Sympathetic Preganglionic Neurons Research Articles

Characterization of neuronal discharge in the thoracic spinal cord during cardiac stress in a porcine model

Sudden cardiac death is the leading cause of death in the United States and is often caused by ventricular tachyarrhythmias (VT; Mozaffarian et al., 2015). Myocardial ischemia triggers imbalances in sympathetic and parasympathetic modulation, via the autonomic nervous system, and leads to the pathophysiology of cardiac arrhythmias. However, the spinal mechanism of this sympathetic neural control remains poorly understood. We hypothesize that cardiac stressors elicit distinct neural signatures in the dorsal horn (DH; the spinal relay point for cardiac afferents) and the intermediolateral (IML) nucleus of the thoracic spinal cord (the primary nexus for modulation of sympathetic efferent outflow). Adult, anesthetized Yorkshire pigs (n=9; 42 ± 1.6 kg) were implanted with high‐density microarrays (64–256 electrodes; Neuronexus) in the thoracic spinal cord to record extracellular potentials. Antidromic stimulation of the T2 paravertebral chain allowed identification of sympathetic preganglionic neurons located in the IML (53 of total 1,757 neurons recorded). To characterize neuronal discharge, after a baseline recording, pigs repeatedly received: 1) chest scratch (SCR), 2) heart touch (THR), 3) ligation of the left anterior descending coronary artery (LAD), 4) occlusion of the inferior vena cava (IVC), or 5) occlusion of the descending aorta (AOC). Preliminary investigation of percent change in firing rate from baseline suggests complex neural signatures in DH and IML neurons during perturbations. A subset of DH neurons increased firing rate during SCR (8.29% of DH neurons), THR (10.70%), LAD (14.40%), IVC (21.57%), and AOC (6.13%). Firing rate increased in a subset of IML neurons as well (3.84% during SCR, 26.92% during THR, 18.87% during LAD, 20.75% during IVC, and 12.12% during AOC). In contrast, firing rate decreased in 4.89% of DH neurons during SCR, 20.88% during THR, 21.63% during LAD, 16.44% during IVC, and 9.85% during AOC. Additionally, rates decreased in a small population of IML neurons (3.84% during SCR, 7.69% during THR, 28.30% during LAD, 5.66% during IVC, and 18.18% during AOC). Subsequent analysis revealed positive correlations between DH and IML neurons, indicating excitatory neuronal connectivity. Further investigation is warranted to understand the temporally related discharge patterns as well as the inhibitory or excitatory nature of these connections. These preliminary data pave a potential pathway to develop targeted neuraxial interventions in cases of intractable ventricular arrhythmia.Support or Funding InformationHL084261, T32‐HD043730This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic, complete cervical6-7 cord transection: distinct autonomic and cardiac deficits.

Spinal cord injury (SCI) resulting in tetraplegia is a devastating, life-changing insult causing paralysis and sensory impairment as well as distinct autonomic dysfunction that triggers compromised cardiovascular, bowel, bladder, and sexual activity. Life becomes a battle for independence as even routine bodily functions and the smallest activity of daily living become major challenges. Accordingly, there is a critical need for a chronic preclinical model of tetraplegia. This report addresses this critical need by comparing, for the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses each week for 4 wk in 12 sham-operated intact rats and 12 rats with chronic, complete C6-7 spinal cord transection. Loss of supraspinal control to all sympathetic preganglionic neurons projecting to the heart and vasculature resulted in a profound bradycardia and hypotension, reduced cardiac sympathetic and parasympathetic tonus, reduced reflex- and stress-induced sympathetic responses, and reduced sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination of the nucleus ambiguus and stellate ganglia supports the profound and distinct autonomic and cardiac deficits and reliance on angiotensin to maintain cardiovascular stability following chronic, complete cervical6-7 cord transection. NEW & NOTEWORTHY For the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses were studied in rats with chronic, complete C6-7 cord transection. Loss of supraspinal control of all sympathetic preganglionic neurons reduced cardiac sympathetic and parasympathetic tonus, reflex and stress-induced sympathetic responses, and sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination supports the distinct deficits associated with cervical cord injury.

Central control of autonomic function.

In this review, current understanding of the control of autonomic function is outlined and its development over the last 50 years highlighted. Using the control of the cardiovascular system as the primary tool, the importance of the patterning of autonomic outflows is shown to be crucial in both homeostasis and behaviour. Technical advances have made it possible to obtain a clearer idea of how the central nervous system evolves patterns of autonomic discharge that optimise autonomic changes to support motor and behavioural responses. The specific roles of sympathetic and parasympathetic preganglionic neurones and premotor neurones are surveyed and the importance of their roles in integrating afferent inputs that result from peripheral sensory inputs and drive from multiple levels of the neuraxis is outlined. The autonomic control of the viscera, including the urinogenital organs and other organs is discussed briefly. The current ability to use animal models to monitor and modulate autonomic neural discharge and simultaneously co-relate this with end-organ activity is shown to have translational potential. There is every prospect that these studies will lead to the identification of new therapies for pathophysiological conditions.

Chapter 17 - Efferent neural pathways for the control of brown adipose tissue thermogenesis and shivering

The fundamental central neural circuits for thermoregulation orchestrate behavioral and autonomic repertoires that maintain body core temperature during thermal challenges that arise from either the ambient or the internal environment. This review summarizes our understanding of the neural pathways within the fundamental thermoregulatory reflex circuitry that comprise the efferent (i.e., beyond thermosensory) control of brown adipose tissue (BAT) and shivering thermogenesis: the motor neuron systems consisting of the BAT sympathetic preganglionic neurons and BAT sympathetic ganglion cells, and the alpha- and gamma-motoneurons; the premotor neurons in the region of the rostral raphe pallidus, and the thermogenesis-promoting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area. Also included are inputs to, and neurochemical modulators of, these efferent neuronal populations that could influence their activity during thermoregulatory responses. Signals of metabolic status can be particularly significant for the energy-hungry thermoeffectors for heat production.

Neuropilins guide preganglionic sympathetic axons and chromaffin cell precursors to establish the adrenal medulla.

ABSTRACTThe adrenal medulla is composed of neuroendocrine chromaffin cells that secrete adrenaline into the systemic circulation to maintain physiological homeostasis and enable the autonomic stress response. How chromaffin cell precursors colonise the adrenal medulla and how they become connected to central nervous system-derived preganglionic sympathetic neurons remain largely unknown. By combining lineage tracing, gene expression studies, genetic ablation and the analysis of mouse mutants, we demonstrate that preganglionic axons direct chromaffin cell precursors into the adrenal primordia. We further show that preganglionic axons and chromaffin cell precursors require class 3 semaphorin (SEMA3) signalling through neuropilins (NRP) to target the adrenal medulla. Thus, SEMA3 proteins serve as guidance cues to control formation of the adrenal neuroendocrine system by establishing appropriate connections between preganglionic neurons and adrenal chromaffin cells that regulate the autonomic stress response.

Deciphering the Neural Control of Sympathetic Nerve Activity: Status Report and Directions for Future Research.

Sympathetic nerve activity (SNA) contributes appreciably to the control of physiological function, such that pathological alterations in SNA can lead to a variety of diseases. The goal of this review is to discuss the characteristics of SNA, briefly review the methodology that has been used to assess SNA and its control, and to describe the essential role of neurophysiological studies in conscious animals to provide additional insights into the regulation of SNA. Studies in both humans and animals have shown that SNA is rhythmic or organized into bursts whose frequency varies depending on experimental conditions and the species. These rhythms are generated by brainstem neurons, and conveyed to sympathetic preganglionic neurons through several pathways, including those emanating from the rostral ventrolateral medulla. Although rhythmic SNA is present in decerebrate animals (indicating that neurons in the brainstem and spinal cord are adequate to generate this activity), there is considerable evidence that a variety of supratentorial structures including the insular and prefrontal cortices, amygdala, and hypothalamic subnuclei provide inputs to the brainstem regions that regulate SNA. It is also known that the characteristics of SNA are altered during stress and particular behaviors such as the defense response and exercise. While it is a certainty that supratentorial structures contribute to changes in SNA during these behaviors, the neural underpinnings of the responses are yet to be established. Understanding how SNA is modified during affective responses and particular behaviors will require neurophysiological studies in awake, behaving animals, including those that entail recording activity from neurons that generate SNA. Recent studies have shown that responses of neurons in the central nervous system to most sensory inputs are context-specific. Future neurophysiological studies in conscious animals should also ascertain whether this general rule also applies to sensory signals that modify SNA.

Autonomic dysreflexia caused by cervical stenosis

Autonomic dysreflexia (AD) is a well-known sequela of high spinal cord injuries (SCI). The characteristic episodic presentation is one of increased sympathetic tone: diaphoresis, hypertension, tachycardia, or reflex bradycardia. The episodes are triggered by visceral sensations and can last days to weeks. This report presents the case of a 73-year-old male with cervical stenosis, with a longstanding history of "hot flashes" accompanied by dizziness, flushing and diaphoresis, and palpitations. The patient was evaluated extensively by cardiology, endocrinology, and neurology with no treatable pathology determined aside from the patient's cervical stenosis. The patient was diagnosed with autonomic dysreflexia caused by cervical spinal stenosis and underwent anterior cervical decompression and fusion (ACDF) at the stenotic C5-C6 level. He found near complete resolution of his autonomic symptoms. We hypothesize that the cervical compression caused a disruption in the regulatory control of the sympathetic preganglionic neurons resulting in the autonomic symptoms. Although numerous studies exist of patients with a traumatic onset of AD, to the best of our knowledge, this is the first case report in the literature of autonomic symptoms that stemmed from cervical stenosis. The purpose of this case report is to alert clinicians to a potential association between AD and spinal stenosis, which may exist outside the realm of SCI.

C1 neurons: a nodal point for stress?

What is the topic of this review? The C1 neurons (C1) innervate sympathetic and parasympathetic preganglionic neurons plus numerous brain nuclei implicated in stress, arousal and autonomic regulations. We consider here the contribution of C1 to stress-induced responses. What advances does it highlight? C1 activation is required for blood pressure stability during hypoxia and mild hemorrhage which exemplifies their homeostatic function. During restraint stress, C1 activate the splenic anti-inflammatory pathway resulting in tissue protection against ischemic injury. This effect, along with glucose release and, possibly, arousal are examples of adaptive non-homeostatic responses to stress that are also mediated by C1. The C1 cells are catecholaminergic and glutamatergic neurons located in the rostral ventrolateral medulla. Collectively, these neurons innervate sympathetic and parasympathetic preganglionic neurons, the hypothalamic paraventricular nucleus and countless brain structures involved in autonomic regulation, arousal and stress. Optogenetic inhibition of rostral C1 neurons has little effect on blood pressure (BP) at rest in conscious rats but produces large reductions in BP when the animals are anaesthetized or exposed to hypoxia. Optogenetic C1 stimulation increases BP and produces arousal from non-rapid eye movement sleep. C1 cell stimulation mimics the effect of restraint stress to attenuate kidney injury caused by renal ischaemia-reperfusion. These effects are mediated by the sympathetic nervous system through the spleen and eliminated by silencing the C1 neurons. These few examples illustrate that, depending on the nature of the stress, the C1 cells mediate adaptive responses of a homeostatic or allostatic nature.

Functional Characterization of Lamina X Neurons in ex-Vivo Spinal Cord Preparation.

Functional properties of lamina X neurons in the spinal cord remain unknown despite the established role of this area for somatosensory integration, visceral nociception, autonomic regulation and motoneuron output modulation. Investigations of neuronal functioning in the lamina X have been hampered by technical challenges. Here we introduce an ex-vivo spinal cord preparation with both dorsal and ventral roots still attached for functional studies of the lamina X neurons and their connectivity using an oblique LED illumination for resolved visualization of lamina X neurons in a thick tissue. With the elaborated approach, we demonstrate electrophysiological characteristics of lamina X neurons by their membrane properties, firing pattern discharge and fiber innervation (either afferent or efferent). The tissue preparation has been also probed using Ca2+ imaging with fluorescent Ca2+ dyes (membrane-impermeable or -permeable) to demonstrate the depolarization-induced changes in intracellular calcium concentration in lamina X neurons. Finally, we performed visualization of subpopulations of lamina X neurons stained by retrograde labeling with aminostilbamidine dye to identify sympathetic preganglionic and projection neurons in the lamina X. Thus, the elaborated approach provides a reliable tool for investigation of functional properties and connectivity in specific neuronal subpopulations, boosting research of lamina X of the spinal cord.

Physiologic regulation of heart rate and blood pressure involves connexin 36-containing gap junctions.

Chronically elevated sympathetic nervous activity underlies many cardiovascular diseases. Elucidating the mechanisms contributing to sympathetic nervous system output may reveal new avenues of treatment. The contribution of the gap junctional protein connexin 36 (Cx36) to the regulation of sympathetic activity and thus blood pressure and heart rate was determined using a mouse with specific genetic deletion of Cx36. Ablation of the Cx36 protein was confirmed in sympathetic preganglionic neurons of Cx36-knockout (KO) mice. Telemetric analysis from conscious Cx36 KO mice revealed higher variance in heart rate and blood pressure during rest and activity compared to wild-type (WT) mice, and smaller responses to chemoreceptor activation when anesthetized. In the working heart–brain stem preparation of the Cx36-KO mouse, respiratory-coupled sympathetic nerve discharge was attenuated and responses to chemoreceptor stimulation and noxious stimulation were blunted compared to WT mice. Using whole cell patch recordings, sympathetic preganglionic neurons in spinal cord slices of Cx36-KO mice displayed lower levels of spikelet activity compared to WT mice, indicating reduced gap junction coupling between neurons. Cx36 deletion therefore disrupts normal regulation of sympathetic outflow with effects on cardiovascular parameters.—Lall, V. K., Bruce, G., Voytenko, L., Drinkhill, M., Wellershaus, K., Willecke, K., Deuchars, J., Deuchars, S. A. Physiologic regulation of heart rate and blood pressure involves connexin 36–containing gap junctions.

Roles of Na+, Ca2+, and K+ channels in the generation of repetitive firing and rhythmic bursting in adrenal chromaffin cells.

Adrenal chromaffin cells (CCs) are the main source of circulating catecholamines (CAs) that regulate the body response to stress. Release of CAs is controlled neurogenically by the activity of preganglionic sympathetic neurons through trains of action potentials (APs). APs in CCs are generated by robust depolarization following the activation of nicotinic and muscarinic receptors that are highly expressed in CCs. Bovine, rat, mouse, and human CCs also express a composite array of Na+, K+, and Ca2+ channels that regulate the resting potential, shape the APs, and set the frequency of AP trains. AP trains of increasing frequency induce enhanced release of CAs. If the primary role of CCs is simply to relay preganglionic nerve commands to CA secretion, why should they express such a diverse set of ion channels? An answer to this comes from recent observations that, like in neurons, CCs undergo complex firing patterns of APs suggesting the existence of an intrinsic CC excitability (non-neurogenically controlled). Recent work has shown that CCs undergo occasional or persistent burst firing elicited by altered physiological conditions or deletion of pore-regulating auxiliary subunits. In this review, we aim to give a rationale to the role of the many ion channel types regulating CC excitability. We will first describe their functional properties and then analyze how they contribute to pacemaking, AP shape, and burst waveforms. We will also furnish clear indications on missing ion conductances that may be involved in pacemaking and highlight the contribution of the crucial channels involved in burst firing.

The caudal pedunculopontine tegmental nucleus may be involved in the regulation of skeletal muscle activity by melanocortin-sympathetic pathway: a virally mediated trans-synaptic tracing study in spinally transected transgenic mice

Understanding neuroanatomical sympathetic circuitry and neuronal connections from the caudal pedunculopontine tegmental nucleus to skeletal muscle is important to the study of possible mechanisms of pedunculopontine tegmental nucleus (PPTg) and cuneiform nucleus (CnF) that are involved in the regulation of skeletal muscle activity of the sympathetic pathway. The aim of this study was to use virus PRV-614 to trace the melanocortin-sympathetic neural pathways from PPTg and CnF to a hindlimb muscle (gastrocnemius) in spinally transected MC4R-GFP transgenic mice. PRV-614 was injected into the gastrocnemius muscle after receiving a complete spinal cord transection below the L2 level. PRV-614/MC4R-GFP and PRV-614/TPH dual-labeled neurons were found in the dissipated parts of PPTg (dpPPTg), but not between the compact parts of PPTg (cpPPTg) and CnF. It is proposed that a hierarchical pathway of neurons within the caudal pedunculopontine tegmental nucleus sends projections to the RVLM, which in turn projects onto the IML sympathetic preganglionic neurons that regulate muscle blood flow through melanocortin-sympathetic signals. Our results collectively indicate that MC4Rs expressed in caudal pedunculopontine tegmental nucleus may be involved in skeletal muscle activity of melanocortin-sympathetic pathways.

The dawn of cardiovascular neuroprosthetics: Epidural spinal cord stimulation acutely restores cardiovascular function in persons with clinically complete spinal cord injury

INTRODUCTIONNeuroprosthetic electrical stimulation of the lumbosacral spinal cord with surgical implants has the capacity to excite dormant neuronal circuitry that has lost supraspinal control due to a spinal cord injury. Very recently, this intervention was even shown to elicit involuntary and voluntary stepping‐like movement of skeletal muscles previously thought to be paralyzed.OBJECTIVEConsidering that autonomic and cardiovascular dysfunctions are the leading cause of death after spinal cord injury, and a higher health priority than walking again by these individuals, we set out to explore if lumbosacral electrical stimulation of the spinal cord could be harnessed to regulate the cardiovascular system after spinal cord injury.METHODSThree of the first individuals with cervical spinal cord injury to be implanted worldwide were assessed in the present study, all of whom presented with cardiovascular dysfunction, in the form of severe orthostatic hypotension as well as impaired cardiac and cerebral regulation. A 16‐electrode array (Fig A) paddle was implanted over the lower lumbar/sacral spinal cord segments and connected to an electrical stimulation unit (both Medtronic). At least one month after implantation, we developed a cardiovascular optimized stimulation paradigm, that excited sympathetic preganglionic neurons but did not elicit skeletal muscle contraction (confirmed with electromyography; Fig A). We measured beat‐by‐beat blood pressure (photoplethysmography), cardiac function (echocardiography), and cerebral blood flow regulation (transcranial Doppler), in the supine position and in response to sit‐up, as well as cognitive function (Stroop test) with and without (in randomized order) cardiovascular optimized stimulation. Statistics on only one to three individuals is not typically recommended and was not performed.RESULTSTargeted cardiovascular electrical stimulation resulted in: [1] abrogated orthostatic hypotension (–39mmHg and severe presyncope vs. −8mmHg and absence of symptoms; Fig A,B); [2] maintained stroke volume (−32ml vs. −8ml; Fig 1E) and cerebral blood flow (−25 cm/s vs. −6cm/s; Fig B) during sit‐up; and [3] restored neurovascular coupling Fig C (+0% vs. 18%); and Stroop performance (P3–P2 time: 42s vs. 21s). Increased low‐frequency power of systolic blood pressure oscillations suggest supraspinal medullary sympathetic control of blood pressure is restored Fig D.CONCLUSIONSNeuroprosthetic modulation of spinal cord circuitry caudal to injury can restore normal autonomic control, which challenges our dogmatic understanding of the inherent functionality of the autonomic pathways in the spinal cord after injury. This data may represent the dawn of a new age for neuroprosthetic management of autonomic and cardiovascular heath.Support or Funding InformationCraig Neilsen Foundation, Rick Hansen Institute, Helmsley Foundation Research Trust.

Role of Orexin-A in Hypertension and Obesity.

Hypertension is one of the most challenging health problems inducing cerebrovascular disease and high percentage of death when associated with diabetes, dyslipidemias, and obesity. Orexin/hypocretin is a peptide expressed by a small number of neurons of the dorsolateral hypothalamus, a brain feeding and autonomic "fight-or-flight" regulatory center. According to this function, orexin has been demonstrated to evoke cardiovascular responses, heart rate, hypertension, hyperarousal, hyperphagia, and obesity. The focus of this review is to provide an overview about the mechanism through which orexin regulates food intake and cardiovascular responses and its role in the pathogenesis of obesity and hypertension which could be of great interest to establish possible new therapies. In normal rats and mice, central administration of orexin increases food intake, blood pressure, and sympathetic nerve activity and these effects are blocked by selective orexin receptor antagonist SB-334867 or almorexant. Moreover, upregulation of orexin signaling, in combination with elevation of epinephrine and norepinephrine circulating levels, occurs in rats exposed to chronic stress, in models of spontaneous hypertension (SHR and BPH/2J Schlager mice) and in obese mice (ob/ob or mice fed with high fat diet). Therefore, hyperactivity of orexinergic neurons could be a factor in the development of obesity and essential hypertension. Because of their widespread projections to the brain regions involved in appetite and cardiovascular responses, as far down as sympathetic preganglionic neurons in the spinal cord, orexin evokes sympathetically mediated cardiovascular responses. Lasting upregulation of orexin signaling can lead to hyperphagia, obesity, and hypertensive state. Dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists (SORAs) have antihypertensive effects that could be of clinical use for regulation of food intake and hypertension, supporting the role of orexinergic neurons as critical checkpoint in the neurogenic control of metabolic and cardiovascular functions.

Descending Influences on Vestibulospinal and Vestibulosympathetic Reflexes.

This review considers the integration of vestibular and other signals by the central nervous system pathways that participate in balance control and blood pressure regulation, with an emphasis on how this integration may modify posture-related responses in accordance with behavioral context. Two pathways convey vestibular signals to limb motoneurons: the lateral vestibulospinal tract and reticulospinal projections. Both pathways receive direct inputs from the cerebral cortex and cerebellum, and also integrate vestibular, spinal, and other inputs. Decerebration in animals or strokes that interrupt corticobulbar projections in humans alter the gain of vestibulospinal reflexes and the responses of vestibular nucleus neurons to particular stimuli. This evidence shows that supratentorial regions modify the activity of the vestibular system, but the functional importance of descending influences on vestibulospinal reflexes acting on the limbs is currently unknown. It is often overlooked that the vestibulospinal and reticulospinal systems mainly terminate on spinal interneurons, and not directly on motoneurons, yet little is known about the transformation of vestibular signals that occurs in the spinal cord. Unexpected changes in body position that elicit vestibulospinal reflexes can also produce vestibulosympathetic responses that serve to maintain stable blood pressure. Vestibulosympathetic reflexes are mediated, at least in part, through a specialized group of reticulospinal neurons in the rostral ventrolateral medulla that project to sympathetic preganglionic neurons in the spinal cord. However, other pathways may also contribute to these responses, including those that dually participate in motor control and regulation of sympathetic nervous system activity. Vestibulosympathetic reflexes differ in conscious and decerebrate animals, indicating that supratentorial regions alter these responses. However, as with vestibular reflexes acting on the limbs, little is known about the physiological significance of descending control of vestibulosympathetic pathways.

Autonomic dysreflexia: a cardiovascular disorder following spinal cord injury.

Autonomic dysreflexia (AD) is a serious cardiovascular disorder in patients with spinal cord injury (SCI). The primary underlying cause of AD is loss of supraspinal control over sympathetic preganglionic neurons (SPNs) caudal to the injury, which renders the SPNs hyper-responsive to stimulation. Central maladaptive plasticity, including C-fiber sprouting and propriospinal fiber proliferation exaggerates noxious afferent transmission to the SPNs, causing them to release massive sympathetic discharges that result in severe hypertensive episodes. In parallel, upregulated peripheral vascular sensitivity following SCI exacerbates the hypertensive response by augmenting gastric and pelvic vasoconstriction. Currently, the majority of clinically employed treatments for AD involve anti-hypertensive medications and Botox injections to the bladder. Although these approaches mitigate the severity of AD, they only yield transient effects and target the effector organs, rather than addressing the primary issue of central sympathetic dysregulation. As such, strategies that aim to restore supraspinal reinnervation of SPNs to improve cardiovascular sympathetic regulation are likely more effective for AD. Recent pre-clinical investigations show that cell transplantation therapy is efficacious in reestablishing spinal sympathetic connections and improving hemodynamic performance, which holds promise as a potential therapeutic approach.

Autonomic disturbances including impaired hand thermoregulation in multiple system atrophy and Parkinson's disease.

Autonomic dysfunction in multiple system atrophy (MSA) comprises cardinal symptoms of orthostatic hypotension (OH) and urinary incontinence. Additionally, cardiovagal and sudomotor abnormalities can be present. Previous studies compared hand skin temperature and its response to cooling in subjects with probable MSA and Parkinson's disease (PD). Significant differences were found indicating that disturbed thermoregulation belongs to MSA autonomic features and could be helpful in differentiation of MSA from PD. The objective of this study was to improve our knowledge about impaired thermoregulation of distal extremities in MSA with parkinsonian features (MSA-P) and PD and to assess the possible interrelations for the different subtypes of autonomic dysfunction in a large cohort of MSA-P, PD and control patients. The patients underwent a standard cooling-rewarming procedure, termed ice test (IT). Electroneurography, heart rate variability, sympathetic skin response and orthostatic tests were performed for the subdivision of the patients. The prevalence of pathological IT was slightly increased in MSA compared with PD and control groups. The presence of pathological IT was related with older patient's age in PD and control groups significantly (p<0.05). This relation was absent for the MSA patients, who themselves were significantly younger (p=0.001). Significant association between the presence of pathological IT and OH was determined (p<0.001). Defective thermoregulation of distal extremities seems to be more severe in the MSA patients. The dysfunction of preganglionic sympathetic neurons might be involved in impaired response to cooling for MSA. The results suggest pathophysiological affinity of impaired sympathetic neurovascular regulation between pathological IT and OH.

The sympathetic regulation of the heart.

Dr Murray Esler discusses the role of the sympathetic innervation to the heart with relevance to Takotsubo cardiomyopathy The spinal cells of origin for the sympathetic nerves of the heart lie in the intermediolateral cell column of the upper 3–4 thoracic segments of the spinal cord. These cardiac pre-ganglionic neurons relay primarily through the stellate (cervicothoracic) and thoracic sympathetic ganglia. The output of post-ganglionic fibres from these ganglia are grouped in the superior, middle and inferior cardiac nerves, to be distributed to the cardiac plexus of nerves on the surface of the heart, then to the individual anatomical components receiving sympathetic innervation. Intrinsic cardiac ganglia are enmeshed in the cardiac neural plexus, and participate in autonomic regulatory influences on the heart. Central reflex and behavioural sympathetic control of the heart resides in four hierarchical levels of the neuroaxis: cortex (insular cortex, anterior cingulate cortex); subcortical forebrain (hypothalamus, amygdala); brainstem (including rostral ventrolateral medulla, caudal ventrolateral medulla, nucleus tractus solitarius, periaqueductal gray, raphe nuclei); spinal level (pre-ganglionic sympathetic neurons of intermediolateral column). From some of these brain regions there are direct, monosynaptic relays to the spinal pre-ganglionic neurons. With behavioural stimuli, CNS inputs to sympathetic outflow from the insular cortex, hypothalamus, and amygdala are prominent. In many and diverse circumstances …

Acute hypoxia activates hypothalamic paraventricular nucleus-projecting catecholaminergic neurons in the C1 region

Catecholaminergic C1 cells reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM) and can be activated by hypoxia. These neurons regulate the hypothalamic pituitary axis via direct projections to the hypothalamic paraventricular nucleus (PVH) and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. Based on the various effects attributed to the C1 cells and what is currently known of their synaptic inputs, our hypothesis is that acute hypoxia (AH) activates RVLM projecting catecholaminergic neurons to PVH. Anterograde tracer, Phaseolus vulgaris leucoagglutinin (PHA-L) was unilaterally injected into the RVLM and a retrograde tracer Cholera toxin b (CTb) was unilaterally injected into the PVH region. After ten days, male Wistar rats that received CTb injection into the PVH were subjected to AH (8% O2, balanced with N2) or normoxia (21% O2) for 3h. Acute hypoxia significantly increased Fos immunoreactivity in the C1 region (68±2 neurons), and half of the RVLM cells activated are catecholaminergic (35±2 neurons). We observed that 23±4% of the RVLM projecting PVH cells that were activated by AH were also C1 cells. The presence of varicosities containing PHA-L in PVH region was also observed. The present results suggest that catecholaminergic C1-PVH projection is hypoxia-sensitive and the pathway between these two important brain areas can be one more piece in the complex puzzle of neural control of autonomic regulation during hypoxia.

Olfactory ensheathing cells but not fibroblasts reduce the duration of autonomic dysreflexia in spinal cord injured rats.

Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia.