Control Of Tone Research Articles

New insights into the molecular basis of allosteric activation of the TMEM16A channel and consequences for the control of vascular tone.

The TMEM16A chloride channel represents a fundamental depolarising mechanism in arterial smooth muscle cells (SMCs) and cerebral contractile pericytes. The channel is a proposed target for diseases of impaired vascular tone including stroke, vascular dementia and hypertension; however, the mechanisms of modulation of the channel by synthetic inhibitors and activators are incompletely understood. Here, we provide a functional characterization of a recently disclosed positive allosteric modulator (PAM) of the TMEM16A channel. In the presence of sub-maximal (300 nM) intracellular free Ca2+ concentration [Ca2+]i, PAM activated the heterologously expressed TMEM16A channels at positive and negative potentials (EC50≈4 nM), while being almost ineffective on the closely related TMEM16B channel. PAM did not activate the TMEM16A currents in either the absence of intracellular Ca2+ or in the presence of saturating [Ca2+]i (12 μM). Mutant TMEM16A channels with the intracellular gate constitutively open were much less sensitive to PAM, suggesting that PAM may act as a modifier of TMEM16A channel gating. Consistent with the effects observed in heterologously expressed TMEM16A channels, PAM activated endogenous TMEM16A currents in isolated rat aortic SMCs, promoted contraction of isolated aortic rings and enhanced capillary (pericyte) constriction evoked by endothelin-1 or oxygen-glucose deprivation (OGD) to stimulate cerebral ischemia. Conversely, inhibiting TMEM16A pharmacologically facilitated arterial and pericyte relaxation, and protected against OGD-mediated pericyte cell death. In summary, this work (i) enhances our understanding of fundamental mechanisms of biophysical modulation of the TMEM16A channel and (ii) supports the view that TMEM16A is a key determinant of SMCs and pericytes tone.

Untangling the inseparable life of an ABC transporter and a potassium channel: Towards understanding the structure-function relationship in the KATP channel complex.

KATP channels are unique protein complexes of a potassium channel, Kir6.1 or Kir6.2, and an ABC transporter, SUR1, SUR2A or SUR2B (splice variants of SUR2), in a 4:4 stoichiometry. Broadly expressed in many cell types and tissues, KATP channels couple changes in cellular metabolic activity with membrane excitability to control a wide range of physiological processes, including hormone secretion, control of vascular tone, learning and memory, and cardiac and neuronal protection against ischemic insults. In pancreatic β-cells KATP channels formed by Kir6.2 and SUR1 control insulin secretion, and gain- or loss-of-function mutations in these channels cause neonatal diabetes or congenital hyperinsulinism, respectively. Physiological activity of pancreatic KATP channels is regulated by intracellular ATP and ADP. Non-hydrolytic binding of ATP to Kir6.2 inhibits channel activity, while MgATP and MgADP binding to the nucleotide binding domains (NBDs) of SUR1 stimulates channel activity. Besides ATP and ADP, membrane phospholipids in particular PIP2 interacts with Kir6.2 and stimulates channel activity. In addition, pharmacological inhibitors and activators act on SUR1 to modulate channel activity. Although Kir6.2 and SUR1 harbor the primary binding sites for specific physiological and pharmacological ligands, both subunits participate in ligand regulation. How do the potassium channel and the silent ABC transporter work together to decipher signals from different ligands for gating has long been a major question in the KATP channel field. Here, I present structural and functional evidence that SUR1 contributes directly to ATP and PIP2 binding via its TMD0 and L0 linker to enhance Kir6.2 sensitivity to both ligands. Moreover, SUR1 regulates Kir6.2 activity allosterically via its dynamic interaction with the N-terminus of Kir6.2.

ОСОБЕННОСТИ КЛИНИКО-ЭКСПЕРТНОГО СОПРОВОЖДЕНИЯ АВИАЦИОННЫХ СПЕЦИАЛИСТОВ С ХРОНИЧЕСКИМИ ВИРУСНЫМИ ГЕПАТИТАМИ

Functional state of skin microcirculation vessels was studied in female subjects during 3-d dry immersion (DI). Microcirculation was investigated on the forehead, shin, forearm, fingers and toes with the use of laser Doppler flowmetry (LDF) and computer based video capillaroscopy. LDF showed that DI induced local changes in the level of perfusion, largely due to an increased myogenic control of the microvascular tone. Video capillaroscopy detected an upward trend in the number of functioning capillaries after DI; dimensions of the pericapillary zone remained unchanged.

ФУНКЦИОНАЛЬНОЕ СОСТОЯНИЕ МИКРОЦИРКУЛЯТОРНОГО РУСЛА КОЖИ ЗДОРОВЫХ ЖЕНЩИН В УСЛОВИЯХ «СУХОЙ» ИММЕРСИИ

Functional state of skin microcirculation vessels was studied in female subjects during 3-d dry immersion (DI). Microcirculation was investigated on the forehead, shin, forearm, fingers and toes with the use of laser Doppler flowmetry (LDF) and computer based video capillaroscopy. LDF showed that DI induced local changes in the level of perfusion, largely due to an increased myogenic control of the microvascular tone. Video capillaroscopy detected an upward trend in the number of functioning capillaries after DI; dimensions of the pericapillary zone remained unchanged.

Distinct profiles of oxylipid mediators in liver, lung, and placenta after maternal nano-TiO2 nanoparticle inhalation exposure.

Nano-titanium dioxide (nano-TiO2) is a widely used nanomaterial found in several industrial and consumer products, including surface coatings, paints, sunscreens and cosmetics, among others. Studies have linked gestational exposure to nano-TiO2 with negative maternal and fetal health outcomes. For example, maternal pulmonary exposure to nano-TiO2 during gestation has been associated not only with maternal, but also fetal microvascular dysfunction in a rat model. One mediator of this altered vascular reactivity and inflammation is oxylipid signaling. Oxylipids are formed from dietary lipids through several enzyme-controlled pathways as well as through oxidation by reactive oxygen species. Oxylipids have been linked to control of vascular tone, inflammation, pain and other physiological and disease processes. In this study, we use a sensitive UPLC-MS/MS based analysis to probe the global oxylipid response in liver, lung, and placenta of pregnant rats exposed to nano-TiO2 aerosols. Each organ presented distinct patterns in oxylipid signaling, as assessed by principal component and hierarchical clustering heatmap analysis. In general, pro-inflammatory mediators, such as 5-hydroxyeicosatetraenoic acid (1.6 fold change) were elevated in the liver, while in the lung, anti-inflammatory and pro-resolving mediators such as 17-hydroxy docosahexaenoic acid (1.4 fold change) were elevated. In the placenta the levels of oxylipid mediators were generally decreased, both inflammatory (e.g. PGE2, 0.52 fold change) and anti-inflammatory (e.g. Leukotriene B4, 0.49 fold change). This study, the first to quantitate the levels of these oxylipids simultaneously after nano-TiO2 exposure, shows the complex interplay of pro- and anti-inflammatory mediators from multiple lipid classes and highlights the limitations of monitoring the levels of oxylipid mediators in isolation.

Epidural Stimulation of the Lumbosacral Spinal Cord After Basal Ganglia Haemorrhage: A Case Study

Lumbar epidural spinal cord stimulation (SCS) was used to improve motor function in a 50-yr old patient who suffered hemiparesis due to a basal ganglia haemorrhagic stroke. Spinal cord stimulation targeted at the dorsal root afferent fibres at the conus improved the tonic control of the muscles at the knee and ankle joints. This allowed the patient better left knee and foot motor control. The improvement was documented initially during ambulation on a treadmill using decreasing body weight support and subsequently when using walking aids. Our observation is consistent with previous human data suggesting that in humans with brain lesions, the stimulation of preserved neural circuitry can increase spontaneous muscle tone in affected muscles and improve locomotion. Article Details How to Cite CHUA, Nicholas HL; JOHN, Thomas; BUCHSER, Eric. Epidural Stimulation of the Lumbosacral Spinal Cord After Basal Ganglia Haemorrhage: A Case Study. Medical Research Archives, [S.l.], v. 11, n. 3, mar. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3689>. Date accessed: 03 apr. 2023. doi: https://doi.org/10.18103/mra.v11i3.3689. ABNT APA BibTeX CBE EndNote - EndNote format (Macintosh & Windows) MLA ProCite - RIS format (Macintosh & Windows) RefWorks Reference Manager - RIS format (Windows only) Turabian Issue Vol 11 No 3 (2023): March issue, Volume 11, Issue 3 Section Research Articles The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives. References

Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone.

Arteries and veins are lined by nonproliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis, rather than mitochondrial oxidative phosphorylation, to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells, and little is known about energy production in endothelial cells within the fully formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial respiration disrupts endothelial control of vascular tone. Basal, mechanically activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. Agonist-evoked calcium activity was also inhibited by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for mitochondria in endothelial cell energy production is independent of species, sex, or vascular bed. These data show that a mitochondrial ATP supply is necessary for calcium-dependent, nitric oxide-mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.

Organ-Specific Endothelial Dysfunction Following Total Body Irradiation Exposure.

As the single cell lining of the heart and all blood vessels, the vascular endothelium serves a critical role in maintaining homeostasis via control of vascular tone, immune cell recruitment, and macromolecular transit. For victims of acute high-dose radiation exposure, damage to the vascular endothelium may exacerbate the pathogenesis of acute and delayed multi-organ radiation toxicities. While commonalities exist between radiation-induced endothelial dysfunction in radiosensitive organs, the vascular endothelium is known to be highly heterogeneous as it is required to serve tissue and organ specific roles. In keeping with its organ and tissue specific functionality, the molecular and cellular response of the endothelium to radiation injury varies by organ. Therefore, in the development of medical countermeasures for multi-organ injury, it is necessary to consider organ and tissue-specific endothelial responses to both injury and candidate mitigators. The purpose of this review is to summarize the pathogenesis of endothelial dysfunction following total or near total body irradiation exposure at the level of individual radiosensitive organs.

Pulmonological issues

Pediatric leukodystrophies are rare neurodegenerative diseases involving multiple systems. Each form has unique neurologic features but are characterized by encephalopathy with accompanying impairments evidenced in reflexes, muscle tone and movement control. Weakness of expiratory, inspiratory, and upper airway muscles may lead to impaired airway secretion clearance resulting in recurrent respiratory infections, dysphagia, sleep-disordered breathing, restrictive lung disease, and ultimately chronic respiratory insufficiency.

Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms.

Being a major component of the midbrain locomotion region, the pedunculopontine nucleus (PPN) is known to have various connections with the basal ganglia, the cerebral cortex, thalamus, and motor regions of the brainstem and spinal cord. Functionally, the PPN is associated with muscle tone control and locomotion modulation, including motor initiation, rhythm and speed. In addition to its motor functions, the PPN also contribute to level of arousal, attention, memory and learning. Recent studies have revealed neuropathologic deficits in the PPN in both patients and animal models of dystonia, and deep brain stimulation of the PPN also showed alleviation of axial dystonia in patients of Parkinson's disease. These findings indicate that the PPN might play an important role in the development of dystonia. Moreover, with increasing preclinical evidences showed presence of dystonia-like behaviors, muscle tone changes, impaired cognitive functions and sleep following lesion or neuromodulation of the PPN, it is assumed that the pathological changes of the PPN might contribute to both motor and non-motor manifestations of dystonia. In this review, we aim to summarize the involvement of the PPN in dystonia based on the current preclinical and clinical evidences. Moreover, potential mechanisms for its contributions to the manifestation of dystonia is also discussed base on the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, providing fundamental insight into the targeting of the PPN for the treatment of dystonia in the future.

Sleep Loss Influences the Interconnected Brain-Body Regulation of Cardiovascular Function in Humans.

Poor sleep is associated with hypertension, a major risk factor for cardiovascular disease. However, the mechanism(s) through which sleep loss affects cardiovascular health remains largely unknown, including the brain and body systems that regulate vascular function. Sixty-six healthy adults participated in a repeated-measures, crossover, experimental study involving assessments of cardiovascular function and brain connectivity after a night of sleep and a night of sleep deprivation. First, sleep deprivation significantly increased blood pressure-both systolic and diastolic. Interestingly, this change was independent of any increase in heart rate, inferring a vasculature-specific rather than direct cardiac pathway. Second, sleep loss compromised functional brain connectivity within the vascular control network, specifically the insula, anterior cingulate, amygdala, and ventral and medial prefrontal cortices. Third, sleep loss-related changes in brain connectivity and vascular tone were not independent, but significantly interdependent, with changes within the vascular control brain network predicting the sleep-loss shift toward hypertension. These findings establish an embodied framework in which sleep loss confers increased risk of cardiovascular disease through an impact upon central brain control of vascular tone, rather than a direct impact on accelerated heart rate itself.

Central serous chorioretinopathy: Pathophysiology, systemic associations, and a novel etiological classification.

Central serous chorioretinopathy (CSC) has remained an enigmatic disease since its initial description by Von Graefe. Over the years, multiple risk factors have been recognized: these include psychological stress, behavioral traits, and corticosteroids. The basic pathophysiology of CSC involves choroidal thickening, vascular congestion, altered choroidal blood flow (ChBF), and choroidal hyperpermeability, leading to retinal pigment epithelium decompensation and subsequent neurosensory detachment. Multiple organ systems, mainly the nervous, cardiovascular, endocrinal, and renal systems participate in the control of the vascular tone and the ChBF via hypothalamus-pituitary-adrenal axis and renin-angiotensin-aldosterone system, while others such as the hepatic system regulate the enzymatic degradation of corticosteroids. Many vasoactive and psychotropic drugs also modulate the ocular perfusion. In addition, there are anatomical and genetic predispositions that determine its progression to the chronic or recurrent form, through cellular response and angiogenesis. We herein review the basic pathophysiology and immunogenetics in CSC along with the role of multiple organ systems. With this background, we propose an etiological classification that should provide a framework for customized therapeutic interventions.

Activation of 5-HT3 receptors in the medulla oblongata is involved in the phasic control of urinary bladder

The control of micturition depends on reflex mechanisms, however, it undergoes modulation from cortex, pons and medullary areas. This study investigated if the activation of 5-HT3 receptors in the medulla influences the urinary bladder (UB) regulation in rats. Isoflurane female Wistar rats were submitted to catheterization of the femoral artery and vein for mean arterial pressure (MAP) and heart rate (HR) recordings and injection of drugs, respectively. The UB was cannulated for intravesical pressure (IP) measurement. The Doppler flow probe was placed around the left renal artery for renal conductance (RC) recordings. Phenylbiguanide (PB) and granisetron (GN) were injected into the 4th brain ventricle in rats with guide cannulas implanted 5 days prior to the experiments; or PB and GN were randomly injected intravenously or applied topically (in situ) on the UB. PB injection into 4th V significantly increased IP (68.67 ± 11.70%) and decreased MAP (−29 ± 6 mmHg) compared to saline (0.34 ± 0.64% and −2 ± 2 mmHg), with no changes in the HR and RC. GN injection into the 4th V did not significantly change the IP and RC compared to saline, nevertheless, significantly increased MAP (25 ± 4 mmHg) and heart rate (36 ± 9 bpm) compared to saline. Intravenous PB and GN only produced cardiovascular effects, whilst PB but not GN in situ on the UB evoked increase in IP (111.60 ± 30.36%). Therefore, the activation of 5HT-3 receptors in medullary areas increases the intravesical pressure and these receptors are involved in the phasic control of UB. In contrast, 5-HT3 receptors in the medulla oblongata are involved in the pathways of the tonic control of the cardiovascular system. The activation of 5-HT3 receptors in the bladder cause increase in intravesical pressure and this regulation seem to be under phasic control as the blockade of such receptors elicits no changes in baseline intravesical pressure.

A multiscale model of the cardiovascular system that regulates arterial pressure viaclosed loopbaroreflex control of chronotropism, cell-level contractility, and vascular tone.

Multiscale models of the cardiovascular system can provide new insights into physiological and pathological processes. PyMyoVent is a computer model that bridges from molecular- to organ-level function and which simulates a left ventricle pumping blood through the systemic circulation. Initial work with PyMyoVent focused on the end-systolic pressure volume relationship and ranked potential therapeutic strategies by their impact on contractility. This manuscript extends the PyMyoVent framework by adding closed-loop feedback control of arterial pressure. The control algorithm mimics important features of the physiological baroreflex and was developed as part of a long-term program that focuses on growth and biological remodeling. Inspired by the underlying biology, the reflex algorithm uses an afferent signal derived from arterial pressure to drive a kinetic model that mimics the net result of neural processing in the medulla and cell-level responses to autonomic drive. The kinetic model outputs control signals that are constrained between limits that represent maximum parasympathetic and maximum sympathetic drive and which modulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and the thin myofilaments, and vascular tone. Simulations show that the algorithm can regulate mean arterial pressure at user-defined setpoints as well as maintaining arterial pressure when challenged by changes in blood volume and/or valve resistance. The reflex also regulates arterial pressure when cell-level contractility is modulated to mimic the idealized impact of myotropes. These capabilities will be important for future work that uses computer modeling to investigate clinical conditions and treatments.

Dual effect of amitriptyline in the control of vascular tone: Direct blockade of calcium channel in smooth muscle cells and reduction of TLR4-dependent NO production in endothelial cells

Background and purposeAmitriptyline (AM) is a classical and typical tricyclic antidepressant drug. Despite its well-known effects on the nervous system, it has been described to work as a TLR4 antagonist and several clinical works suggested some unexpected cardiovascular effects. The role of amitriptyline on vascular tone is not clear, thus we hypothesized that amitriptyline has a double effect on vascular tone by both endothelial TLR4-dependent nitric oxide down-regulation and calcium channel blockade in smooth muscle cells. Experimental approachChanges in isometric tension were recorded on a wire myograph. NO production was evaluated by fluorescence microscopy and flow cytometry in the mouse aorta and EAhy926 cells using DAF fluorescence intensity. Calcium influx was evaluated in A7r5 cells by flow cytometry. Western blot was used to analyze eNOS and nNOS phosphorylation. Key resultsAM reduced PE-induced contraction by calcium influx diminution in smooth muscle cells (F/F0 = 225.6 ± 15.9 and 118.6 ± 17.6 to CT and AM, respectively). AM impaired Ach-dependent vasodilation (Emax = 95.8 ± 1.4; 78.1 ± 1.8; 60.4 ± 2.9 and −7.4 ± 1.0 for CT, 0.01, 0,1 and 1 μmol/L AM, respectively) through reduction of calcium influx and NO availability and TLR4 antagonism in a concentration-dependent manner. AM or TLR4 gene deletion significantly reduced NO production (Fluorescence = 9503 ± 871.7, 2561 ± 282, 4771 ± 728 and 1029 ± 103 to CT, AM, TLR4−/− and AM + TLR4−/−, respectively) by an increase in nNOSser852 and reduction in eNOSser1177 phosphorylation in endothelial cells. Conclusions and implicationsOur data show that amitriptyline impaired vascular function through two different mechanisms: blockade of TLR4 in endothelial cells and consequent decrease in NO production and calcium influx reduction in smooth muscle and endothelial cells. We also suggest, for the first time, nNOS activity reduction by AM in non-neuronal cells.

Abstract 057: Macula Densa Stimulation Acutely Increases Afferent Renal Nerve Activity And Blood Pressure

Macula densa (MD) cells in the kidney are known to regulate renal hemodynamics and the renin-angiotensin system, and indirectly systemic blood pressure (BP). However, neuron-like differentiation and activity as non-traditional MD functions are emerging. This study addressed the hypothesis that MD cells function similarly to peripheral ganglia, form neuronal networks that are part of the peripheral (renal) nervous system and synapse with renal afferent/efferent nerves as a new pathway for the direct control of sympathetic tone and BP. Single cell MD Ca 2+ signaling was analyzed in vivo using intravital multiphoton microscopy (MPM) of MD-G6 mice that selectively express the ratiometric Ca 2+ reporter GCaMP6f/tdTomato in MD cells. Afferent renal nerve activity (ARNA) was isolated and measured via recording electrodes. Systemic BP was monitored via the cannulated carotid artery. Optogenetic MD stimulation was induced by blue light (470nm) exposure of the whole left kidney of MD-Ai27 mice that selectively express the depolarizing channelrhodopsin ChR2 in MD cells. Pacemaker-like regular Ca 2+ oscillations (4-fold elevations in baseline Ca 2+ and frequency of 0.03 Hz) and their cell-to-cell propagation via long, axon-like processes were exclusively confined to the MD area. Bulk and scRNA seq and MD transcriptome analysis identified the high expression of genes related to synaptic transmission that was validated by immunohistochemistry. Acute intra-renal infusion of arginine-vasopressin (AVP) produced 3-fold increase in MD Ca 2+ firing frequency (via the MD-specific AVPR1a) and a dose-dependent increase in ARNA and BP (saline: -1±1; 0.01ug/mL: 2±1; 0.1ug/mL: 7±2; 0.25ug/mL: 7±3; 0.5ug/mL: 10±3; 1.0ug/mL: 23±13). IV administration of AVP (0.25ug/mL) did not significantly alter ARNA (108±3%, n=3) but produced a significant increase in arterial blood pressure (40±6mmHg, n=3). Blue light exposure of MD-Ai27 mouse kidneys acutely and reversibly increased systemic BP by 22±5mmHg (P<0.05, n=5). In summary, MD cells send interoceptive signals to the brain via renal sensory afferent nerves to directly control BP. Targeting of novel MD mechanisms may result in exciting new therapeutic opportunities for renal and cardiovascular diseases and hypertension.

Abstract P333: Influence Of RSK2 On Blood Pressure In Aging

Hypertension (HTN) is highly prevalent and is a significant risk factor for CVD. Excessive vasoconstriction contributes to HTN. Recently, p90 ribosomal S6 kinase, isoform 2 (RSK2) signaling has been shown to play a significant role in the regulation of basal vascular tone and BP control by phosphorylating RLC20 to promote smooth muscle contractility. Young adult Rsk2 KO mice have lower BP than WT littermates. Here, we examine the role of RSK2 in a geriatric HTN mouse model. Male >2-year old WT and Rsk2 KO mice underwent daily BP measurements using tail cuff manometry. After 2 weeks of training, baseline (BL) BP was recorded, followed by 2 weeks of HTN induced by 20 mg/kg/day of L-N G -Nitroarginine methyl ester (L-NAME) via drinking water. Echocardiographic studies were performed at BL. WT mice had significant mortality (7 of 11 died), not seen in KO (1 of 8 died). At BL, WT mice had a significantly higher SBP compared to KOs (123±10 vs. 99±12 mmHg). L-NAME elevated SBP in WT but not KO mice (137±2 vs. 97±8 mmHg). Echocardiographic studies at BL showed no differences between genotypes. However, when ejection fraction (EF) was correlated with SBP, EF was negatively correlated with SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6) but not KO mice (p = 0.15, n = 7). Clinically, HTN-associated mortality and morbidity primarily affects older populations. Here, we show that the loss of RSK2 reduces BP in geriatric mice, similar to findings in young adult mice, and that it also abolished the hypertensive effects of L-NAME. Aged Rsk2 KO mice appear to be protected from cardiovascular effects of aging. RSK2 is a potential target for pharmacologic inhibition to treat HTN and related risks in geriatric populations.

Differential contributions of cardiac, coronary and pulmonary artery vagal mechanoreceptors to reflex control of the circulation.

Distinct populations of stretch‐sensitive mechanoreceptors attached to myelinated vagal afferents are found in the heart and adjoining coronary and pulmonary circulations. Receptors at atrio‐venous junctions appear to be involved in control of intravascular volume. These atrial receptors influence sympathetic control of the heart and kidney, but contribute little to reflex control of systemic vascular resistance. Baroreceptors at the origins of the coronary circulation elicit reflex vasodilatation, like feedback control from systemic arterial baroreceptors, as well as having characteristics that could contribute to regulation of mean pressure. In contrast, feedback from baroreceptors in the pulmonary artery and bifurcation is excitatory and elicits a pressor response. Elevation of pulmonary arterial pressure resets the vasomotor limb of the systemic arterial baroreflex, which could be relevant for control of sympathetic vasoconstrictor outflow during exercise and other states associated with elevated pulmonary arterial pressure. Ventricular receptors, situated mainly in the inferior posterior wall of the left ventricle, and attached to unmyelinated vagal afferents, are relatively inactive under basal conditions. However, a change to the biochemical environment of cardiac tissue surrounding these receptors elicits a depressor response. Some ventricular receptors respond, modestly, to mechanical distortion. Probably, ventricular receptors contribute little to tonic feedback control; however, reflex bradycardia and hypotension in response to chemical activation may decrease the work of the heart during myocardial ischaemia. Overall, greater awareness of heterogeneous reflex effects originating from cardiac, coronary and pulmonary artery mechanoreceptors is required for a better understanding of integrated neural control of circulatory function and arterial blood pressure.

Insular functional connectivity in migraine with aura

IntroductionInsula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA.MethodsTwenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis.ResultsSeed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO.DiscussionThe anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA.ConclusionThe anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA.Trial registrationNCT02708797.

Elevation of GABA levels in the globus pallidus disinhibits the thalamic reticular nucleus and desynchronized cortical beta oscillations

The external globus pallidus (GP) is a GABAergic node involved in motor control regulation and coordinates firing and synchronization in the basal ganglia–thalamic–cortical network through inputs and electrical activity. In Parkinson's disease, high GABA levels alter electrical activity in the GP and contribute to motor symptoms. Under normal conditions, GABA levels are regulated by GABA transporters (GATs). GAT type 1 (GAT-1) is highly expressed in the GP, and pharmacological blockade of GAT-1 increases the duration of currents mediated by GABA A receptors and induces tonic inhibition. The functional contribution of the pathway between the GP and the reticular thalamic nucleus (RTn) is unknown. This pathway is important since the RTn controls the flow of information between the thalamus and cortex, suggesting that it contributes to cortical dynamics. In this work, we investigated the effect of increased GABA levels on electrical activity in the RTn by obtaining single-unit extracellular recordings from anesthetized rats and on the motor cortex (MCx) by corticography. Our results show that high GABA levels increase the spontaneous activity rate of RTn neurons and desynchronize oscillations in the beta frequency band in the MCx. Our findings provide evidence that the GP exerts tonic control over RTn activity through the GP–reticular pathway and functionally contributes to cortical oscillation dynamics.