The neural circuits of thermal perception

Thermal information about skin surface temperature is a key sense for the perception of object identity and valence. The identification of ion channels involved in the transduction of thermal changes has provided a genetic access point to the thermal system. However, from sensory specific 'labeled-lines' to multimodal interactive pathways, the functional organization and identity of the neural circuits mediating innocuous thermal perception have been debated for over 100 years. Here we highlight points in the system that require further attention and review recent advances using in vivo electrophysiology, cellular resolution calcium imaging, optogenetics and thermal perceptual tasks in behaving mice that have begun to uncover the anatomical principles and neural processing mechanisms underlying innocuous thermal perception

Somatostatin 2 receptors in the spinal cord tonically restrain thermogenic, cardiac and other sympathetic outflows

The anatomical and functional characterization of somatostatin (SST) and somatostatin receptors (SSTRs) within the spinal cord have been focused in the dorsal horn, specifically in relation to sensory afferent processing. However, SST is also present within the intermediolateral cell column (IML), which contains sympathetic preganglionic neurons (SPN). We investigated the distribution of SSTR2 within the thoracic spinal cord and show that SSTR2A and SSTR2B are expressed in the dorsal horn and on SPN and non-SPN in or near the IML. The effects of activating spinal SSTR and SSTR2 were sympathoinhibition, hypotension, bradycardia, as well as decreases in interscapular brown adipose tissue temperature and expired CO2, in keeping with the well-described inhibitory effects of activating SSTR receptors. These data indicate that spinal SST can decrease sympathetic, cardiovascular and thermogenic activities. Unexpectedly blockade of SSTR2 revealed that SST tonically mantains sympathetic, cardiovascular and thermogenic functions, as activity in all measured parameters increased. In addition, high doses of two antagonists evoked biphasic responses in sympathetic and cardiovascular outflows where the initial excitatory effects were followed by profound but transient falls in sympathetic nerve activity, heart rate and blood pressure. These latter effects, together with our findings that SSTR2A are expressed on GABAergic, presumed interneurons, are consistent with the idea that SST2R tonically influence a diffuse spinal GABAergic network that regulates the sympathetic cardiovascular outflow. As described here and elsewhere the source of tonically released spinal SST may be of intra- and/or supra-spinal origin

Brain-wide connectivity map of mouse thermosensory cortices

In the thermal system, skin cooling is represented in the primary somatosensory cortex (S1) and the posterior insular cortex (pIC). Whether S1 and pIC are nodes in anatomically separate or overlapping thermal sensorimotor pathways is unclear, as the brain-wide connectivity of the thermal system has not been mapped. We address this using functionally targeted, dual injections of anterograde viruses or retrograde tracers into the forelimb representation of S1 (fS1) and pIC (fpIC). Our data show that inputs to fS1 and fpIC originate from separate neuronal populations, supporting the existence of parallel input pathways. Outputs from fS1 and fpIC are more widespread than their inputs, sharing a number of cortical and subcortical targets. While, axonal projections were separable, they were more overlapping than the clusters of input cells. In both fS1 and fpIC circuits, there was a high degree of reciprocal connectivity with thalamic and cortical regions, but unidirectional output to the midbrain and hindbrain. Notably, fpIC showed connectivity with regions associated with thermal processing. Together, these data indicate that cutaneous thermal information is routed to the cortex via parallel circuits and is forwarded to overlapping downstream regions for the binding of somatosensory percepts and integration with ongoing behavior

Polysialic acid regulates sympathetic outflow by facilitating information transfer within the nucleus of the solitary tract

Expression of the large extracellular glycan, polysialic acid (polySia), is restricted in the adult, to brain regions exhibiting high levels of plasticity or remodeling, including the hippocampus, prefrontal cortex, and the nucleus of the solitary tract (NTS). The NTS, located in the dorsal brainstem, receives constant viscerosensory afferent traffic as well as input from central regions controlling sympathetic nerve activity, respiration, gastrointestinal functions, hormonal release, and behavior. Our aims were to determine the ultrastructural location of polySia in the NTS and the functional effects of enzymatic removal of polySia, both in vitro and in vivo polySia immunoreactivity was found throughout the adult rat NTS. Electron microscopy demonstrated polySia at sites that influence neurotransmission: the extracellular space, fine astrocytic processes, and neuronal terminals. Removing polySia from the NTS had functional consequences. Whole-cell electrophysiological recordings revealed altered intrinsic membrane properties, enhancing voltage-gated K+ currents and increasing intracellular Ca2+ Viscerosensory afferent processing was also disrupted, dampening low-frequency excitatory input and potentiating high-frequency sustained currents at second-order neurons. Removal of polySia in the NTS of anesthetized rats increased sympathetic nerve activity, whereas functionally related enzymes that do not alter polySia expression had little effect. These data indicate that polySia is required for the normal transmission of information through the NTS and that changes in its expression alter sympathetic outflow. polySia is abundant in multiple but discrete brain regions, including sensory nuclei, in both the adult rat and human, where it may regulate neuronal function by mechanisms identified here.SIGNIFICANCE STATEMENT All cells are coated in glycans (sugars) existing predominantly as glycolipids, proteoglycans, or glycoproteins formed by the most complex form of posttranslational modification, glycosylation. How these glycans influence brain function is only now beginning to be elucidated. The adult nucleus of the solitary tract has abundant polysialic acid (polySia) and is a major site of integration, receiving viscerosensory information which controls critical homeostatic functions. Our data reveal that polySia is a determinant of neuronal behavior and excitatory transmission in the nucleus of the solitary tract, regulating sympathetic nerve activity. polySia is abundantly expressed at distinct brain sites in adult, including major sensory nuclei, suggesting that sensory transmission may also be influenced via mechanisms described here. These findings hint at the importance of elucidating how other glycans influence neural function.Phillip Bokiniec, Shila Shahbazian, Stuart J. McDougall, Britt A. Berning, Delfine Cheng, Ida J. Llewellyn-Smith ... et al

The effects of aromatase inhibitors on lipids and thrombosis

Oestrogen is known to influence blood lipid levels and though its cardioprotective effects are less clear than once thought, there remains concern that reduction of oestrogen levels during hormonal treatment for breast cancer may have an adverse effect on cardiovascular risk. While tamoxifen has been shown to improve lipid profiles, the aromatase inhibitors have a very different mode of action and do not possess the oestrogen-agonistic effects of tamoxifen. At present, there are few data on the effects of these agents on lipid profiles. Available data are mixed, but suggest that the different aromatase inhibitors have different effects on lipid profiles. Some studies show anastrozole as generally having little effect on lipids, while others have indicated adverse effects on lipid profiles/increased hypercholesterolaemia. Letrozole has been associated with adverse effects on lipid profiles in some studies, including BIG 1-98, but short-term data from randomised trials do not show increased cardiovascular morbidity. By contrast, exemestane, which has been studied in slightly more detail, may either have little effect or may be associated with slightly improved lipid profiles. In general, the changes have been small and are likely to be of little relevance in women with advanced breast cancer, but if these agents come to be used in early breast cancer, their impact on lipid profiles may become more important. Many studies are currently underway with the aromatase inhibitors, with safety assessments including monitoring lipid levels. The results of these studies are keenly awaited

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

Polysialic acid in the rat brainstem and thoracolumbar spinal cord: distribution, cellular location and comparison with mouse

Polysialic acid (polySia), a homopolymer of α2,8-linked glycans, is a post translational modification on a few glycoproteins, most commonly in the brain, on the neural cell adhesion molecule. Most research in the adult central nervous system has focused on its expression in higher brain regions, where its distribution coincides with regions known to exhibit high levels of synaptic plasticity. In contrast, scant attention has been paid to the expression of polySia in the hindbrain. The main aims of the study were to examine the distribution of polySia immunoreactivity in the brainstem and thoracolumbar spinal cord, to compare the distribution of polySia revealed by two commercial antibodies commonly used for its investigation, and to compare labelling in the rat and mouse. We present a comprehensive atlas of polySia immunoreactivity: we report that polySia labelling is particularly dense in the dorsal tegmentum, medial vestibular nuclei and lateral parabrachial nucleus, and in brainstem regions associated with autonomic function, including the dorsal vagal complex, A5, RVL, A1 and midline raphe, as well as sympathetic preganglionic neurons in the spinal cord and central targets of primary sensory afferents (nucleus of the solitary tract, spinal trigeminal nucleus, and dorsal horn). Ultrastructural examination showed labelling was present predominantly on the plasma membrane/within the extracellular space/in or on astrocytes. Labelling throughout the brainstem and spinal cord were very similar for the two antibodies and was eliminated by the polySia-specific sialidase, Endo-NF. Similar patterns of distribution were found in rat and mouse brainstem with differences evident in dorsal horn

Zawartosc olowiu i kadmu we wlosach ludzi z Pomorza Srodkowego [polnocna Polska]

Samples of hair collected in 2004-2007 from 416 persons living in Central Pomerania were analyzed. The subjects donating hair represented a vast spectrum of age, from a tenmonth- old child to a 75-year-old person. The subjects were selected randomly. Lead and cadmium were determined by atomic absorption spectrophotometry using an ASA-3 spectrometer. The average content of the metals in the hair samples was 3.20 μg g–1 (Pb) and 0.284 μg g–1 (Cd). The highest concentration of lead in human hair (about 3.88 μg g–1) was determined for the age group 61-75 years, and that of cadmium (0.406 μg g–1) – for the age group 26-50 years. The lowest concentrations of these metals in human hair (2.07 and 0.152 μg g–1, respectively) were determined for the age group of 0-15 years. Most hair samples (50%) contained 2.01-4.00 μg g–1 Pb, while 45% of the samples contained 0.001- -0.300 μg g–1 of cadmium. Studying the dependence of the content of lead and cadmium in hair on the gender of subjects, it was discovered that in all age groups males had more lead and cadmium (3.79 and 0.334 μg g–1, respectively) than females (2.63 μg g–1 and 0.236 μg g–1). This study has also demonstrated that the environment affects the content of the analyzed metals in hair. The average value of lead and cadmium concentrations for people living in the country were 2.39 μg g–1 for Pb and 0.214 μg g–1 for Cd, while for the people living in towns and cities, the respective values were 4.17 and 0.361 μg g–1. The present study has demonstrated how nutrition affects lead and cadmium content in human hair. Among the subjects, 17% had been on some kind of a diet, predominatly easily digestible and light foods. The lowest content of these metals (on average, 2.08 μg g–1 Pb and 0.141 μg g–1 Cd) was found in hair of people on a diet, while the hiest levels (3.54 μg g–1 Pb and 0.315 μg g–1 Cd) were determined in people who did not limit consumption of meat and dairy products. Among the analyzed population, 241 persons suffered from chronic disease. The average content of lead and cadmium in hair of healthy subjects was 3.05 μg g–1 Pb and 0.257 μg g–1 Cd, but in patients suffering from arthrosclerosis, allergy and hyperplasia prostate the levels of lead and cadmium in hair reached the upper values of the se limits. Hair of the patients who suffered from cardiovascular disease showed deificiency of these metals (on average, 1.73 μg g–1 Pb and 0.182 μg g–1 Cd).W latach 2004-2007 dokonano analizy włosów 416 osób pochodzących z Pomorza Środkowego, w szerokim zakresie wiekowym, od kilkumiesięcznych dzieci do osób w wieku 75 lat. W badanych włosach oznaczano zawartość kadmu i ołowiu metodą spektrofotometrycznej absorpcji atomowej. Średnia ich zawartość wyniosła odpowiednio 3,20 μg g–1 (Pb) i 0,284 μg g–1 (Cd). Najwyższe stężenie ołowiu (średnio 3,88 μg g–1) we włosach stwierdzono w grupie wiekowej 61-75 lat, a kadmu (0,406 μg g–1) w grupie 26-50 lat. Natomiast najmniejszą koncentrację tych metali (odpowiednio 2,07 i 0,152 μg g–1) odnotowano wśród dzieci 0-15 lat. Włosy większości badanych osób zawierały od 2,01 do 4,00 μg g–1 Pb i od 0,001 do 0,300 μg g–1 Cd. Badając zależność zawartości metali we włosach od płci, stwierdzono, że we wszystkich grupach wiekowych u płci męskiej stwierdzono więcej ołowiu i kadmu (3,79 i 0,334 μg g–1) niż u płci żeńskiej (2,63 i 0,236 μg g–1). Na zawartość analizowanych metali we włosach istotny wpływ wywiera środowisko. U osób mieszkających na wsi stwierdzono we włosach znacznie mniej tych metali (średnio: 2,39 μg g–1 Pb i 0,214 μg g–1 Cd) niż u osób mieszkających w mieście (odpowiednio 4,17 i 0,361 μg g–1). Znaczący wpływ na koncentrację ołowiu i kadmu we włosach wywiera rodzaj spożywanych pokarmów. Stwierdzono, że osoby, które nie spożywały mięsa i wyrobów mięsnych oraz mleka i jego produktów miały we włosach najmniej tych metali (średnio 2,08 Pb i 0,141 μg g–1 Cd), a u osób, które nie unikały tych produktów, włosy zawierały najwięcej ołowiu i kadmu (3,54 i 0,315 μg g–1). Wykazano, że może istnieć związek między niektórymi przewlekłymi chorobami u badanych osób a poziomem wymienionych pierwiastków w ich włosach. Przeciętna zawartość ołowiu i kadmu we włosach ludzi zdrowych wynosiła odpowiednio 3,05 i 0,257 μg g–1. U alergików i osób chorujących na rozrost gruczołu krokowego lub niedokrwistość stwierdzono we włosach więcej tych metali niż u ludzi zdrowych, a u osób chorujących na nadciśnienie tętnicze znacznie mniej

Miedź we włosach mieszkańców Pomorza Środkowego

The scalp hair has been suggested as a potentially valuable tissue, where short-term variation are averged out. Besides, hair has been demonstrated to be a major vehicle for the excretion of toxic metals, which concentration may be to 10 times higher than the amount found in blood or urine. Undoubtedly, hair analysis is a non-invasive method of diagnosis. The content of metals in hair depends on many factors. Hair samples (N = 416) were collected between the years 2003 and 2004 from Middle Pomerania (north Poland) population. Cu was determined by the electro-thermal graphite furnance AAS method. Hair from Middle Pomerania people contented in average 12.7 μg g-1 (range 5.2-32.0 μg g-1). The level of copper in hair was the function of age, sex, obesity, nutrition and disease, but was not the function of stature and weight. The obtained results were confirmed in comparison with the findings of other authors. Hair analysis might soon become a powerful diagnostic tool in monitoring of environmental exposure and studying the nutritional status of individuals.Pod względem badawczym włosy stanowią wartościową tkankę, którą można pozyskać w bardzo krótkim czasie. Można z nich łatwo wyekstrahować metale ciężkie, których koncentracja we włosach jest dziesięciokrotnie większa niż we krwi lub moczu. Poza tym analiza włosów jest nieinwazyjną metodą diagnostyczną. Zawartość metali we włosach zależy od wielu czynników. Próbki włosów (N = 416) zbierano w latach 2003-2004 wśród ludności Pomorza Środkowego. Włosy osób z badanego obszaru zawierały średnio 12,7 μg g-1 miedzi (zakres: 5,2-32,0 μg g-1). Poziom tego metalu we włosach zależał od wieku, płci, wskaźnika otyłości, sposobu odżywiania i stanu zdrowia badanych osób, a nie był związany z wzrostem i masą ich ciała. Obserwowane wyniki były porównywalne z wynikami innych badaczy. Analiza włosów może w sposób zadowalający być stosowana w monitoringu środowiska lub miejsc pracy narażonych na oddziaływanie metali, sposobu odżywiania poszczególnych osób i pomocniczo w diagnostyce lekarskiej

Cynk we włosach mieszkańców Pomorza Środkowego

The aim of this work was the assessment of the age, sex, way of nutrition, environment and health state influence on zinc content in hair of population living in the Middle Pomerania. Within years of 2005-2007 hair coming from 416 persons from a ten months old child to a 75 years old person was analyzed. All people were divided into four age groups: children (0-15 years), youth (16-25), adults (26-50) and the elderly (51-75). 3-centimeters long hair (counting from the skin) were put to chemical analyze. Then dried samples were weighed and mineralized with mixture of nitric and tetraoxochloric acides (mixed in proportion of 5:1). Zink determination was done by method of atomic absorption spectrophotometry using spectrometer ASA-3. Average zinc content in hair of researched population amounted to 167±58 7g g-1. Least of all zinc was ascertained in children hair (av. 125 7g g-1), and most of all in youth (194 7g g-1). In all age groups females had more of this metal (av. 180 7g g-1) than males (156 7g g-1). Average value of zinc for people living in a village was 147 7g g-1, and living in towns and cities 181 7g g-1. The least of zinc we have found at persons being on the meat- or milk-free diet (av. 157 7g g-1) and the most at persons that did not restrict in eating meat and milk products (197 7g g-1). The persons suffering from cardiovascular disease or hyperplasia prostate had adequately 221 and 195 7g g-1 Zn, considerably above the level in hair of without symptoms diseases persons (156 7g g-1). Smaller content of this element had persons suffering from atherosclerosis or hypertension (adequately 132 and 142 7g g-1).Celem pracy było określenie zależności między wiekiem, płcią, sposobem odżywiania, środowiskiem i stanem zdrowia a zawartością cynku we włosach ludzi zamieszkujących Pomorze Środkowe. W latach 2005-2007 poddano badaniom 416 osób w wieku od 10 miesięcy do 75 lat. Wszystkich podzielono na cztery grupy wiekowe. Zawartość cynku we włosach badanych osób wynosiła średnio 167}58 μg g-1. Najmniej cynku stwierdzono we włosach dzieci (0-15 lat), średnio 125 μg g-1, a najwięcej we włosach młodzieży (16-25 lat) – 194 μg g-1. We wszystkich grupach wiekowych włosy osob płci żeńskiej zawierały więcej tego metalu (śr. 180 μg g-1) niż osób płci męskiej (156 μg g-1). Zawartość cynku we włosach mieszkańców wsi była mniejsza (147 μg g-1) niż u mieszkańców miast (181 μg g-1). Znacznie mniejszy poziom tego metalu (śr. 157 μg g-1) wykazywały włosy osób, które w swoim odżywianiu stosowały bezmięsną lub bezmleczną dietę, niż włosy osób, których jadłospis zawierał zarówno produkty mięsne, jak i mleczne (197 μg g-1). Osoby chorujące na miażdżycę lub prostatę miały we włosach znacznie wyższy poziom cynku (odpowiednio 221 i 195 μg g-1) niż osoby zdrowe (156 μg g-1). Najmniej tego pierwiastka we włosach znaleziono u osób chorujących na artretyzm i nadciśnienie (odpowiednio 132 i 142 μg g-1)