The role of the signalling protein XLalphas in cardiovascular control in mice

Loss of the signalling protein XLαs in mice leads to a lean phenotype characterised by increased energy expenditure due to elevated sympathetic nervous system (SNS) stimulation of brown adipose tissue. XLαs is the protein produced from the Gnasxl transcript of the imprinted Gnas locus, and has a restricted expression pattern that includes a number of brain regions essential for SNS control of both energy expenditure and the cardiovascular system. However, it is unknown to what degree XLαs influences overall sympathetic tone, or how XLαs signalling in the brain causes these phenotypic changes. Using arterial cannulation, anaesthetised Gnasxl knockout mice had elevated blood pressure, shown to be caused by increased SNS stimulation by a greater blood pressure response to the sympatholytic reserpine in knockouts. Using electrocardiogram (ECG) telemetry, conscious Gnasxl knockout mice had elevated heart rate at night, as well as a significant heart rate response to both reserpine and the parasympatholytic atropine. This supported the previous results showing elevated SNS stimulation of the cardiovascular system, but paradoxically also suggested elevated parasympathetic stimulation. Therefore, autonomic control of the cardiovascular system was investigated in further detail by analysing heart rate variability (HRV). A number of HRV analyses were experimentally validated in wildtype mice. The most reliable method was the fast Fourier transform (FFT); high frequency (HF) power was used as a measure of parasympathetic activity, and low frequency (LF)/HF ratio was used as a measure of sympathetic activity. Gnasxl knockouts had a greater LF/HF response to reserpine, but an equivalent HF response to atropine, suggesting the mice had elevated SNS activity only. Additionally, knockouts had elevated LF/HF ratio at night, suggesting consistently elevated SNS output. Neuronal signalling pathways that may be deregulated in Gnasxl knockouts were investigated by injection of MTII and Exendin-4, agonists to the melanocortin 3/4 and GLP-1 receptors, respectively. Gnasxl knockouts had a hypersensitive heart rate response both to centrally injected MTII in anaesthetised mice and peripherally injected Exendin-4 in conscious mice. The hypersensitivity to Exendin-4 was investigated further by HRV analysis, which showed that Exendin-4 had no effect on the SNS, but caused a potent reduction in parasympathetic activity in both wildtypes and knockouts. Neuronal signalling changes in response to Exendin-4 were investigated by antibody staining for the early response gene c-fos. No significant differences were seen in overall numbers of activated neurones between wildtypes and knockouts in a number of brain regions including the nucleus of the solitary tract (NTS). Interestingly, neurones expressing XLαs showed no c-fos response to Exendin-4, except in the area postrema. In summary, loss of XLαs in mice resulted in elevated SNS stimulation of the cardiovascular system, as well as hypersensitivity to Exendin-4 that was unlikely to be caused by increased activation of XLαs-deficient neurones

Elevated blood pressure, heart rate and body temperature in mice lacking the XL alpha s protein of the Gnas locus is due to increased sympathetic tone

NEW FINDINGS: What is the central question of this study? Previously, we showed that Gnasxl knock-out mice are lean and hypermetabolic, with increased sympathetic stimulation of adipose tissue. Do these mice also display elevated sympathetic cardiovascular tone? Is the brain glucagon-like peptide-1 system involved? What is the main finding and its importance? Gnasxl knock-outs have increased blood pressure, heart rate and body temperature. Heart rate variability analysis suggests an elevated sympathetic tone. The sympatholytic reserpine had stronger effects on blood pressure, heart rate and heart rate variability in knock-out compared with wild-type mice. Stimulation of the glucagon-like peptide-1 system inhibited parasympathetic tone to a similar extent in both genotypes, with a stronger associated increase in heart rate in knock-outs. Deficiency of Gnasxl increases sympathetic cardiovascular tone. Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS-related phenotypes, we have now investigated the cardiovascular system. The Gnasxl KO mice were ∼20 mmHg hypertensive in comparison to wild-type (WT) littermates (P≤ 0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate in conscious KOs (630 ± 10 versus 584 ± 12 beats min(−1), KO versus WT, P≤ 0.05). Body temperature was also elevated (38.1 ± 0.3 versus 36.9 ± 0.4°C, KO versus WT, P≤ 0.05). To investigate autonomic nervous system influences, we used heart rate variability analyses. We empirically defined frequency power bands using atropine and reserpine and verified high-frequency (HF) power and low-frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. The LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. In contrast, atropine and exendin-4, a centrally acting agonist of the glucagon-like peptide-1 receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a greater increase in heart rate in KOs. Mild stress had a blunted effect on the LF/HF ratio in KOs consistent with elevated basal sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues

A solid state light-matter interface at the single photon level

Coherent and reversible mapping of quantum information between light and matter is an important experimental challenge in quantum information science. In particular, it is a decisive milestone for the implementation of quantum networks and quantum repeaters. So far, quantum interfaces between light and atoms have been demonstrated with atomic gases, and with single trapped atoms in cavities. Here we demonstrate the coherent and reversible mapping of a light field with less than one photon per pulse onto an ensemble of 10 millions atoms naturally trapped in a solid. This is achieved by coherently absorbing the light field in a suitably prepared solid state atomic medium. The state of the light is mapped onto collective atomic excitations on an optical transition and stored for a pre-programmed time up of to 1 mu s before being released in a well defined spatio-temporal mode as a result of a collective interference. The coherence of the process is verified by performing an interference experiment with two stored weak pulses with a variable phase relation. Visibilities of more than 95% are obtained, which demonstrates the high coherence of the mapping process at the single photon level. In addition, we show experimentally that our interface allows one to store and retrieve light fields in multiple temporal modes. Our results represent the first observation of collective enhancement at the single photon level in a solid and open the way to multimode solid state quantum memories as a promising alternative to atomic gases.Comment: 5 pages, 5 figures, version submitted on June 27 200

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

This work was funded by an MRC Career Development Award (MR/ P009824/1 and MR/P009824/2) to GD’A, as well as an MRC grant to SML/GD’A (MR/T032669/1), a BBSRC grant to SML (BB/M001067/1), and an additional direct contribution from Eli Lilly. D.J.H. was sup- ported by MRC (MR/N00275X/1 and MR/S025618/1), Diabetes UK (17/ 0005681), and the European Research Council (ERC) under the Eu- ropean Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). AC was supported for part of this project by a travel grant from the Italian Society of Pharmacology and a fellowship from the Veronesi Foundation (Italy).Peer reviewedPublisher PD

Do Synesthetes Have a General Advantage in Visual Search and Episodic Memory? A Case for Group Studies

BACKGROUND: Some studies, most of them case-reports, suggest that synesthetes have an advantage in visual search and episodic memory tasks. The goal of this study was to examine this hypothesis in a group study. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we tested thirteen grapheme-color synesthetes and we compared their performance on a visual search task and a memory test to an age-, handedness-, education-, and gender-matched control group. The results showed no significant group differences (all relevant ps>.50). For the visual search task effect sizes indicated a small advantage for synesthetes (Cohen's d between .19 and .32). No such advantage was found for episodic memory (Cohen's d<.05). CONCLUSIONS/SIGNIFICANCE: The results indicate that synesthesia per se does not seem to lead to a strong performance advantage. Rather, the superior performance of synesthetes observed in some case-report studies may be due to individual differences, to a selection bias or to a strategic use of synesthesia as a mnemonic. In order to establish universal effects of synesthesia on cognition single-case studies must be complemented by group studies

Phylogeny, Diet, and Cranial Integration in Australodelphian Marsupials

Studies of morphological integration provide valuable information on the correlated evolution of traits and its relationship to long-term patterns of morphological evolution. Thus far, studies of morphological integration in mammals have focused on placentals and have demonstrated that similarity in integration is broadly correlated with phylogenetic distance and dietary similarity. Detailed studies have also demonstrated a significant correlation between developmental relationships among structures and adult morphological integration. However, these studies have not yet been applied to marsupial taxa, which differ greatly from placentals in reproductive strategy and cranial development and could provide the diversity necessary to assess the relationships among phylogeny, ecology, development, and cranial integration. This study presents analyses of morphological integration in 20 species of australodelphian marsupials, and shows that phylogeny is significantly correlated with similarity of morphological integration in most clades. Size-related correlations have a significant affect on results, particularly in Peramelia, which shows a striking decrease in similarity of integration among species when size is removed. Diet is not significantly correlated with similarity of integration in any marsupial clade. These results show that marsupials differ markedly from placental mammals in the relationships of cranial integration, phylogeny, and diet, which may be related to the accelerated development of the masticatory apparatus in marsupials

Genetic Diversity, Morphological Uniformity and Polyketide Production in Dinoflagellates (Amphidinium, Dinoflagellata)

Dinoflagellates are an intriguing group of eukaryotes, showing many unusual morphological and genetic features. Some groups of dinoflagellates are morphologically highly uniform, despite indications of genetic diversity. The species Amphidinium carterae is abundant and cosmopolitan in marine environments, grows easily in culture, and has therefore been used as a ‘model’ dinoflagellate in research into dinoflagellate genetics, polyketide production and photosynthesis. We have investigated the diversity of ‘cryptic’ species of Amphidinium that are morphologically similar to A. carterae, including the very similar species Amphidinium massartii, based on light and electron microscopy, two nuclear gene regions (LSU rDNA and ITS rDNA) and one mitochondrial gene region (cytochrome b). We found that six genetically distinct cryptic species (clades) exist within the species A. massartii and four within A. carterae, and that these clades differ from one another in molecular sequences at levels comparable to other dinoflagellate species, genera or even families. Using primers based on an alignment of alveolate ketosynthase sequences, we isolated partial ketosynthase genes from several Amphidinium species. We compared these genes to known dinoflagellate ketosynthase genes and investigated the evolution and diversity of the strains of Amphidinium that produce them

Postnatal Changes in the Expression Pattern of the Imprinted Signalling Protein XLαs Underlie the Changing Phenotype of Deficient Mice

The alternatively spliced trimeric G-protein subunit XLαs, which is involved in cAMP signalling, is encoded by the Gnasxl transcript of the imprinted Gnas locus. XLαs deficient mice show neonatal feeding problems, leanness, inertia and a high mortality rate. Mutants that survive to weaning age develop into healthy and fertile adults, which remain lean despite elevated food intake. The adult metabolic phenotype can be attributed to increased energy expenditure, which appears to be caused by elevated sympathetic nervous system activity. To better understand the changing phenotype of Gnasxl deficient mice, we compared XLαs expression in neonatal versus adult tissues, analysed its co-localisation with neural markers and characterised changes in the nutrient-sensing mTOR1-S6K pathway in the hypothalamus. Using a newly generated conditional Gnasxl lacZ gene trap line and immunohistochemistry we identified various types of muscle, including smooth muscle cells of blood vessels, as the major peripheral sites of expression in neonates. Expression in all muscle tissues was silenced in adults. While Gnasxl expression in the central nervous system was also developmentally silenced in some midbrain nuclei, it was upregulated in the preoptic area, the medial amygdala, several hypothalamic nuclei (e.g. arcuate, dorsomedial, lateral and paraventricular nuclei) and the nucleus of the solitary tract. Furthermore, expression was detected in the ventral medulla as well as in motoneurons and a subset of sympathetic preganglionic neurons of the spinal cord. In the arcuate nucleus of Gnasxl-deficient mice we found reduced activity of the nutrient sensing mTOR1-S6K signalling pathway, which concurs with their metabolic status. The expression in these brain regions and the hypermetabolic phenotype of adult Gnasxl-deficient mice imply an inhibitory function of XLαs in energy expenditure and sympathetic outflow. By contrast, the neonatal phenotype of mutant mice appears to be due to a transient role of XLαs in muscle tissues