Receptor in the brain controls breathingControl of breathing in mammals depends primarily not on sensing oxygen, but rather on detecting concentrations of carbon dioxide in the blood. Failure of this ...system can cause potentially deadly sleep apnias. Taking a hint from insects, which use a heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) to sense carbon dioxide, Kumar et al. demonstrate that the GPCR GPR4 is essential to control breathing in mice. GPR4 senses protons generated by the formation of carbonic acid in the blood and works with a pH-sensitive potassium channel called TASK-2 in a set of brain cells that control breathing.Science, this issue p. 1255 Blood gas and tissue pH regulation depend on the ability of the brain to sense CO2 and/or H+ and alter breathing appropriately, a homeostatic process called central respiratory chemosensitivity. We show that selective expression of the proton-activated receptor GPR4 in chemosensory neurons of the mouse retrotrapezoid nucleus (RTN) is required for CO2-stimulated breathing. Genetic deletion of GPR4 disrupted acidosis-dependent activation of RTN neurons, increased apnea frequency, and blunted ventilatory responses to CO2. Reintroduction of GPR4 into RTN neurons restored CO2-dependent RTN neuronal activation and rescued the ventilatory phenotype. Additional elimination of TASK-2 (K2P5), a pH-sensitive K+ channel expressed in RTN neurons, essentially abolished the ventilatory response to CO2. The data identify GPR4 and TASK-2 as distinct, parallel, and essential central mediators of respiratory chemosensitivity.
Decadal and centennial mean state changes in South American summer monsoon (SASM) precipitation during the last 2,300 years are detailed using an annually resolved authigenic calcite record of ...precipitation δ¹⁸O from a varved lake in the Central Peruvian Andes. This unique sediment record shows that δ¹⁸O peaked during the Medieval Climate Anomaly (MCA) from A.D. 900 to 1100, providing evidence that the SASM weakened considerably during this period. Minimum δ¹⁸O values occurred during the Little Ice Age (LIA) between A.D. 1400 and 1820, reflecting a prolonged intensification of the SASM that was regionally synchronous. After the LIA, δ¹⁸O increased rapidly, particularly during the current warm period (CWP; A.D. 1900 to present), indicating a return to reduced SASM precipitation that was more abrupt and sustained than the onset of the MCA. Diminished SASM precipitation during the MCA and CWP tracks reconstructed Northern Hemisphere and North Atlantic warming and a northward displacement of the Intertropical Convergence Zone (ITCZ) over the Atlantic, and likely the Pacific. Intensified SASM precipitation during the LIA follows reconstructed Northern Hemisphere and North Atlantic cooling, El Niño-like warming in the Pacific, and a southward displacement of the ITCZ over both oceans. These results suggest that SASM mean state changes are sensitive to ITCZ variability as mediated by Western Hemisphere tropical sea surface temperatures, particularly in the Atlantic. Continued Northern Hemisphere and North Atlantic warming may therefore help perpetuate the recent reductions in SASM precipitation that characterize the last 100 years, which would negatively impact Andean water resources.
Catecholaminergic neurons of the rostral ventrolateral medulla (RVLM‐CA neurons; C1 neurons) contribute to the sympathetic, parasympathetic and neuroendocrine responses elicited by physical stressors ...such as hypotension, hypoxia, hypoglycemia, and infection. Most RVLM‐CA neurons express vesicular glutamate transporter (VGLUT)2, and may use glutamate as a ionotropic transmitter, but the importance of this mode of transmission in vivo is uncertain. To address this question, we genetically deleted VGLUT2 from dopamine‐β‐hydroxylase‐expressing neurons in mice DβHCre/0;VGLUT2flox/flox mice (cKO mice). We compared the in vivo effects of selectively stimulating RVLM‐CA neurons in cKO vs. control mice (DβHCre/0), using channelrhodopsin‐2 (ChR2–mCherry) optogenetics. ChR2–mCherry was expressed by similar numbers of rostral ventrolateral medulla (RVLM) neurons in each strain (~400 neurons), with identical selectivity for catecholaminergic neurons (90–99% colocalisation with tyrosine hydroxylase). RVLM‐CA neurons had similar morphology and axonal projections in DβHCre/0 and cKO mice. Under urethane anesthesia, photostimulation produced a similar pattern of activation of presumptive ChR2‐positive RVLM‐CA neurons in DβHCre/0 and cKO mice. Photostimulation in conscious mice produced frequency‐dependent respiratory activation in DβHCre/0 mice but no effect in cKO mice. Similarly, photostimulation under urethane anesthesia strongly activated efferent vagal nerve activity in DβHCre/0 mice only. Vagal responses were unaffected by α1‐adrenoreceptor blockade. In conclusion, two responses evoked by RVLM‐CA neuron stimulation in vivo require the expression of VGLUT2 by these neurons, suggesting that the acute autonomic responses driven by RVLM‐CA neurons are mediated by glutamate.
Catecholaminergic neurons of the rostral ventrolateral medulla (RVLM‐CA neurons, viz. C1 neurons) contribute to the sympathetic, parasympathetic and neuroendocrine responses elicited by physical stressors such as hypotension, hypoxia, hypoglycemia and infection. Most RVLM‐CA neurons express vesicular glutamate transporter 2 (VGLUT2) and may use glutamate as a ionotropic transmitter but the importance of this mode of transmission in vivo is uncertain.
The two-stage vibration isolation and positioning platform (BSC-ISI) provides three orders of magnitude of isolation at all frequencies above 1Hz.
•The paper presents near a decade of research on the ...two-stage twelve-axis vibration isolation platforms developed for Advanced LIGO.•This system positions and isolates 1000kg of very sensitive equipment in all directions of translation and rotation.•The system provides more than three orders of magnitude of isolation over a very large bandwidth.•We show how results from the prototyping phases have been used for the production and commissioning of 15 units.•Isolation results show that the system brings the motion below 10−11m/Hz at 1Hz and 10−12 m/Hz at 10Hz.
This paper presents the results of the past seven years of experimental investigation and testing done on the two-stage twelve-axis vibration isolation platform for Advanced LIGO gravity waves observatories. This five-ton two-and-half-meter wide system supports more than a 1000kg of very sensitive equipment. It provides positioning capability and seismic isolation in all directions of translation and rotation. To meet the very stringent requirements of Advanced LIGO, the system must provide more than three orders of magnitude of isolation over a very large bandwidth. It must bring the motion below 10−11 m/Hz at 1Hz and 10−12 m/Hz at 10Hz. A prototype of this system has been built in 2006. It has been extensively tested and analyzed during the following two years. This paper shows how the experimental results obtained with the prototype were used to engineer the final design. It highlights how the engineering solutions implemented not only improved the isolation performance but also greatly simplified the assembly, testing, and commissioning process. During the past two years, five units have been constructed, tested, installed and commissioned at each of the two LIGO observatories. Five other units are being built for an upcoming third observatory. The test results presented show that the system meets the motion requirements, and reach the sensor noise in the control bandwidth.
Hydroclimate sensitivity simulations were conducted with a lake-catchment hydrologic and isotope mass balance model adapted to two small, closed lakes (Castor and Scanlon) located in the Pacific ...Northwest. Model simulations were designed to investigate the combined influences of persistent disequilibrium, reddening, and equifinality on lake water and sediment (i.e., biogenic and endogenic carbonate mineral) oxygen isotope (δ18O) values and to provide a basis for quantitative, probabilistic climate reconstructions using lake sediment δ18O records. Simulation results indicate that within closed-basin lakes changes in long-term (i.e., multi-decadal) precipitation amounts produce inconsistent responses in lake water and sediment δ18O values that are strongly influenced by lake basin outseepage and morphometry. Simulations of variable initial conditions in which randomly generated monthly climate data (i.e., precipitation, temperature, and relative humidity) were used to force the model during the equilibration period (which precedes the application of instrumental climate data) demonstrate that Castor Lake and Scanlon Lake have a somewhat limited isotopic ‘memory’ of ∼10years. Additional tests conducted using a Monte Carlo ensemble (in which random climate data were used to force the model) combined with δ18O analyses of water samples collected from 2003 to 2011 AD, indicate that within small, closed lakes in the Pacific Northwest November–February precipitation is the strongest seasonal, climatic control on sediment oxygen-isotope values. Further, a Monte Carlo based reconstruction of 20year average November–February precipitation amounts strongly correlates (R2=0.66) to instrumental values from the 20th century (with all observed values falling within modeled 95% prediction limits), indicating that probabilistic, quantitative paleoclimate interpretations of lake sediment δ18O records are attainable.
C1 catecholaminergic neurons and neurons of the retrotrapezoid nucleus are integrative nodes within the brain stem network regulating cardiorespiratory reflexes elicited by hypoxia and hypercapnia, ...stimuli that also produce arousal from sleep. In the present study, Channelrhodopsin-2 was selectively introduced into these neurons with a lentiviral vector to determine whether their selective activation also produces arousal in sleeping rats. Sleep stages were identified from electroencephalographic and neck muscle electromyographic recordings. Breathing was measured using unrestrained whole body plethysmography and blood pressure by telemetry. During nonrapid eye movement sleep, unilateral photostimulation of the C1 region caused arousal in 83.0±14.7% of trials and immediate and intense cardiorespiratory activation. Arousal during photostimulation was also observed during rapid eye movement sleep (41.9±5.6% of trials), but less reliably than during nonrapid eye movement sleep. The cardiorespiratory responses elicited by photostimulation were dramatically smaller during rapid eye movement sleep than nonrapid eye movement sleep or wakefulness. Systemic α1-adrenoreceptor blockade reduced the cardiorespiratory effects of photostimulation but had no effect on the arousal caused by photostimulation during nonrapid eye movement sleep. Postmortem histology showed that neurons expressing Channelrhodopsin 2-mCherry were predominantly catecholaminergic (81%). These results show that selective activation of C1 and retrotrapezoid nucleus neurons produces state-dependent arousal and cardiorespiratory stimulation. These neurons, which are powerfully activated by chemoreceptor stimulation, may contribute to the sleep disruption associated with obstructive sleep apnea.
The retrotrapezoid nucleus contains Phox2b-expressing glutamatergic neurons (RTN-Phox2b neurons) that regulate breathing in a CO₂-dependent manner. Here we use channelrhodopsin-based optogenetics to ...explore how these neurons control breathing in conscious and anesthetized adult rats. Respiratory entrainment (pacing) of breathing frequency (fR) was produced over 57% (anesthetized) and 28% (conscious) of the natural frequency range by burst activation of RTN-Phox2b neurons (3-8 × 0.5-20 ms pulses at 20 Hz). In conscious rats, pacing under normocapnic conditions increased tidal volume (V(T)) and each inspiration was preceded by active expiration, denoting abdominal muscle contraction. During long-term pacing V(T) returned to prestimulation levels, suggesting that central chemoreceptors such as RTN-Phox2b neurons regulate V(T) partly independently of their effect on fR. Randomly applied light trains reset the respiratory rhythm and shortened the expiratory phase when the stimulus coincided with late-inspiration or early-expiration. Importantly, continuous (20 Hz) photostimulation of the RTN-Phox2b neurons and a saturating CO₂ concentration produced similar effects on breathing that were much larger than those elicited by phasic RTN stimulation. In sum, consistent with their anatomical projections, RTN-Phox2b neurons regulate lung ventilation by controlling breathing frequency, inspiration, and active expiration. Adult RTN-Phox2b neurons can entrain the respiratory rhythm if their discharge is artificially synchronized, but continuous activation of these neurons is much more effective at increasing lung ventilation. These results suggest that RTN-Phox2b neurons are no longer rhythmogenic in adulthood and that their average discharge rate may be far more important than their discharge pattern in driving lung ventilation.
Collectively, the retrotrapezoid nucleus (RTN) and adjacent C1 neurons regulate breathing, circulation and the state of vigilance, but previous methods to manipulate the activity of these neurons ...have been insufficiently selective to parse out their relative roles. We hypothesize that RTN and C1 neurons regulate distinct aspects of breathing (e.g., frequency, amplitude, active expiration, sighing) and differ in their ability to produce arousal from sleep. Here we use optogenetics and a combination of viral vectors in adult male and female
-Cre rats to transduce selectively RTN (Phox2b
) or C1 neurons (Phox2b
/
) with Channelrhodopsin-2. RTN photostimulation modestly increased the probability of arousal. RTN stimulation robustly increased breathing frequency and amplitude; it also triggered strong active expiration but not sighs. Consistent with these responses, RTN innervates the entire pontomedullary respiratory network, including expiratory premotor neurons in the caudal ventral respiratory group, but RTN has very limited projections to brainstem regions that regulate arousal (locus ceruleus, CGRP
parabrachial neurons). C1 neuron stimulation produced robust arousals and similar increases in breathing frequency and amplitude compared with RTN stimulation, but sighs were elicited and active expiration was absent. Unlike RTN, C1 neurons innervate the locus ceruleus, CGRP
processes within the parabrachial complex, and lack projections to caudal ventral respiratory group. In sum, stimulating C1 or RTN activates breathing robustly, but only RTN neuron stimulation produces active expiration, consistent with their role as central respiratory chemoreceptors. Conversely, C1 stimulation strongly stimulates ascending arousal systems and sighs, consistent with their postulated role in acute stress responses.
The C1 neurons and the retrotrapezoid nucleus (RTN) reside in the rostral ventrolateral medulla. Both regulate breathing and the cardiovascular system but in ways that are unclear because of technical limitations (anesthesia, nonselective neuronal actuators). Using optogenetics in unanesthetized rats, we found that selective stimulation of either RTN or C1 neurons activates breathing. However, only RTN triggers active expiration, presumably because RTN, unlike C1, has direct excitatory projections to abdominal premotor neurons. The arousal potential of the C1 neurons is far greater than that of the RTN, however, consistent with C1's projections to brainstem wake-promoting structures. In short, C1 neurons orchestrate cardiorespiratory and arousal responses to somatic stresses, whereas RTN selectively controls lung ventilation and arterial Pco
stability.
Important unknowns remain about how abrupt permafrost collapse (thermokarst) affects carbon balance and greenhouse gas flux, limiting our ability to predict the magnitude and timing of the permafrost ...carbon feedback. We measured monthly, growing‐season fluxes of CO2, CH4, and N2O at a large thermokarst feature in alpine tundra on the northern Qinghai‐Tibetan Plateau (QTP). Thermokarst formation disrupted plant growth and soil hydrology, shifting the ecosystem from a growing‐season carbon sink to a weak source but decreasing feature level CH4 and N2O flux. Temperature‐corrected ecosystem respiration from decomposing permafrost soil was 2.7 to 9.5‐fold higher than in similar features from Arctic and Boreal regions, suggesting that warmer and dryer conditions on the northern QTP could accelerate carbon decomposition following permafrost collapse. N2O flux was similar to the highest values reported for Arctic ecosystems and was 60% higher from exposed mineral soil on the feature floor, confirming Arctic observations of coupled nitrification and denitrification in collapsed soils. Q10 values for respiration were typically over 4, suggesting high‐temperature sensitivity of thawed carbon. Taken together, these results suggest that QTP permafrost carbon in alpine tundra is highly vulnerable to mineralization following thaw, and that N2O production could be an important noncarbon permafrost climate feedback. Permafrost collapse altered soil hydrology, shifting the ecosystem from a carbon sink to carbon source but decreasing CH4 and N2O flux. Little to no vegetation recovery after stabilization suggests potentially large net carbon losses. High N2O flux compared to Arctic and Boreal systems suggests noncarbon permafrost climate feedback.
Key Points
Permafrost collapse altered soil hydrology, shifting the ecosystem from a carbon sink to carbon source but decreasing CH4 and N2O flux
Little to no vegetation recovery after stabilization suggests potentially large net carbon losses
High N2O flux compared to Arctic and Boreal systems suggest non‐carbon permafrost climate feedback
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