Respiratory chemoreceptor activity encoding arterial Pco
and Po
is a critical determinant of ventilation. Currently, the relative importance of several putative chemoreceptor mechanisms for ...maintaining eupneic breathing and respiratory homeostasis is debated. Transcriptomic and anatomic evidence suggests that bombesin-related peptide Neuromedin-B (
) expression identifies chemoreceptor neurons in the retrotrapezoid nucleus (RTN) that mediate the hypercapnic ventilatory response, but functional support is missing. In this study, we generated a transgenic
-Cre mouse and used Cre-dependent cell ablation and optogenetics to test the hypothesis that RTN
neurons are necessary for the CO
-dependent drive to breathe in adult male and female mice. Selective ablation of ∼95% of RTN
neurons causes compensated respiratory acidosis because of alveolar hypoventilation, as well as profound breathing instability and respiratory-related sleep disruption. Following RTN
lesion, mice were hypoxemic at rest and were prone to severe apneas during hyperoxia, suggesting that oxygen-sensitive mechanisms, presumably the peripheral chemoreceptors, compensate for the loss of RTN
neurons. Interestingly, ventilation following RTN
-lesion was unresponsive to hypercapnia, but behavioral responses to CO
(freezing and avoidance) and the hypoxia ventilatory response were preserved. Neuroanatomical mapping shows that RTN
neurons are highly collateralized and innervate the respiratory-related centers in the pons and medulla with a strong ipsilateral preference. Together, this evidence suggests that RTN
neurons are dedicated to the respiratory effects of arterial Pco
/pH and maintain respiratory homeostasis in intact conditions and suggest that malfunction of these neurons could underlie the etiology of certain forms of sleep-disordered breathing in humans.
Respiratory chemoreceptors stimulate neural respiratory motor output to regulate arterial Pco
and Po
, thereby maintaining optimal gas exchange. Neurons in the retrotrapezoid nucleus (RTN) that express the bombesin-related peptide Neuromedin-B are proposed to be important in this process, but functional evidence has not been established. Here, we developed a transgenic mouse model and demonstrated that RTN neurons are fundamental for respiratory homeostasis and mediate the stimulatory effects of CO
on breathing. Our functional and anatomic data indicate that
-expressing RTN neurons are an integral component of the neural mechanisms that mediate CO
-dependent drive to breathe and maintain alveolar ventilation. This work highlights the importance of the interdependent and dynamic integration of CO
- and O
-sensing mechanisms in respiratory homeostasis of mammals.
Abstract
Drought has long been suspected as playing an important role in the abandonment of pre-Columbian Native American settlements across the midcontinental United States between 1350 and 1450 CE. ...However, high-resolution paleoclimatic reconstructions reflecting local effective moisture (the ratio of precipitation to evaporation) that are located in proximity to Mississippi period (1050–1450 CE) population centers are lacking. Here, we present a 1600-year-long decadally resolved oxygen isotope (δ
18
O) record from Horseshoe Lake (Collinsville, IL), an evaporatively influenced oxbow lake that is centrally located within the largest and mostly densely populated series of Mississippian settlements known as Greater Cahokia. A shift to higher δ
18
O in the Horseshoe Lake sediment record from 1200 to 1400 CE indicates that strongly evaporative conditions (i.e., low effective moisture) were persistent during the leadup to Cahokia’s abandonment. These results support the hypothesis that climate, and drought specifically, strongly impacted agriculturally based pre-Columbian Native American cultures in the midcontinental US and highlights the susceptibility of this region, presently a global food production center, to hydroclimate extremes.
The retrotrapezoid "nucleus" (RTN), located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 1000 glutamatergic noncatecholaminergic ...Phox2b-expressing propriobulbar neurons that are activated by CO(2) in vivo and by acidification in vitro. These cells are thought to function as central respiratory chemoreceptors, but this theory still lacks a crucial piece of evidence, namely that stimulating these particular neurons selectively in vivo increases breathing. The present study performed in anesthetized rats seeks to test whether this expectation is correct. We injected into the left RTN a lentivirus that expresses the light-activated cationic channel ChR2 (channelrhodopsin-2) (H134R mutation; fused to the fluorescent protein mCherry) under the control of the Phox2-responsive promoter PRSx8. Transgene expression was restricted to 423 +/- 38 Phox2b-expressing neurons per rat consisting of noncatecholaminergic and C1 adrenergic neurons (3:2 ratio). Photostimulation delivered to the RTN region in vivo via a fiberoptic activated the CO(2)-sensitive neurons vigorously, produced a long-lasting (t(1/2) = 11 s) increase in phrenic nerve activity, and caused a small and short-lasting cardiovascular stimulation. Selective lesions of the C1 cells eliminated the cardiovascular response but left the respiratory stimulation intact. In rats with C1 cell lesions, the mCherry-labeled axon terminals originating from the transfected noncatecholaminergic neurons were present exclusively in the lower brainstem regions that contain the respiratory pattern generator. These results provide strong evidence that the Phox2b-expressing noncatecholaminergic neurons of the RTN region function as central respiratory chemoreceptors.
Key points
The retrotrapezoid nucleus (RTN) drives breathing proportionally to brain PCO2 but its role during various states of vigilance needs clarification.
Under normoxia, RTN lesions increased ...the arterial PCO2 set‐point, lowered the PO2 set‐point and reduced alveolar ventilation relative to CO2 production. Tidal volume was reduced and breathing frequency increased to a comparable degree during wake, slow‐wave sleep and REM sleep. RTN lesions did not produce apnoeas or disordered breathing during sleep.
RTN lesions in rats virtually eliminated the central respiratory chemoreflex (CRC) while preserving the cardiorespiratory responses to hypoxia; the relationship between CRC and number of surviving RTN Nmb neurons was an inverse exponential.
The CRC does not function without the RTN. In the quasi‐complete absence of the RTN and CRC, alveolar ventilation is reduced despite an increased drive to breathe from the carotid bodies.
The retrotrapezoid nucleus (RTN) is one of several CNS nuclei that contribute, in various capacities (e.g. CO2 detection, neuronal modulation) to the central respiratory chemoreflex (CRC). Here we test how important the RTN is to PCO2 homeostasis and breathing during sleep or wake. RTN Nmb‐positive neurons were killed with targeted microinjections of substance P–saporin conjugate in adult rats. Under normoxia, rats with large RTN lesions (92 ± 4% cell loss) had normal blood pressure and arterial pH but were hypoxic (−8 mmHg PaO2) and hypercapnic (+10 mmHg ). In resting conditions, minute volume (VE) was normal but breathing frequency (fR) was elevated and tidal volume (VT) reduced. Resting O2 consumption and CO2 production were normal. The hypercapnic ventilatory reflex in 65% FiO2 had an inverse exponential relationship with the number of surviving RTN neurons and was decreased by up to 92%. The hypoxic ventilatory reflex (HVR; FiO2 21–10%) persisted after RTN lesions, hypoxia‐induced sighing was normal and hypoxia‐induced hypotension was reduced. In rats with RTN lesions, breathing was lowest during slow‐wave sleep, especially under hyperoxia, but apnoeas and sleep‐disordered breathing were not observed. In conclusion, near complete RTN destruction in rats virtually eliminates the CRC but the HVR persists and sighing and the state dependence of breathing are unchanged. Under normoxia, RTN lesions cause no change in VE but alveolar ventilation is reduced by at least 21%, probably because of increased physiological dead volume. RTN lesions do not cause sleep apnoea during slow‐wave sleep, even under hyperoxia.
Key points
The retrotrapezoid nucleus (RTN) drives breathing proportionally to brain PCO2 but its role during various states of vigilance needs clarification.
Under normoxia, RTN lesions increased the arterial PCO2 set‐point, lowered the PO2 set‐point and reduced alveolar ventilation relative to CO2 production. Tidal volume was reduced and breathing frequency increased to a comparable degree during wake, slow‐wave sleep and REM sleep. RTN lesions did not produce apnoeas or disordered breathing during sleep.
RTN lesions in rats virtually eliminated the central respiratory chemoreflex (CRC) while preserving the cardiorespiratory responses to hypoxia; the relationship between CRC and number of surviving RTN Nmb neurons was an inverse exponential.
The CRC does not function without the RTN. In the quasi‐complete absence of the RTN and CRC, alveolar ventilation is reduced despite an increased drive to breathe from the carotid bodies.
Abstract
Abrupt warming events recorded in Greenland ice cores known as Dansgaard-Oeschger (DO) interstadials are linked to changes in tropical circulation during the last glacial cycle. ...Corresponding variations in South American summer monsoon (SASM) strength are documented, most commonly, in isotopic records from speleothems, but less is known about how these changes affected precipitation and Andean glacier mass balance. Here we present a sediment record spanning the last ~50 ka from Lake Junín (Peru) in the tropical Andes that has sufficient chronologic precision to document abrupt climatic events on a centennial-millennial time scale. DO events involved the near-complete disappearance of glaciers below 4700 masl in the eastern Andean cordillera and major reductions in the level of Peru’s second largest lake. Our results reveal the magnitude of the hydroclimatic disruptions in the highest reaches of the Amazon Basin that were caused by a weakening of the SASM during abrupt arctic warming. Accentuated warming in the Arctic could lead to significant reductions in the precipitation-evaporation balance of the southern tropical Andes with deleterious effects on this densely populated region of South America.
The combination of hypoxia and hypercapnia during sleep produces arousal, which helps restore breathing and normalizes blood gases. Hypercapnia and hypoxia produce arousal in mammals by activating ...central (pH-sensitive) and peripheral (primarily O
-sensitive) chemoreceptors. The relevant chemoreceptors and the neuronal circuits responsible for arousal are largely unknown. Here we examined the contribution of two lower brainstem nuclei that could be implicated in CO
and hypoxia-induced arousal: the retrotrapezoid nucleus (RTN), a CO
-responsive nucleus, which mediates the central respiratory chemoreflex; and the C1 neurons, which are hypoxia activated and produce arousal and blood pressure increases when directly stimulated. Additionally, we assessed the contribution of the carotid bodies (CBs), the main peripheral chemoreceptors in mammals, to hypoxia and CO
-induced arousal. In unanesthetized male rats, we tested whether ablation of the RTN, CBs, or C1 neurons affects arousal from sleep and respiratory responses to hypercapnia or hypoxia. The sleep-wake pattern was monitored by EEG and neck EMG recordings and breathing by whole-body plethysmography. The latency to arousal in response to hypoxia or hypercapnia was determined along with changes in ventilation coincident with the arousal. RTN lesions impaired CO
-induced arousal but had no effect on hypoxia-induced arousal. CB ablation impaired arousal to hypoxia and, to a lesser extent, hypercapnia. C1 neuron ablation had no effect on arousal. Thus, the RTN contributes to CO
-induced arousal, whereas the CBs contribute to both hypoxia and CO
-induced arousal. Asphyxia-induced arousal likely requires the combined activation of RTN, CBs and other central chemoreceptors.
Hypercapnia and hypoxia during sleep elicit arousal, which facilitates airway clearing in the case of obstruction and reinstates normal breathing in the case of hypoventilation or apnea. Arousal can also be detrimental to health by interrupting sleep. We sought to clarify how CO
and hypoxia cause arousal. We show that the retrotrapezoid nucleus, a brainstem nucleus that mediates the effect of brain acidification on breathing, also contributes to arousal elicited by CO
but not hypoxia. We also show that the carotid bodies contribute predominantly to hypoxia-induced arousal. Lesions of the retrotrapezoid nucleus or carotid bodies attenuate, but do not eliminate, arousal to CO
or hypoxia; therefore, we conclude that these structures are not the sole trigger of CO
or hypoxia-induced arousal.
Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two ...receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca
) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd
). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A
(PLA
), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.
The response of dissolved organic carbon (DOC) flux to permafrost degradation is one of the major sources of uncertainty in predicting the permafrost carbon feedback. We investigated DOC export and ...properties over two complete flow seasons in a catchment on the northern Qinghai‐Tibetan Plateau. DOC concentration and biodegradability decreased systematically as thaw depth increased through the season, attributable to changing carbon sources and degree of microbial processing. Increasing DOC aromaticity and δ13C‐DOC indicated shifts toward more recalcitrant carbon sources and greater residence time in soils prior to reaching the stream network. These strong and consistent seasonal trends suggest that gradual active layer deepening may decrease DOC export and biodegradability from permafrost catchments. Because these patterns are opposite observations from areas experiencing abrupt permafrost collapse (thermokarst), the overall impact of permafrost degradation on DOC flux and biodegradability may depend on the proportion of the landscape experiencing gradual thaw versus thermokarst.
Key Points
Catchment‐scale dissolved organic carbon dynamics were investigated over two complete flow seasons
Dissolved organic carbon export and biodegradability decreased as thaw depth and soil temperature increased
Biodegradability of dissolved organic carbon was strongly associated with δ13C and specific ultraviolet absorbance at 254 nm
Thomas Kirk (1828-1898) was one of New Zealand's leading botanists. The completed sections of his final work, The Students' Flora of New Zealand and the Outlying Islands, were published posthumously ...in 1899. This short communication outlines factors surrounding its initiation, and argues that Kirk deserves more recognition for describing New Zealand's indigenous plants and weeds in one sequence. The preparation of the Students' Flora also triggered arrangements to bring to New Zealand for the first time, specimens, plates and a manuscript resulting from Banks' and Solander's collections on Cook's first voyage in 1769.
Protecting water quality at catchment scales is complicated by the high spatiotemporal variability in water chemistry. Consequently, determining pollutant sources requires costly monitoring ...strategies to diagnose causes and guide management solutions. However, recent studies have shown that spatial patterns in water chemistry can be persistent at catchment scales, potentially allowing identification of pollution sources and sinks with just a few sampling campaigns. Here, we tested a new method to quantify spatial persistence (SP) of water chemistry patterns with data from synoptic samplings in 22 headwater subcatchments within a 375 km2 catchment in western France (March 2018 to July 2019). This new method to quantify SP reduces dependence on long‐term metrics such as flow‐weighted concentrations, which are usually uncertain or unavailable. We applied the method to 16 ecologically relevant water quality parameters, including soluble reactive phosphorus, nitrate, and dissolved organic carbon. The results showed an average SP of 0.68 among parameters during the study period. For most parameters, SP was higher during the high‐flow winter period but lower and more variable during the low‐flow summer period. We found that the SP ultimately depended on the ratio between the temporal and spatial coefficients of variation (variance explained: 70%) rather than the temporal synchrony among subcatchments (variance explained: 4%). These results demonstrate that in these temperate catchments, synoptic sampling during the high‐flow winter period allows efficient identification of source and sink subcatchments, while more frequent samplings are needed to characterize ecological conditions at low flow.
Key Points
We found high spatial persistence of water chemistry, despite high spatiotemporal variability in water chemistry
Spatial persistence of water chemistry is primarily determined by the ratio between spatial and temporal variability
A single synoptic sampling during the high‐flow season allows efficient identification of source and sink subcatchments
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