry, location, descending inputs and patterns of activity. Part of this heterogeneity is bestowed by local spinal circuitry. Our understanding of the role of these local circuits, including the significance of connections between the SPNs themselves through specialized gap junctions, is patchy. This report focuses on interneurones and gap junctions within these circuits. Gap junctions play a role in sympathetic control; they are located on SPNs in the intermediolateral cell column. Mefloquine, a chemical that blocks these gap junctions, reduces local rhythmic activity in the spinal cord slice and disrupts autonomic control in the working heart–brainstem preparation. The role that these gap junctions may play in health and disease in adult animals remains to be elucidated fully. Presympathetic interneurones are located in laminae V, VII and X and the intermediolateral cell column; those in lamina X are GABAergic and directly inhibit SPNs. The GABAergic inputs onto SPNs exert their effects through activation of synaptic and extrasynaptic receptors, which stabilize the membrane at negative potentials. The GABAergic interneurones contribute to rhythmic patterns of activity that can be generated in the spinal cord, because bicuculline reduces network oscillatory activity. These studies indicate that local spinal cord circuitry is critical in enabling appropriate levels and patterning of activity in sympathetic outflow. We need to understand how these circuits may be harnessed in the situation of spinal cord injury.

Hydralazine administration activates sympathetic preganglionic neurons whose activity mobilizes glucose and increases cardiovascular function

Hypotensive drugs have been used to identify central neurons that mediate compensatory baroreceptor reflex responses. Such drugs also increase blood glucose. Our aim was to identify the neurochemical phenotypes of sympathetic preganglionic neurons (SPN) and adrenal chromaffin cells activated following hydralazine (HDZ; 10mg/kg) administration in rats, and utilize this and SPN target organ destination to ascribe their function as cardiovascular or glucose regulating. Blood glucose was measured and adrenal chromaffin cell activation was assessed using c-Fos immunoreactivity (-ir) and phosphorylation of tyrosine hydroxylase, respectively. The activation and neurochemical phenotype of SPN innervating the adrenal glands and celiac ganglia were determined using the retrograde tracer cholera toxin B subunit, in combination with in situ hybridization and immunohistochemistry. Blood glucose was elevated at multiple time points following HDZ administration but little evidence of chromaffin cell activation was seen suggesting non-adrenal mechanisms contribute to the sustained hyperglycemia. 16±0.1% of T4-T11 SPN contained c-Fos and of these: 24.3±1.4% projected to adrenal glands and 29±5.5% projected to celiac ganglia with the rest innervating other targets. 62.8±1.4% of SPN innervating adrenal glands were activated and 29.9±3.3% expressed PPE mRNA whereas 53.2±8.6% of SPN innervating celiac ganglia were activated and 31.2±8.8% expressed PPE mRNA. CART-ir SPN innervating each target were also activated and did not co-express PPE mRNA. Neurochemical coding reveals that HDZ administration activates both PPE+SPN, whose activity increase glucose mobilization causing hyperglycemia, as well as CART+SPN whose activity drive vasomotor responses mediated by baroreceptor unloading to raise vascular tone and heart rate.

Mapping the cellular electrophysiology of rat sympathetic preganglionic neurones to their roles in cardiorespiratory reflex integration: a whole cell recording study in situ

Sympathetic preganglionic neurones (SPNs) convey sympathetic activity flowing from the CNS to the periphery to reach the target organs. Although previous in vivo and in vitro cell recording studies have explored their electrophysiological characteristics, it has not been possible to relate these characteristics to their roles in cardiorespiratory reflex integration. We used the working heart–brainstem preparation to make whole cell patch clamp recordings from T3–4 SPNs (n = 98). These SPNs were classified by their distinct responses to activation of the peripheral chemoreflex, diving response and arterial baroreflex, allowing the discrimination of muscle vasoconstrictor-like (MVClike, 39%) from cutaneous vasoconstrictor-like (CVClike, 28%) SPNs. The MVClike SPNs have higher baseline firing frequencies (2.52 ± 0.33 Hz vs. CVClike 1.34 ± 0.17 Hz, P = 0.007). The CVClike have longer after-hyperpolarisations (314 ± 36 ms vs. MVClike 191 ± 13 ms, P < 0.001) and lower input resistance (346 ± 49 MΩ vs. MVClike 496 ± 41 MΩ, P < 0.05). MVClike firing was respiratory-modulated with peak discharge in the late inspiratory/early expiratory phase and this activity was generated by both a tonic and respiratory-modulated barrage of synaptic events that were blocked by intrathecal kynurenate. In contrast, the activity of CVClike SPNs was underpinned by rhythmical membrane potential oscillations suggestive of gap junctional coupling. Thus, we have related the intrinsic electrophysiological properties of two classes of SPNs in situ to their roles in cardiorespiratory reflex integration and have shown that they deploy different cellular mechanisms that are likely to influence how they integrate and shape the distinctive sympathetic outputs.

Single unit recordings from putative presympathetic neurons in the rostral ventrolateral medulla of sedentary and physically active rats (686.35)

A sedentary lifestyle has been linked to the development of cardiovascular disease (CVD). The RVLM is believed to contribute to CVD through direct activation of sympathetic preganglionic neurons. Our previous work showed that sedentary rats exhibit enhanced sympathoexcitation after glutamate activation of the RVLM compared to active counterparts. We have also recently shown increased dendritic arborization in spinally‐projecting C1 RVLM neurons from sedentary rats. We hypothesized that the RVLM exhibits increased excitability due to structural and functional differences in sedentary versus active rats (14 weeks wheel running). To our knowledge, we are the first group to have performed in vivo single unit recordings from putative presympathetic RVLM neurons in sedentary and active rats to examine functional differences in presympathetic RVLM neurons. Preliminary results from Inactin‐anesthetized rats indicate that individual presympathetic RVLM neurons from sedentary rats appeared to have higher resting firing rates (14.0±5.1 Hz, n=4) compared to active rats (8.7±3.0 Hz, n=4). RVLM neurons also appeared to have greater responses to acute increases in blood pressure (∆‐11.4±5.3 Hz vs. ∆‐5.6±1.4 Hz, respectively), but decreases in blood pressure did not appear to elicit different responses (∆+3.1±1.4 Hz vs. ∆+2.9±0.3 Hz). Though our current sample size does not yet permit us to draw definitive conclusions, these preliminary data support our hypothesis and suggest that a sedentary lifestyle may increase sympathetic nerve activity by causing an increase in the activity of individual presympathetic RVLM neurons.Grant Funding Source: HL096787, WSU Rumble Fellowship

Mechanisms of a Decapitation-Induced Increase in the Plasma Catecholamine Levels in Rats

Decapitation induces excessive increases in the plasma catecholamine levels in the blood obtained from the body of sacrificed animals. However, the mechanisms responsible for this phenomenon remain unknown. We investigated the neuronal pathways responsible for such increases in the plasma epinephrine and norepinephrine levels. To investigate this, we completely or partially transected the spinal cord at the upper thoracic level in Sprague–Dawley rats. Functionally, the successfulness of interruption of interconnections between brain and spinal preganglionic neurons was confirmed by almost complete blockade of immobilization-induced increases in the catecholamine plasma levels. After complete transection of the spinal cord and subsequent decapitation of rats, we found significant reduction of decapitation-induced effects on the catecholamine release from the adrenal medulla and sympathetic nerve endings. Our data indicate that the activity of the sympathoadrenal system is under significant inhibitory influence from the brain structures regulating the activity of sympathetic preganglionic neurons.

The viscerosympathetic response in rabbits is mediated by GABAergic and glutamatergic inputs into the sympathetic premotor neurons of the rostral ventrolateral medulla

Neurons in the rostral ventrolateral medulla (RVLM) receive inputs from various sources, including baroreceptors, and then regulate the activity of sympathetic preganglionic neurons in the spinal cord. Whether RVLM neurons mediate the viscerosympathetic reflex has yet to be clarified. In the present study, we investigated the role of RVLM neurons in the viscerosympathetic reflex in anaesthetized and vagotomized rabbits. Electrical stimulation of the greater splanchnic nerve (SplN) evoked reflex responses in renal sympathetic activity that were composed of inhibitory and/or excitatory components. Bilateral microinjection of muscimol, a GABA(A) receptor agonist, into the RVLM blocked the reflex responses. Bilateral microinjection of bicuculline, a GABA(A) receptor antagonist, largely attenuated the inhibitory component, whereas kynurenic acid, a glutamate receptor antagonist, eliminated the excitatory component. The activities of 21 RVLM barosensitive bulbospinal neurons were recorded. Twenty of the neurons responded to the SplN stimulation. The responses also consisted of inhibitory and/or excitatory components. The excitatory component of these neurons preceded that of the renal sympathetic nerve activity by about 100 ms. This latency difference was almost the same as that of the inhibitory responses evoked by aortic nerve stimulation. Therefore, the renal sympathetic reflex responses evoked by SplN stimulation are mediated by RVLM neurons, and GABAergic and glutamatergic transmission in the RVLM are related to this reflex.

A spinal muscarinic M2 receptor-GABAergic disinhibition pathway that modulates peripheral inflammation in mice

Previous data from our laboratories using the mouse air pouch model demonstrated that intrathecal injection of the cholinomimetic drug, neostigmine, produces a significant peripheral anti-inflammatory effect through activation of spinal muscarinic type 2 receptors. This anti-inflammatory effect is mediated by activation of sympathetic preganglionic neurons and subsequent release of adrenomedullary catecholamines. It has been established that adrenomedullary catecholamine release is controlled by sympathetic preganglionic neurons and that these neurons are modulated by GABAergic inhibitory input. To further establish the neurochemical circuitry underlying spinally mediated anti-inflammation, the present study examined whether spinal muscarinic type 2 receptors are associated with this spinal GABAergic pathway. Intrathecal injection of the M 2 receptor agonist, arecaidine but-2-ynyl ester tosylate (ABET) dose-dependently suppressed zymosan-induced leukocyte migration into the air pouch and increased Fos (neuronal activation marker) expression in sympathetic preganglionic neurons of the T7–T11 spinal cord segments (which mainly project to the adrenal medulla), but not in sympathetic preganglionic neurons of the T1–T6 or T12–L2 segments. These effects of arecaidine but-2-ynyl ester tosylate were completely blocked by intrathecal pretreatment with baclofen (a GABA BR agonist) but not muscimol (a GABA AR agonist). Intrathecal saclofen (a GABA BR antagonist), but not bicuculline (a GABA AR antagonist), significantly reduced leukocyte migration and increased Fos expression in T7–T11 sympathetic preganglionic neurons. More importantly, this intrathecal saclofen-induced anti-inflammatory effect was completely blocked by adrenalectomy or systemic pretreatment with propranonol (a β-adrenoceptor antagonist). Collectively, these novel findings suggest that activation of spinal muscarinic type 2 receptors suppress spinal GABA B receptor input and that this disinhibition mechanism ultimately leads to the release of adrenal catecholamines and a subsequent reduction in peripheral inflammation.

Peripheral bee venom's anti-inflammatory effect involves activation of the coeruleospinal pathway and sympathetic preganglionic neurons

There are several reports indicating that the locus coeruleus (LC) is capable of altering immune responses. Moreover, it is well established that the LC is the major source of descending noradrenergic system. Recently we have demonstrated that subcutaneous bee venom (BV) injection dramatically suppressed peripheral inflammation through activation of sympathetic preganglionic neurons (SPNs) leading to release of adreno-medullary catecholamines. Importantly, this ‘BV-induced anti-inflammatory effect’ (BVAI) is also associated with an increase of the activity of LC. Based on these data, present study examined whether BV-induced LC activation increased the activity of SPNs and this pathway played a role in BVAI using a zymosan-induced inflammatory air pouch model in mice. Unilateral BV injection into left hind limb produced anti-inflammation and specifically increased Fos expression in SPNs of the T7–T11 (which mainly project to adrenal medulla), but not those of the T1–T6 or T12–L2 spinal cord. 6-Hydroxydopamine-induced unilateral lesion of the contralateral, but not ipsilateral (to the BV injection site) LC significantly blocked BVAI and BV-induced Fos expression in SPNs. Additionally, intrathecal administration of idazoxan (α 2-adrenoceptor antagonist), blocked BVAI. These results indicate that BV-induced activation of the contralateral LC-descending noradrenergic pathway increased the activity of SPNs that project to the adrenal medulla and this pathway is necessary for BVAI.

The anti-inflammatory effect of peripheral bee venom stimulation is mediated by central muscarinic type 2 receptors and activation of sympathetic preganglionic neurons

The anti-inflammatory effect (AI) induced by peripheral injection of diluted bee venom (dBV) involves activation of spinal cord circuits and is mediated by catecholamine release from adrenal medulla, but the precise neuronal mechanisms involved are not fully understood. In a recent study, we demonstrated that an increase in spinal acetylcholine is involved in mediating the anti-inflammatory effect of dBV and that this mediation also involves adrenomedullary activation. The present study utilized the mouse air pouch inflammation model to evaluate the involvement of spinal acetylcholine receptors and sympathetic preganglionic neurons (SPNs) in dBV's anti-inflammatory effect (dBVAI). Intrathecal (IT) pretreatment with atropine (muscarinic cholinergic antagonist) but not hexamethonium (nicotinic cholinergic antagonist) significantly suppressed dBVAI on zymosan-evoked leukocyte migration. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic receptor type 2; M 2 antagonist), but not pirenzepine (an M 1 antagonist) or 4-DAMP (an M 3 antagonist), suppressed the dBVAI. In addition, dBV stimulation specifically increased Fos expression in SPNs of the T7–T11, but not the T1–T6 or T12–L2 spinal cord segments, in animals with zymosan-induced inflammation. Moreover, IT methoctramine pretreatment suppressed this dBV-induced Fos expression specifically in SPNs of T7–T11 level. Peripheral sympathetic denervation using 6-hydroxydopamine (6-OHDA) treatment (which spares sympathetic adrenal medullary innervation) did not alter dBVAI. Collectively these results indicate that dBV stimulation leads to spinal cord acetylcholine release that in turn acts on spinal M 2 receptors, which via a hypothesized disinhibition mechanism activates SPNs that project to the adrenal medulla. This activation ultimately leads to the release of adrenal catecholamines that contribute to dBVAI.

Neurochemistry of nerve fibers apposing sympathetic preganglionic neurons activated by sustained hypotension.

Sympathetic preganglionic neurons (SPN) in rat spinal cord were activated by the reflex stimulation of bulbospinal sympathetic neuronal pathways after a nitroprusside-induced hypotension. Hypotension-sensitive SPN, identified by immunoreactivity (IR) to the product of the immediate early gene c-fos and to choline acetyltransferase, were localized in the intermediolateral cell column of thoracic and upper lumbar cord, particularly middle to lower thoracic cord. Putative neurotransmitters, or their markers, in varicose fiber networks around SPN were identified. Nearly all hypotension-sensitive (Fos-IR) SPN were apposed by varicose fibers immunoreactive for tyrosine hydroxylase, serotonin, substance P, or enkephalin. Neuropeptide Y (NPY)- or phenylethanolamine-N-methyl transferase (PNMT)-IR varicose fibers apposed Fos-IR SPN in the upper and middle thoracic spinal cord, but in lower thoracic segments some Fos-IR SPN lacked these appositions. In thoracic segment 12, 51% +/- 5% of Fos-IR SPN (n = 9 rats) lacked PNMT contacts and 25% +/- 3% of Fos-IR SPN (n = 8 rats) lacked NPY contacts. In contrast to other chemically defined afferents, galanin-IR varicose fibers apposed fewer than half of the Fos-IR SPN in the middle to lower thoracic cord. Neurotransmitters/neuromodulators that might influence the activity of SPN acting in the baroreflex-mediated control of blood pressure have been identified. Uniformity in the neurochemistry of some fibers making connections with Fos-IR SPN, regardless of their segmental origin, suggests that common sets of neurons provide convergent inputs to all hypotension-sensitive SPN. Other fibers show topographic differences in their contacts with Fos-IR SPN, suggesting that subgroups of hypotension-sensitive SPN are targeted by particular neuron groups.

Nociceptin inhibits rat sympathetic preganglionic neurons in situ and in vitro.

In vitro and in situ experiments were conducted to evaluate the hypothesis that the nonclassical opioid peptide nociceptin acting on sympathetic preganglionic neurons (SPNs) inhibits spinal sympathetic outflow. First, whole cell patch recordings were made from antidromically identified SPNs from immature (12-16 day old) rat spinal cord slices. Nociceptin (0.1, 0.3, and 1 microM) concentration dependently suppressed the excitatory postsynaptic potentials (EPSPs) evoked by focal stimulation and hyperpolarized a population of SPNs; these effects were naloxone insensitive. L-Glutamate-induced depolarizations were not significantly changed by nociceptin. Results from this series of experiments indicate that nociceptin inhibits the activity of SPNs by either a presynaptic or postsynaptic site of action, whereby the peptide reduces, respectively, the amplitude of EPSPs or the excitability of SPNs. Second, intrathecal injection of nociceptin (3, 10, and 30 nmol) to urethan-anesthetized rats dose dependently reduced the mean arterial pressure and heart rate; these effects were not prevented by prior intravenous administration of naloxone (1 mg/kg). Physiological saline given intrathecally was without appreciable effects. These results, together with earlier observations of the detection of nociceptin-immunoreactive nerve fibers and nociceptin receptor immunoreactivity in the rat intermediolateral cell column, raise the possibility that the opioid peptide, which may be released endogenously, reduces spinal sympathetic outflow by depressing the activity of SPNs.

An immunocytochemical investigation of the relationship between substance P and the neurokinin-1 receptor in the lateral horn of the rat thoracic spinal cord

The relationship between substance P-containing axons and sympathetic preganglionic neurons possessing the neurokinin-1 receptor was investigated in the lateral horn of the rat thoracic spinal cord. Sympathetic preganglionic neurons were labelled retrogradely with Fluorogold. Sections containing labelled cells were reacted with antibodies against choline acetyltransferase, substance P and the neurokinin-1 receptor and examined with three-colour confocal laser scanning microscopy. In all, 95 sympathetic preganglionic neurons were examined and 79% of these were immunoreactive for the neurokinin-1 receptor. Substance P-immunoreactive axons not only made contacts with preganglionic neurons which were immunoreactive for the receptor but also made contacts with cells which did not express the receptor. Dendrites, labelled with immunoreactivity for choline actyltransferase, also received contacts from substance P-immunoreactive varicosities but this was not related to the presence or the absence of receptor. An electron microscopic analysis was performed to investigate the relationship between substance P-containing boutons and dendrites possessing the neurokinin-1 receptor. Immunoreactivity for substance P was detected with peroxidase immunocytochemistry and immunoreactivity for the receptor was detected with the silver-intensified gold method. Substance P-containing boutons made synapses with dendrites which were positively and negatively labelled for the receptor. Receptor immunoreactivity was not usually present at synapses formed by substance P boutons with neurokinin-1-immunoreactive dendrites. It is concluded that substance P may modulate much of the activity of sympathetic preganglionic neurons through an indirect non-synaptic mechanism.

Neurotransmitters involved in the central regulation of the cardiovascular system.

Arterial blood pressure is maintained by the tonic vasomotor activity of sympathetic preganglionic neurons which are located in the intermediolateral cell column of the thoracic and lumbar spinal cord. Supraspinal inputs are critical in maintaining the activity of SPN. The medulla and pons have been recognized as essential for maintaining tonic sympathetic activity since the late 1800’s when experiments showed that transection of the brain stem caudal to the inferior colliculus failed to lower blood pressure. Transections more caudally produced increasingly greater falls in blood pressure. Reductions in blood pressure reached a maximum with transections at the level of the obex (see ref [1] for historical review). A major goal of central autonomic research has been to identify the descending neuronal pathways which project to SPN and to determine the neurotransmitters contained within these pathways (see ref [2–6] for review). Neuroanatomical and immunocytochemical techniques have been used to identify chemically specific pathways between areas thought to be important in central autonomic regulation. This information combined with experiments utilizing sophisticated electrophysiological and pharmacological analysis have begun to elucidate the role of these pathways in central autonomic regulation and to determine the functional significance of putative neurotransmitters contained within these pathways. This review describes recent developments which have had a major influence on our understanding of the central neurotransmitters involved in the regulation of sympathetic nerve discharge.KeywordsNucleus Tractus SolitariusVentrolateral MedullaRostral Ventromedial MedullaNucleus AmbiguusPreganglionic NeuronThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Substance P and serotonergic inputs to sympathetic preganglionic neurons.

Sympathetic preganglionic neurons are the final central links in the sympathetic pathways that control the heart and blood vessels. The neurotransmitters present in the supraspinal pathways that control the activity of sympathetic preganglionic neurons include amino acids, amines and peptides. In this paper we discuss evidence that suggests a role for serotonin and substance P in these pathways. Both of these neurotransmitters are present in bulbospinal neurons. Our results suggest that they have an important physiological role in the central regulation of blood pressure.

Monosynaptic projections from the rostral ventrolateral medulla oblongata to identified sympathetic preganglionic neurons

The rostral ventrolateral medulla oblongata plays an important role in the control of arterial blood pressure and it has strong descending projections into the intermediolateral nucleus of the thoracic spinal cord, where the majority of sympathetic preganglionic neurons are located. The purpose of this study was to see whether these projections form synaptic contacts with sympathetic preganglionic neurons in the rat. Projections from both the lateral part of the rostral ventrolateral medulla (rostroventrolateral reticular nucleus) and from the more medial region (lateral paragigantocellular nucleus) were investigated separately in view of their different functional roles in sympatho-regulation and their different chemical composition. Using anterograde tract-tracing of descending medullary pathways with Phaseolus vulgaris leucoagglutinin and retrograde labelling of sympatho-adrenal preganglionic neurons with cholera B chain conjugated to horseradish peroxidase, the existence of monosynaptic connections was sought by electron microscopy. Synaptic inputs from both the lateral and medial aspects of the rostral ventrolateral medulla oblongata were found on identified sympathetic preganglionic neurons. Synaptic specializations were of both the symmetrical and asymmetrical type. The targets of boutons forming asymmetrical synaptic contacts differed according to their origin: boutons originating from neurons in the rostroventrolateral reticular nucleus were mainly in contact with dendrites of sympathetic preganglionic neurons, while those originating from the lateral paragigantocellular nucleus mainly innervated the cell bodies. Our observations provide anatomical support for the view that there are two distinct classes of sympatho-regulatory cells in the rostral ventrolateral medulla, each of which can directly influence the activity of sympathetic preganglionic neurons; they also emphasize the importance of detailed investigation of the subrogions of the ventrolateral medulla with respect to their sympatho-regulatory functions.

Essential organization of the sympathetic nervous system

The sympathetic nervous system consists of efferent neurones supplying the viscera. The cell bodies of preganglionic neurones are located in four areas in the thoracolumbar cord; however, the majority are found in the IML. Various tracing techniques have provided information concerning the location of the cell bodies of sympathetic preganglionic neurones projecting into various nerves and ganglia and regulating the adrenal gland, the kidney and the sympathetic supply to skeletal muscle. Numerous supraspinal neurones project to the neuropil surrounding sympathetic preganglionic neurones and may form synaptic contacts with these neurones. The areas of the brain that project to the IML appear to be part of a network of reciprocally connected supraspinal cell groups. Although much emphasis has been placed on the importance of the RVLM in the mediation of tonic and phasic inputs to sympathetic preganglionic neurones, it appears that other areas are of significant import; the RVLM should not be considered to be 'the vasomotor centre'. Spinal and cranial afferents influence the sympathetic nervous system. Baroreceptor afferents terminate in the NTS and may utilize an excitatory amino acid as their neurotransmitter. However, a number of neuropeptides are also associated with these afferents. Neurones within the NTS project to a number of brain stem areas thought to be involved in the regulation of sympathetic activity; consequently the baroreceptor reflex may be mediated over a number of parallel pathways involving both supraspinal and spinal sites of inhibition. Many neurotransmitters are thought to regulate the activity of sympathetic preganglionic neurons: monoamines, peptides and amino acids. Matching the chemical content of the cell bodies of neurones within a particular cell group with physiological characteristics is a challenging task; some barosensitive neurones of the RVLM do not appear to be adrenergic although they are in the midst of the C1 adrenergic cell group. Besides acetylcholine and noradrenaline, neurotransmission in the periphery appears to involve numerous peptides and ATP.

Vasodepressor neurons in medulla alter cardiac contractility and cardiac output.

We injected neuroexcitatory and neuroinhibitory agents into the depressor region of the caudal ventrolateral medulla of anesthetized rabbits and determined the effect on arterial pressure, myocardial contractility, cardiac output, and plasma catecholamines and neuropeptide Y. Brief excitation of the sympathoinhibitory neurons with medullary injection of L-glutamate reduced arterial pressure, peripheral vascular resistance, and myocardial contractility. Cardiac output was unaffected. Prolonged inhibition of the sympathoinhibitory neurons with medullary injection of muscimol increased arterial pressure, peripheral vascular resistance, and myocardial contractility. There was a progressive fall in cardiac output. These changes were accompanied by an increase in plasma neuropeptide Y and plasma norepinephrine, but no change in plasma epinephrine. Our findings indicate that the sympathoinhibitory vasomotor neurons in the caudal ventrolateral medulla tonically suppress the activity of sympathetic preganglionic neurons controlling myocardial contractility as well as peripheral vasomotor tone. Dysfunction of these medullary neurons could underly some forms of experimental hypertension.