Immediate and sustained increases in the activity of vagal preganglionic neurons during exercise and after exercise training.

AIMS: The brain controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic (vagal) and sympathetic activity. Autonomic control is essential for the development of cardiovascular responses during exercise, however, the patterns of changes in the activity of the two autonomic limbs, and their functional interactions in orchestrating physiological responses during exercise, are not fully understood. The aim of this study was to characterize changes in vagal parasympathetic drive in response to exercise and exercise training by directly recording the electrical activity of vagal preganglionic neurons in experimental animals (rats). METHODS AND RESULTS: Single unit recordings were made using carbon-fibre microelectrodes from the populations of vagal preganglionic neurons of the nucleus ambiguus (NA) and the dorsal vagal motor nucleus of the brainstem. It was found that (i) vagal preganglionic neurons of the NA and the dorsal vagal motor nucleus are strongly activated during bouts of acute exercise, and (ii) exercise training markedly increases the resting activity of both populations of vagal preganglionic neurons and augments the excitatory responses of NA neurons during exercise. CONCLUSIONS: These data show that central vagal drive increases during exercise and provide the first direct neurophysiological evidence that exercise training increases vagal tone. The data argue against the notion of exercise-induced central vagal withdrawal during exercise. We propose that robust increases in the activity of vagal preganglionic neurons during bouts of exercise underlie activity-dependent plasticity, leading to higher resting vagal tone that confers multiple health benefits associated with regular exercise.

Downstream projection of Barrington's nucleus to the spinal cord in mice.

Barrington's nucleus (Bar), which controls micturition behavior through downstream projections to the spinal cord, contains two types of projection neurons, BarCRH and BarESR1, that have different functions and target different spinal circuitry. Both types of neurons project to the L6-S1 spinal intermediolateral (IML) nucleus, whereas BarESR1 neurons also project to the dorsal commissural nucleus (DCN). To obtain more information about the spinal circuits targeted by Bar, we used patch-clamp recording in spinal slices from adult mice in combination with optogenetic stimulation of Bar terminals. Recording of opto-evoked excitatory postsynaptic currents (oEPSCs) in 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine, 4-chlorobenzenesulfonate (DiI)-labeled lumbosacral preganglionic neurons (LS-PGNs) revealed that both Bar neuronal populations make strong glutamatergic monosynaptic connections with LS-PGNs, whereas BarESR1 neurons also elicited smaller-amplitude glutamatergic polysynaptic oEPSCs or polysynaptic opto-evoked inhibitory postsynaptic currents (oIPSCs) in some LS-PGNs. Optical stimulation of BarCRH and BarESR1 terminals also elicited monosynaptic oEPSCs and polysynaptic oIPSCs in sacral DCN neurons, some of which must include interneurons projecting to either the IML or ventral horn. Application of capsaicin increased opto-evoked firing during repetitive stimulation of Bar terminals through the modulation of spontaneous postsynaptic currents in LS-PGNs. In conclusion, our experiments have provided insights into the synaptic mechanisms underlying the integration of inputs from Bar to autonomic circuitry in the lumbosacral spinal cord that may control micturition.NEW & NOTEWORTHY Photostimulation of BarCRH or BarESR1 axons in the adult mouse spinal cord elicits excitatory or inhibitory postsynaptic responses in multiple cell types related to the autonomic nervous system including preganglionic neurons (PGNs) in the lumbosacral intermediolateral nucleus and interneurons in the lumbosacral dorsal commissure nucleus. Integration of excitatory inputs from Bar and from visceral primary afferents in PGNs may be important in the regulation of micturition behavior.

Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility.

The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.

Spinal cord neural network interactions: implications for sympathetic control of the porcine heart.

Inherent and acquired factors determine the integrated autonomic response to cardiovascular stressors. Excessive sympathoexcitation to ischemic stress is a major contributor to the potential for sudden cardiac death. To define fundamental aspects of cardiac-related autonomic neural network interactions within the thoracic cord, specifically as related to modulating sympathetic preganglionic (SPN) neural activity. Adult, anesthetized Yorkshire pigs (n = 10) were implanted with penetrating high-density microarrays (64 electrodes) at the T2 level of the thoracic spinal cord to record extracellular potentials concurrently from left-sided dorsal horn (DH) and SPN neurons. Electrical stimulation of the T2 paravertebral chain allowed for antidromic identification of SPNs located in the intermediolateral cell column (57 of total 1,760 recorded neurons). Cardiac stressors included epicardial touch, occlusion of great vessels to transiently alter preload/afterload, and transient occlusion of the left anterior descending coronary artery (LAD). Spatial/temporal assessment of network interactions was characterized by cross-correlation analysis. While some DH neurons responded solely to changes in preload/afterload (8.5 ± 1.9%) or ischemic stress (10.5 ± 3.9%), the majority of cardiovascular-related DH neurons were multimodal (30.2 ± 4.7%) with ischemia sensitivity being one of the modalities (26.1 ± 4.7%). The sympathoexcitation associated with transient LAD occlusion was associated with increased correlations from baseline within DH neurons (2.43 ± 0.61 to 7.30 ± 1.84%, P = 0.04) and between SPN to DH neurons (1.32 ± 0.78 to 7.24 ± 1.84%, P = 0.02). DH to SPN network correlations were reduced during great vessel occlusion. In conclusion, increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation.NEW & NOTEWORTHY In an in vivo pig model, we demonstrate using novel high-resolution neural electrode arrays that increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation.

On the presence and functional significance of sympathetic premotor neurons with collateralized spinal axons in the rat.

KEY POINTS: Spinally-projecting neurons of the rostral ventrolateral medulla (RVLM) determine sympathetic outflow to different territories of the body. Previous studies suggest the existence of RVLM neurons with distinct functional classes, such as neurons that target sympathetic nerves bound for functionally-similar tissue types (e.g. muscle vasculature). The existence of RVLM neurons with more general actions had not been critically tested. Using viral tracing, we show that a significant minority of RVLM neurons send axon collaterals to disparate spinal segments (T2 and T10 ). Furthermore, optogenetic activation of sympathetic premotor neurons projecting to lumbar spinal segments also produced activation of sympathetic nerves from rostral spinal segments that innervate functionally diverse tissues (heart and forelimb muscle). These findings suggest the existence of individual RVLM neurons for which the axons branch to drive sympathetic preganglionic neurons of more than one functional class and may be able to produce global changes in sympathetic activity. ABSTRACT: We investigate the extent of spinal axon collateralization of rat rostral ventrolateral medulla (RVLM) sympathetic premotor neurons and its functional consequences. In anatomical tracing experiments, two recombinant herpes viral vectors with retrograde tropism and expressing different fluorophores were injected into the intermediolateral column at upper thoracic and lower thoracic levels. Histological analysis revealed that ∼21% of RVLM bulbospinal neurons were retrogradely labelled by both vectors, indicating substantial axonal collateralization to disparate spinal segments. In functional experiments, another virus with retrograde tropism, a canine adenovirus expressing Cre recombinase, was injected into the left intermediolateral horn around the thoracolumbar junction, whereas a Cre-dependent viral vector encoding Channelrhodopsin2 under LoxP control was injected into the ipsilateral RVLM. In subsequent terminal experiments, blue laser light (473 nm × 20 ms pulses at 10 mW) was used to activate RVLM neurons that had been transduced by both vectors. Stimulus-locked activation, at appropriate latencies, was recorded in the following pairs of sympathetic nerves: forelimb and hindlimb muscle sympathetic fibres, as well as cardiac and either hindlimb muscle or lumbar sympathetic nerves. The latter result demonstrates that axon collaterals of lumbar-projecting RVLM neurons project to, and excite, both functionally similar (forelimb and hindlimb muscle) and functionally dissimilar (lumbar and cardiac) preganglionic neurons. Taken together, these findings show that the axons of a significant proportion of RVLM neurons collateralise widely within the spinal cord, and that they may excite preganglionic neurons of more than one functional class.

Adrenergic agonist induces rhythmic firing in quiescent cardiac preganglionic neurons in nucleus ambiguous via activation of intrinsic membrane excitability.

Cholinergic vagal nerves projecting from neurons in the brain stem nucleus ambiguus (NAm) play a predominant role in cardiac parasympathetic pacemaking control. Central adrenergic signaling modulates the tone of this vagal output; however, the exact excitability mechanisms are not fully understood. We investigated responses of NAm neurons to adrenergic agonists using in vitro mouse brain stem slices. Preganglionic NAm neurons were identified by ChAT-tdTomato fluorescence in young adult transgenic mice, and their cardiac projection was confirmed by retrograde dye tracing. Juxtacellular recordings detected sparse or absent spontaneous action potentials (AP) in NAm neurons. However, bath application of epinephrine or norepinephrine strongly and reversibly activated most NAm neurons regardless of their basal firing rate. Epinephrine was more potent than norepinephrine, and this activation largely depends on α1-adrenoceptors. Interestingly, adrenergic activation of NAm neurons does not require an ionotropic synaptic mechanism, because postsynaptic excitatory or inhibitory receptor blockade did not occlude the excitatory effect, and bath-applied adrenergic agonists did not alter excitatory or inhibitory synaptic transmission. Instead, adrenergic agonists significantly elevated intrinsic membrane excitability to facilitate generation of recurrent action potentials. T-type calcium current and hyperpolarization-activated current are involved in this excitation pattern, although not required for spontaneous AP induction by epinephrine. In contrast, pharmacological blockade of persistent sodium current significantly inhibited the adrenergic effects. Our results demonstrate that central adrenergic signaling enhances the intrinsic excitability of NAm neurons and that persistent sodium current is required for this effect. This central balancing mechanism may counteract excessive peripheral cardiac excitation during increased sympathetic tone. NEW & NOTEWORTHY Cardiac preganglionic cholinergic neurons in the nucleus ambiguus (NAm) are responsible for slowing cardiac pacemaking. This study identified that adrenergic agonists can induce rhythmic action potentials in otherwise quiescent cholinergic NAm preganglionic neurons in brain stem slice preparation. The modulatory influence of adrenaline on central parasympathetic outflow may contribute to both physiological and deleterious cardiovascular regulation.

Central inspiratory activity rhythmically activates synaptic currents of airway vagal preganglionic neurons in neonatal rats.

The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) can be separated into inspiratory-activated AVPNs (IA-AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs). IA-AVPNs are activated by excitatory presynaptic inputs during inspiratory bursts, but the composition and the roles of these excitatory inputs still remain obscure. II-AVPNs are inhibited by inhibitory presynaptic inputs but whether these inhibitory inputs are regulated by excitatory inputs is also unclear. In the current study, AVPNs were retrogradely fluorescent labeled. The IA-AVPNs were discriminated from II-AVPNs by their different synaptic inputs during inspiratory bursts. The excitatory inputs to IA-AVPNs and the presynaptic regulation of II-AVPNs were examined by whole-cell patch clamping. Topical application of 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) to the recorded IA-AVPNs almost abolished the tonic EPSCs during inspiratory intervals, inhibited the phasic excitatory currents during inspiratory bursts and attenuated the phasic inspiratory inward currents (PIICs) driven by central inspiratory activity. Blockade of α4ß2 and α7 nicotinic acetylcholine receptors (nAChRs) respectively inhibited PIICs in some IA-AVPNs. Carbenoxolone, a gap junction uncoupler, partly inhibited the PIICs of IA-AVPNs. Focal application of CNQX to the II-AVPNs significantly inhibited the frequency, peak amplitude and area of the phasic inspiratory outward currents (PIOCs). These findings demonstrated that glutamatergic non-NMDA receptors played a predominant role in the excitatory drive to the IA-AVPNs, and that α4ß2, α7 nAChRs and gap junctions were also rhythmically activated by central inspiratory activity. Additionally, glycinergic neurons making inhibitory inputs to the II-AVPNs were pre-synaptically facilitated by excitatory glutamatergic synaptic inputs.

Cardiorespiratory interactions previously identified as mammalian are present in the primitive lungfish.

The present study has revealed that the lungfish has both structural and functional features of its system for physiological control of heart rate, previously considered solely mammalian, that together generate variability (HRV). Ultrastructural and electrophysiological investigation revealed that the nerves connecting the brain to the heart are myelinated, conferring rapid conduction velocities, comparable to mammalian fibers that generate instantaneous changes in heart rate at the onset of each air breath. These respiration-related changes in beat-to-beat cardiac intervals were detected by complex analysis of HRV and shown to maximize oxygen uptake per breath, a causal relationship never conclusively demonstrated in mammals. Cardiac vagal preganglionic neurons, responsible for controlling heart rate via the parasympathetic vagus nerve, were shown to have multiple locations, chiefly within the dorsal vagal motor nucleus that may enable interactive control of the circulatory and respiratory systems, similar to that described for tetrapods. The present illustration of an apparently highly evolved control system for HRV in a fish with a proven ancient lineage, based on paleontological, morphological, and recent genetic evidence, questions much of the anthropocentric thinking implied by some mammalian physiologists and encouraged by many psychobiologists. It is possible that some characteristics of mammalian respiratory sinus arrhythmia, for which functional roles have been sought, are evolutionary relics that had their physiological role defined in ancient representatives of the vertebrates with undivided circulatory systems.

Pre- and postganglionic vasomotor dysfunction causes distal limb coldness in multiple system atrophy.

BACKGROUND: The detailed pathophysiology of limb coldness in multiple system atrophy (MSA) is unknown. METHODS: We evaluated cutaneous vasomotor neural function in 18 MSA patients with or without limb coldness, and in 20 healthy volunteers as controls. We measured resting skin sympathetic nerve activity (SSNA) and spontaneous changes of the sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex: SVR), as well as SVR and reflex changes of SSNA after electrical stimulation. The parameters investigated were the SSNA frequency at rest, amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and skin blood flow velocity. RESULTS: Both the resting frequency of SSNA and the amplitude of SSNA reflex bursts were significantly lower in the MSA group than the control group (p<0.001 and p<0.05, respectively). There were no significant differences between the two groups with regard to the absolute decrease or percent reduction of SVR volume. The recovery time showed no significant difference between all MSA patients and control groups, but it was significantly prolonged in six MSA patients with limb coldness compared with that in the control group and that in MSA patients without limb coldness (p<0.01). The skin blood flow velocity was significantly slower in the MSA group than in the control group (p<0.001). CONCLUSION: In MSA patients, limb coldness might occur due to impairments of the peripheral circulation based on prolongation of vasoconstriction and a decrease of skin blood flow velocity secondary to combined pre- and postganglionic skin vasomotor dysfunction.

Corticotropin-releasing hormone modulates airway vagal preganglionic neurons of Sprague-Dawley rats at multiple synaptic sites via activation of its type 1 receptors: Implications for stress-associated airway vagal excitation.

Corticotropin-releasing hormone release is the final common pathway of stress-associated neuroendocrine responses. This study tested how corticotropin-releasing hormone modulates airway vagal preganglionic neurons. Airway vagal preganglionic neurons in neonatal rats were retrogradely labeled with fluorescent dye and identified in medullary slices, and their responses to corticotropin-releasing hormone (200nmolL-1) were examined using whole-cell patch clamp. The results show that under current clamp, corticotropin-releasing hormone (200nmolL-1) depolarized airway vagal preganglionic neurons and significantly increased the rate of their spontaneous firing. Under voltage clamp, corticotropin-releasing hormone caused a tonic inward current and significantly facilitated the spontaneous glutamatergic and GABAergic inputs of these neurons. Corticotropin-releasing hormone had no impact on the spontaneous glycinergic inputs of these neurons. In the preexistence of tetrodotoxin (1µmolL-1), corticotropin-releasing hormone had no impact on the miniature excitatory or inhibitory postsynaptic currents, but still induced a tonic inward current and significantly increased the input resistance. The responses induced by corticotropin-releasing hormone were prevented by Antalarmin hydrochloride (50µmolL-1), an antagonist of type 1 corticotropin-releasing hormone receptors, but insensitive to Astressin 2B (200nmolL-1), an antagonist of type 2 corticotropin-releasing hormone receptors. These results suggest that corticotropin-releasing hormone excites airway vagal preganglionic neurons via activation of its type 1 receptors at multiple sites, which includes a direct postsynaptic excitatory action and presynaptic facilitation of both glutamatergic and GABAergic inputs. In stress, corticotropin-releasing hormone might be able to activate the airway vagal nerves and, consequently, participate in induction or exacerbation of airway disorders.

Cardiac vagal preganglionic neurones: An update.

The autonomic nervous system controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic and sympathetic activities. These activities are generated by groups of sympathoexcitatory and vagal preganglionic neurones residing in a close proximity to each other within well-defined structures of the brainstem. This short essay provides a general overview and an update on the latest developments in our understanding of the central nervous origins and functional significance of cardiac vagal tone. Significant experimental evidence suggests that distinct groups of cardiac vagal preganglionic neurones with different patterns of activity control nodal tissue (controlling the heart rate and atrioventricular conductance) and the ventricular myocardium (modulating its contractility and excitability).

Exercise training preserves vagal preganglionic neurones and restores parasympathetic tonus in heart failure.

KEY POINTS: Heart Failure (HF) is accompanied by reduced ventricular function, activation of compensatory neurohormonal mechanisms and marked autonomic dysfunction characterized by exaggerated sympathoexcitation and reduced parasympathetic activity. With 6 weeks of exercise training, HF-related loss of choline acetyltransferase (ChAT)-positive vagal preganglionic neurones is avoided, restoring the parasympathetic tonus to the heart, and the immunoreactivity of dopamine ß-hydroxylase-positive premotor neurones that drive sympathetic outflow to the heart is reduced. Training-induced correction of autonomic dysfunction occurs even with the persistence of abnormal ventricular function. Strong positive correlation between improved parasympathetic tonus to the heart and increased ChAT immunoreactivity in vagal preganglionic neurones after training indicates this is a crucial mechanism to restore autonomic function in heart failure. ABSTRACT: Exercise training is an efficient tool to attenuate sympathoexcitation, a hallmark of heart failure (HF). Although sympathetic modulation in HF is widely studied, information regarding parasympathetic control is lacking. We examined the combined effects of sympathetic and vagal tonus to the heart in sedentary (Sed) and exercise trained (ET) HF rats and the contribution of respective premotor and preganglionic neurones. Wistar rats submitted to coronary artery ligation or sham surgery were assigned to training or sedentary protocols for 6 weeks. After haemodynamic, autonomic tonus (atropine and atenolol i.v.) and ventricular function determinations, brains were collected for immunoreactivity assays (choline acetyltransferase, ChATir; dopamine ß-hydroxylase, DBHir) and neuronal counting in the dorsal motor nucleus of vagus (DMV), nucleus ambiguus (NA) and rostroventrolateral medulla (RVLM). HF-Sed vs. SHAM-Sed exhibited decreased exercise capacity, reduced ejection fraction, increased left ventricle end diastolic pressure, smaller positive and negative dP/dt, decreased intrinsic heart rate (IHR), lower parasympathetic and higher sympathetic tonus, reduced preganglionic vagal neurones and ChATir in the DMV/NA, and increased RVLM DBHir. Training increased treadmill performance, normalized autonomic tonus and IHR, restored the number of DMV and NA neurones and corrected ChATir without affecting ventricular function. There were strong positive correlations between parasympathetic tonus and ChATir in NA and DMV. RVLM DBHir was also normalized by training, but there was no change in neurone number and no correlation with sympathetic tonus. Training-induced preservation of preganglionic vagal neurones is crucial to normalize parasympathetic activity and restore autonomic balance to the heart even in the persistence of cardiac dysfunction.

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.

Segmental origins of cardiac sympathetic nerve activity in rats.

The segmental origins of cardiac sympathetic nerve activity (CSNA) were investigated in 8 urethane-anesthetized, artificially ventilated rats. The left upper thoracic sympathetic chain was exposed retropleurally after removing the heads of the second to fourth ribs. The preganglionic inputs to the chain from segments T1-T3 and the trunk distal to T3 were marked for later sectioning. CSNA was recorded conventionally, amplified, rectified and smoothed. Its mean level was quantified before and after each preganglionic input was cut, usually in rostro-caudal sequence. The level after all inputs were cut (i.e. noise and residual ECG pickup) was subtracted from previous measurements. The signal decrement from cutting each preganglionic input was then calculated as a percentage. CSNA in all rats depended on preganglionic drive from two or more segments, which were not always contiguous. Over the population, most preganglionic drive came from T3 and below, while the least came from T1. But there was striking inter-individual variation, such that the strongest drive to CSNA in any one rat could come from T1, T2, T3, or below T3. These findings provide new functional data on the segmental origins of CSNA in rats.

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 (MVC(like), 39%) from cutaneous vasoconstrictor-like (CVC(like), 28%) SPNs. The MVC(like) SPNs have higher baseline firing frequencies (2.52 ± 0.33 Hz vs. CVC(like) 1.34 ± 0.17 Hz, P = 0.007). The CVC(like) have longer after-hyperpolarisations (314 ± 36 ms vs. MVC(like) 191 ± 13 ms, P < 0.001) and lower input resistance (346 ± 49 MΩ vs. MVC(like) 496 ± 41 MΩ, P < 0.05). MVC(like) 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 CVC(like) 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.

Nervous glucose sensing regulates postnatal ß cell proliferation and glucose homeostasis.

How glucose sensing by the nervous system impacts the regulation of ß cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The ß cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower ß cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for ß cell mass establishment in the postnatal period and for long-term maintenance of ß cell function.

Changes in contractile activity of rabbit colon under stress conditions and during post-stress period before and after blockade of muscarinic and nicotinic cholinergic receptors.

Psychogenic stress in rabbits induced by fixation of the animal to a frame was accompanied by an increase in contractile activity of the initial portion of the distal colon, which was abolished by blockade of muscarinic and nicotinic cholinergic receptors. Increased contractile activity of the colon was due to centrogenic stimulation of preganglionic neurons of the parasympathetic nervous system followed by the involvement of the effector cholinergic neurons of the enteric nervous system into excitation.

Partial restoration of cardiovascular function by embryonic neural stem cell grafts after complete spinal cord transection.

High-level spinal cord injury can lead to cardiovascular dysfunction, including disordered hemodynamics at rest and autonomic dysreflexia during noxious stimulation. To restore supraspinal control of sympathetic preganglionic neurons (SPNs), we grafted embryonic brainstem-derived neural stem cells (BS-NSCs) or spinal cord-derived neural stem cells (SC-NSCs) expressing green fluorescent protein into the T4 complete transection site of adult rats. Animals with injury alone served as controls. Implanting of BS-NSCs but not SC-NSCs resulted in recovery of basal cardiovascular parameters, whereas both cell grafts alleviated autonomic dysreflexia. Subsequent spinal cord retransection above the graft abolished the recovery of basal hemodynamics and reflexic response. BS-NSC graft-derived catecholaminergic and serotonergic neurons showed remarkable long-distance axon growth and topographical innervation of caudal SPNs. Anterograde tracing indicated growth of medullar axons into stem cell grafts and formation of synapses. Thus, grafted embryonic brainstem-derived neurons can act as functional relays to restore supraspinal regulation of denervated SPNs, thereby contributing to cardiovascular functional improvement.