Sympathetic Preganglionic Neurons Research Articles

Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons. The role of orexin in the increased SNA response to AIH was investigated in urethane-anesthetized, vagotomized, and artificially ventilated Sprague-Dawley rats (n = 58). A spinally infused subthreshold dose of orexin-A (intermittent; 0.1 nmol × 10) produced long-term enhancement in SNA (41.4% ± 6.9%) from baseline. This phenomenon was not produced by the same dose of orexin-A administered as a bolus intrathecal infusion (1 nmol; 7.3% ± 2.3%). The dual orexin receptor blocker, Almorexant, attenuated the effect of sympathetic long-term facilitation generated by intermittent orexin-A (20.7% ± 4.5% for Almorexant at 30 mg∙kg(-1) and 18.5% ± 1.2% for 75 mg∙kg(-1)), but not in AIH. The peripheral chemoreflex sympathoexcitatory response to hypoxia was greatly enhanced by intermittent orexin-A and AIH. In both cases, the sympathetic chemoreflex sensitization was reduced by Almorexant. Taken together, spinally acting orexin-A is mechanistically sufficient to evoke sympathetic long-term facilitation. However, AIH-induced sympathetic long-term facilitation appears to rely on mechanisms that are independent of orexin neurotransmission. Our findings further reveal that the activation of spinal orexin receptors is critical to enhance peripheral chemoreceptor responses to hypoxia after AIH.

Endogenous nitric oxide derived from NOS I or II in thoracic spinal cord exerts opposing tonic modulation on sympathetic vasomotor tone via disparate mechanisms in anesthetized rats.

The sympathetic preganglionic neurons (SPN) in the thoracic spinal cord regulate vasomotor tone via norepinephrine released from sympathetic terminals and adrenal medulla. We assessed the hypothesis that nitric oxide synthase I (NOS I)- and NOS II-derived nitric oxide (NO) in the thoracic spinal cord differentially modulate sympathetic outflow and that the adrenal medulla may be involved in those modulatory actions. In Sprague-Dawley rats, NOS I immunoreactivity was distributed primarily in the perikaryon, proximal dendrites, or axons of SPN, and small clusters of NOS II immunoreactivity impinged mainly on the circumference of SPN. Intrathecal administration of 7-nitroindazole (7-NI), a specific NOS I antagonist, into the thoracic spinal cord significantly reduced arterial pressure, heart rate, and basal or baroreflex-mediated sympathetic vasomotor tone. On the other hand, intrathecal application of S-methylisothiourea (SMT), a specific NOS II antagonist, elevated arterial pressure with a transient reduction of heart rate, induced a surge of plasma norepinephrine, and reduced baroreflex-mediated but not basal sympathetic vasomotor tone. Bilateral adrenalectomy significantly exacerbated the cardiovascular responses to 7-NI but antagonized those to SMT. We conclude that both NOS I and NOS II are present in the thoracic spinal cord and are tonically active under physiological conditions. Furthermore, the endogenous NO generated by NOS I-containing SPN exerts a tonic excitatory action on vasomotor tone mediated by norepinephrine released from the adrenal medulla and sympathetic nerve terminals. On the other hand, NO derived from NOS II exerts a tonic inhibitory action on sympathetic outflow from the SPN that targets primarily the blood vessels.

Segregation of Acetylcholine and GABA in the Rat Superior Cervical Ganglia: Functional Correlation.

Sympathetic neurons have the capability to segregate their neurotransmitters (NTs) and co-transmitters to separate varicosities of single axons; furthermore, in culture, these neurons can even segregate classical transmitters. In vivo sympathetic neurons employ acetylcholine (ACh) and other classical NTs such as gamma aminobutyric acid (GABA). Herein, we explore whether these neurons in vivo segregate these classical NTs in the superior cervical ganglia of the rat. We determined the topographical distribution of GABAergic varicosities, somatic GABAA receptor, as well as the regional distribution of the segregation of ACh and GABA. We evaluated possible regional differences in efficacy of ganglionic synaptic transmission, in the sensitivity of GABAA receptor to GABA and to the competitive antagonist picrotoxin (PTX). We found that sympathetic preganglionic neurons in vivo do segregate ACh and GABA. GABAergic varicosities and GABAA receptor expression showed a rostro-caudal gradient along ganglia; in contrast, segregation exhibited a caudo-rostral gradient. These uneven regional distributions in expression of GABA, GABAA receptors, and level of segregation correlate with stronger synaptic transmission found in the caudal region. Accordingly, GABAA receptors of rostral region showed larger sensitivity to GABA and PTX. These results suggest the presence of different types of GABAA receptors in each region that result in a different regional levels of endogenous GABA inhibition. Finally, we discuss a possible correlation of these different levels of GABA modulation and the function of the target organs innervated by rostral and caudal ganglionic neurons.

An Optogenetic Test for the Functional Specificity of Bulbospinal Sympathoexcitatory Neurons

Sympathetic preganglionic neurons are functionally specialised, each belonging to one of a limited number of functional classes (e.g. muscle vasoconstrictor, cutaneous vasoconstrictor, sudomotor). How far this functional specificity applies to the premotor neurons that drive them is uncertain. We devised an optogenetic test for the existence of premotor neurons that are collateralised to drive more than one functional class of sympathetic neuron.Bulbospinal neurons were transduced by a retrogradely transported viral vector (canine adenovirus) encoding Cre recombinase (CAV‐CMV‐Cre; provided by Eric Kremer, Montpellier). This was injected around sympathetic preganglionic neurons at the T12‐L1 spinal levels. At the same time, a Cre‐activated adeno‐associated virus (AAV) encoding Channelrhodopsin‐2 (ChR2) and the fluorescent label mCherry (AAV1.EF1.dflox.hChR2(H134R)‐mCherry.WPRE.hGH; provided by Deisseroth, Stanford via UPenn) was injected into the left RVLM. Only neurons transduced by both viral vectors should then express the ChR2 and mCherry. Spinal injections were made at T12‐L1 because they were considered unlikely to overlap with the preganglionic supply to the heart. The bulbospinal presynaptic terminals infected with CAV‐Cre were thus presumably on preganglionic neurons that supplied end organs such as hindlimb muscle, but not the heart.Terminal functional experiments under urethane anaesthesia were performed 2–8 weeks after the viral injections. Activity was simultaneously recorded from the left cardiac and lumbar sympathetic nerves, whilst pulses of blue laser light (473 nm, 10–12 mW, 20 ms) were flashed onto the left RVLM through a 100 μm diameter fibre‐optic probe.In about one‐third of experiments, we were able to show functional activation of sympathetic nerves that was time‐locked to the flashed laser light. In all successful experiments, we found cardiac sympathetic activation as well as lumbar sympathetic activation (peak response latencies 135–150 ms and 215–230 ms, respectively). Subsequent fluorescence microscopy on brainstem sections confirmed the presence of small numbers of mCherry expressing bulbospinal neurons in those rats.This study demonstrates that at least some bulbospinal neurons send excitatory synaptic inputs to preganglionic neurons of more than one functional type. It also demonstrates the feasibility of using anatomically‐based optogenetic transduction as a test for functional collateralisation in central pathways.Support or Funding InformationAustralian Research Council DP13014661

Vagal tone: effects on sensitivity, motility, and inflammation.

The vagus nerve (VN) is a key element of the autonomic nervous system. As a mixed nerve, the VN contributes to the bidirectional interactions between the brain and the gut, i.e., the brain-gut axis. In particular, after integration in the central autonomic network of peripheral sensations such as inflammation and pain via vagal and spinal afferents, an efferent response through modulation of preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus and/or preganglionic sympathetic neurons of the spinal cord is able to modulate gastrointestinal nociception, motility, and inflammation. A low vagal tone, as assessed by heart rate variability, a marker of the sympatho-vagal balance, is observed in functional digestive disorders and inflammatory bowel diseases. To restore a normal vagal tone appears as a goal in such diseases. Among the therapeutic tools, such as drugs targeting the cholinergic system and/or complementary medicine (hypnosis, meditation…), deep breathing, physical exercise, VN stimulation (VNS), either invasive or non-invasive, appears as innovative. There is new evidence in the current issue of this Journal supporting the role of VNS in the modulation of gastrointestinal functions.

Autonomic Dysfunction: A Predictive Factor of Risk to Develop Rheumatoid Arthritis?

Autonomic Dysfunction: A Predictive Factor of Risk to Develop Rheumatoid Arthritis?

The rostral ventromedial medulla control of cutaneous vasomotion of paws and tail in the rat: implication for pain studies.

Thermal neutrality in rodents is achieved by large cyclic variations of the sympathetic drive of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Given the pivotal functional role of rostral ventromedial medulla (RVM) in nociception and rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, we aimed at circumscribing the brainstem regions that are the source of premotor afferents to sympathetic preganglionic neurons that control the vasomotor tone of the tail and hind paws. A thermometric infrared camera recorded indirectly the vasomotor tone of the tail and hind paws. During the control period, the rat was maintained in vasoconstriction by preserving a stable, homogeneous, and constant surrounding temperature, slightly below the core temperature. The functional blockade of the RVM/rMR by the GABAA receptor agonist muscimol (0.5 nmol, 50 nl) elicited an extensive increase of the temperature of the paws and tail, associated with a slight decrease of blood pressure and heart rate. Both the increased heat loss through vasodilatation and the decrease heart-induced heat production elicited a remarkable reduction of the central temperature. The effective zones were circumscribed to the parts of the RVM/rMR facing the facial nucleus. They match very exactly the brain regions often described as specifically devoted to the control of nociception. Our data support and urge on the highest cautiousness regarding the interpretation of results aimed at studying the effects of any pharmacological manipulations of RVM/rMR with the usual tests of pain.

Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

Calbindin-Immunoreactive Interneurons in the Intermediate Zone and Ventral Horn of the Gray Matter of the SC in White Rats

The aim of the present work was to study the topography and structure of 28-kDa calbindin (CB)-containing interneurons in the ventral horn and intermediate zone of the gray matter at levels TII and LIV of the spinal cord (SC). Experiments were performed in adult female Wistar rats (n = 4) using immunohistochemical and morphometric methods. Cryostat transverse sections of the SC of thickness 14 μm were studied. The intermediate zone of the SC was found to contain two subpopulations of CB-immunoreactive (IR) interneurons in lamina VII in both segments: sympathetic preganglionic neurons and “partition” cells. The ventral horn also contained two subpopulations of CB-IR interneurons: Renshaw cells in lamina IX in TII and lamina VII in LIV and large interneurons in lamina VIII in TII and lamina VII in LIV. The only differences between segments were in the larger numbers of Renshaw cells and partition cells in LIV. The mean cross-sectional areas of CB-IR Renshaw cells and autonomic preganglionic neurons were greater in TII, while large interneurons of the ventral horn and partition cells were larger in LIV.

A slow-fast approach to studying the emergence and amplitude of respiratory bursting in sympathetic preganglionic neurones

A slow-fast approach to studying the emergence and amplitude of respiratory bursting in sympathetic preganglionic neurones

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

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 PVH projecting catecholaminergic neurons in the RVLM. 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 3 hours. Acute hypoxia significantly increased Fos immunoreactivity in the C1 region (68.5 ± 2.0), and half of the RVLM cells activated are catecholaminergic (35.5 ± 2.3). We observed that 30 ± 4% of the PVH projecting RVLM 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 certainly be one more piece in the complex puzzle of neural control of autonomic regulation during hypoxia. Financial support: FAPESP, CNPq and CAPES/PROEX.

Respiratory modulated bursting of sympathetic activity

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 PVH projecting catecholaminergic neurons in the RVLM. 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 3 hours. Acute hypoxia significantly increased Fos immunoreactivity in the C1 region (68.5 ± 2.0), and half of the RVLM cells activated are catecholaminergic (35.5 ± 2.3). We observed that 30 ± 4% of the PVH projecting RVLM 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 certainly be one more piece in the complex puzzle of neural control of autonomic regulation during hypoxia. Financial support: FAPESP, CNPq and CAPES/ PROEX.

GABA and enkephalin tonically alter sympathetic outflows in the rat spinal cord.

GABA and enkephalin provide significant innervation of sympathetic preganglionic neurons. Despite some investigation as to the identity of premotor sources of these innervations no comprehensive analyses have been conducted. Similarly, although data describing the cardiovascular effects of blockade of GABAA receptors in the spinal cord is available, the effects at other sympathetic outflows are unknown. In contrast the sympathetic effects of opioid blockade in the spinal cord are unclear. The aims of this study were to identify potential sympathetic premotor sources of GABAergic and enkephalinergic input to the spinal cord and to describe the sympathetic and cardiovascular effects of spinal GABAA receptor and delta/mu opioid receptor blockade in urethane anaesthetised rats. Glutamic acid decarboxylase (GAD67) and preproenkephalin (PPE) mRNA were found in all regions containing sympathetic premotor neurons, with the medullary raphe and RVMM providing the major GABAergic projections, while the PVN, RVMM and medullary raphe provided the major enkephalinergic projections. Intrathecal injection of bicuculline, a GABAA antagonist, elicited large and prolonged increases in all outflows measured, confirming previous work describing a tonic GABAergic influence on vasomotor tone, and revealing a tonic GABAergic inhibition of interscapular brown adipose tissue temperature. Intrathecal naloxone elicited transient small inhibitory effects only on MAP and HR. Thus GABA acting in the spinal cord plays an important role in the tonic suppression of sympathetic outflows while enkephalin appears to play only a minor role.

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation.

Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short- and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation.

Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and Energy Expenditure

Brain-derived neurotrophic factor (BDNF) is a key regulator of energy balance; however, its underlying mechanism remains unknown. By analyzing BDNF-expressing neurons in paraventricular hypothalamus (PVH), we have uncovered neural circuits that control energy balance. The Bdnf gene in the PVH was mostly expressed in previously undefined neurons, and its deletion caused hyperphagia, reduced locomotor activity, impaired thermogenesis, and severe obesity. Hyperphagia and reduced locomotor activity were associated with Bdnf deletion in anterior PVH, whereas BDNF neurons in medial and posterior PVH drive thermogenesis by projecting to spinal cord and forming polysynaptic connections to brown adipose tissues. Furthermore, BDNF expression in the PVH was increased in response to cold exposure, and its ablation caused atrophy of sympathetic preganglionic neurons. Thus, BDNF neurons in anterior PVH control energy intake and locomotor activity, whereas those in medial and posterior PVH promote thermogenesis by releasing BDNF into spinal cord to boost sympathetic outflow.

Calbindin-D28k immunoreactivity in the mice thoracic spinal cord after space flight

AbstractThe aim of the work was to analyse changes in the location and morphological characteristics of calbindin (CB)-immunoreactive (IR) neurons of the thoracic spinal cord of C57BL/6N male mice after completion of a 30-day space flight on board the BION-M1 biosatellite (Russia, 2013). Space flight induced multidirectional changes of the number and morphological parameters of CB-positive neurons. The number of IR neurons increased in laminae I (from 10 to 17 neurons per section), II (from 42 to 67 cells per section) and IX (from two neurons per segment to two neurons per section), but CB disappeared in neurons of lamina VIII. Weightlessness did not affect the number of CB-IR neurons in laminae III–V and VII, including preganglionic sympathetic neurons. The cross-sectional area of CB-IR neurons decreased in lamina II and VII (group of partition cells) and increased in laminae III–V and IX. After a space flight, few very large neurons with long dendrites appeared in lamina IV. The results obtained give evidence about substantial changes in the calcium buffer system and imbalance of different groups of CB-IR neurons due to reduction of afferent information under microgravity.

Sweating on the palm and sole: physiological and clinical relevance.

In mammals, sweating is a multifunctional response that aids in locomotion, thermal regulation, self-protection, and communication of psychological state. Humans possess three types of sweat glands (apocrine, eccrine, and apoeccrine) that are differentially distributed on the body surface and make unique contributions to these distinct functions of the sweating response. In humans, eccrine glands, which are widely distributed on hairy skin, play an important role in thermoregulation. They are also found on the glabrous skin of the palm and sole, where they are not usually activated by heat, but rather by deep respiration, mental stress, and local tactile stimulation. Sweating on the palm and sole, so-called "emotional sweating", acts to prevent slippage while grasping or performing a delicate task using the fingertips. Although the central pathways of emotional sweating are not yet elucidated in detail, it is thought that the amygdala, cingulate cortex, and medulla participate via efferent fibers that descend through the spinal cord and connect to preganglionic sympathetic neurons in the nucleus intermediolateralis. The limbic system, including the amygdala and cingulate cortex, is critical for emotional processing and many cognitive functions. Thus, measurement of sweat output on the palm or sole is useful for evaluating sympathetic function and limbic activity in autonomic and psychiatric disorders.

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.

Inhibitory Regulation of Skeletal Muscle Shivering

Skeletal muscle shivering thermogenesis contributes to the cold‐defensive maintenance of core body temperature and to the elevated body temperature during fever. The thermoregulatory reflex pathway through which skin and core cooling, or injection of prostaglandin E2 into the preoptic area of the hypothalamus, leads to activation of skeletal muscle shivering has been described (J Physiol 589.14: 3641–3658, 2011). Although this pathway influences the discharge of alpha‐motoneurons in the ventral horn, rather than sympathetic preganglionic neurons in the intermediolateral nucleus, it is remarkably parallel to the thermoregulatory pathway mediating cold‐defensive activation of brown adipose tissue (Cell Metabolism 19: 741‐756, 2014). To determine if this similarity extends to the central and vagal afferent inhibitory regulation of skeletal muscle shivering, neurons in the paraventricular hypothalamus, in the nucleus of the tractus solitarii, or in the ventrolateral medulla were activated; or electrical stimuli were applied to afferents in the cervical vagus nerve, during cold‐ or PGE2 injection‐evoked increases in masseter, neck and gastrocnemius muscle EMGs in Inactin‐anesthetized rats. Activation of neurons in each of these regions, or vagus nerve stimulation elicits a marked inhibition of cold‐evoked and PGE2‐evoked brown adipose tissue sympathetic outflow and thermogenesis. Overall, the results, indicate strong parallels between the inhibitory regulation of shivering and brown adipose tissue thermogenesis and energy consumption. The specific physiological stimuli for, and the synaptic integration sites supporting these inhibitions of shivering remain to be determined. Supported by NIH grant NS40987.

Reduced Ability to Maintain Cardiac Output and Arterial Pressure During Coronary Artery Occlusion in Conscious Paraplegic Mice

Cardiovascular morbidity and mortality are high in individuals with spinal cord injuries (SCI) due to a relatively sedentary life style and higher prevalence of other cardiovascular disease risk factors including obesity and diabetes. Furthermore, the risk for cardiovascular disease is exacerbated by abnormal and unstable autonomic control of the heart and vasculature. In this context, the response to myocardial ischemia is complex and involves an excitatory sympathetic reflex that supports arterial pressure during ventricular injury and reductions in cardiac output. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an excitatory sympathetic reflex which plays a major role in maintaining perfusion pressure. Individuals and animals with SCI at thoracic level 5 (T5X) maintain the cardio-cardiac sympathetic reflex but fail to excite sympathetic pre-ganglionic neurons below the level of the injury. Accordingly, the tolerance to coronary artery occlusion (CAO) was expected to be markedly reduced in T5X mice. As expected, T5X mice had a reduced ability to maintain cardiac output and arterial pressure during CAO. External lower body compression (20mmHg) markedly improved the tolerance to CAO by supporting arterial pressure and cardiac output. Results suggest that loss of sympathetic control below thoracic level 5 prevented the support of arterial pressure and cardiac output while external lower body compression markedly improved the tolerance to CAO in paraplegic mice. The results have the potential to impact the lives of individuals living with SCI by harnessing endogenous homeostatic control systems with a simple and easily administered therapeutic intervention.