‘Tipping points’ in the Earth system are characterised by a nonlinear response to gradual forcing, and may have severe and wide-ranging impacts. Many abrupt events result from simple underlying ...system dynamics termed ‘critical transitions’ or ‘bifurcations’. One of the best ways to identify and potentially predict threshold behaviour in the climate system is through analysis of natural (‘palaeo’) archives. Specifically, on the approach to a tipping point, early warning signals can be detected as characteristic fluctuations in a time series as a system loses stability. Testing whether these early warning signals can be detected in highly complex real systems is a key challenge, since much work is either theoretical or only tested with simple models. This is particularly problematic in palaeoclimate and palaeoenvironmental records with low resolution, non-equidistant data, which can limit accurate analysis. Here, a range of different datasets are examined to explore generic rules that can be used to detect such dramatic events. A number of key criteria are identified to be necessary for the reliable identification of early warning signals in natural archives, most crucially, the need for a low-noise record of sufficient data length, resolution and accuracy. A deeper understanding of the underlying system dynamics is required to inform the development of more robust system-specific indicators, or to indicate the temporal resolution required, given a known forcing. This review demonstrates that time series precursors from natural archives provide a powerful means of forewarning tipping points within the Earth System.
•Natural archives can help to detect and determine the impact of future abrupt changes.•Early warning signals must be tested for their robustness in highly complex real systems.•Significant potential for the development of new techniques and system-specific indicators.
The periaqueductal gray (PAG) is a brain region involved in nociception modulation, and an important relay center for the descending nociceptive pathway through the rostral ventral lateral medulla. ...Given the dense expression of mu opioid receptors and the role of dopamine in pain, the recently characterized dopamine neurons in the ventral PAG (vPAG)/dorsal raphe (DR) region are a potentially critical site for the antinociceptive actions of opioids. The objectives of this study were to (1) evaluate synaptic modulation of the vPAG/DR dopamine neurons by mu opioid receptors and to (2) dissect the anatomy and neurochemistry of these neurons, in order to assess the downstream loci and functions of their activation. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase (TH) promoter, we found that mu opioid receptor activation led to a decrease in inhibitory inputs onto the vPAG/DR dopamine neurons. Furthermore, combining immunohistochemistry, optogenetics, electrophysiology, and fast-scan cyclic voltammetry in a TH-cre mouse line, we demonstrated that these neurons also express the vesicular glutamate type 2 transporter and co-release dopamine and glutamate in a major downstream projection structure-the bed nucleus of the stria terminalis. Finally, activation of TH-positive neurons in the vPAG/DR using Gq designer receptors exclusively activated by designer drugs displayed a supraspinal, but not spinal, antinociceptive effect. These results indicate that vPAG/DR dopamine neurons likely play a key role in opiate antinociception, potentially via the activation of downstream structures through dopamine and glutamate release.
Timely and effective contact tracing is an essential public health measure for curbing the transmission of COVID-19. App-based contact tracing has the potential to optimize the resources of ...overstretched public health departments. However, its efficiency is dependent on widespread adoption.
This study aimed to investigate the uptake of the Australian Government's COVIDSafe app among Australians and examine the reasons why some Australians have not downloaded the app.
An online national survey, with representative quotas for age and gender, was conducted between May 8 and May 11, 2020. Participants were excluded if they were a health care professional or had been tested for COVID-19.
Of the 1802 potential participants contacted, 289 (16.0%) were excluded prior to completing the survey, 13 (0.7%) declined, and 1500 (83.2%) participated in the survey. Of the 1500 survey participants, 37.3% (n=560) had downloaded the COVIDSafe app, 18.7% (n=280) intended to do so, 27.7% (n=416) refused to do so, and 16.3% (n=244) were undecided. Equally proportioned reasons for not downloading the app included privacy (165/660, 25.0%) and technical concerns (159/660, 24.1%). Other reasons included the belief that social distancing was sufficient and the app was unnecessary (111/660, 16.8%), distrust in the government (73/660, 11.1%), and other miscellaneous responses (eg, apathy and following the decisions of others) (73/660, 11.1%). In addition, knowledge about COVIDSafe varied among participants, as some were confused about its purpose and capabilities.
For the COVIDSafe app to be accepted by the public and used correctly, public health messages need to address the concerns of citizens, specifically privacy, data storage, and technical capabilities. Understanding the specific barriers preventing the uptake of contact tracing apps provides the opportunity to design targeted communication strategies aimed at strengthening public health initiatives, such as downloading and correctly using contact tracing apps.
Neuroadaptations in brain regions that regulate emotional and reward-seeking behaviors have been suggested to contribute to pathological behaviors associated with alcohol-use disorder. One such ...region is the bed nucleus of the stria terminalis (BNST), which has been linked to both alcohol consumption and alcohol withdrawal-induced anxiety and depression. Recently, we identified a GABAergic microcircuit in the BNST that regulates anxiety-like behavior. In the present study, we examined how chronic alcohol exposure alters this BNST GABAergic microcircuit in mice. We selectively targeted neurons expressing corticotropin releasing factor (CRF) using a CRF-reporter mouse line and combined retrograde labeling to identify BNST projections to the ventral tegmental area (VTA) and lateral hypothalamus (LH). Following 72 h of withdrawal from four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure, the excitability of a sub-population of putative local CRF neurons that did not project to either VTA or LH (CRFnon−VTA/LH neurons) was increased. Withdrawal from CIE also increased excitability of non-CRF BNST neurons that project to both LH and VTA (BNSTnon−CRF-proj neurons). Furthermore, both populations of neurons had a reduction in spontaneous EPSC amplitude while frequency was unaltered. Withdrawal from chronic alcohol was accompanied by a significant increase in spontaneous IPSC frequency selectively in the BNSTnon−CRF-proj neurons. Together, these data suggest that withdrawal from chronic ethanol dysregulates local CRF-GABAergic microcircuit to inhibit anxiolytic outputs of the BNST which may contribute to enhanced anxiety during alcohol withdrawal and drive alcohol-seeking behavior.
This article is part of the special issue on ‘Neuropeptides’.
•CIE increased the excitability of a subset of BNST-CRF neurons.•CIE increased GABAergic signaling on non-CRF BNST neurons projecting to VTA and LH.•These data show withdrawal-induced dysregulation of BNST microcircuit.
Emerging ice-sheet modeling suggests once initiated, retreat of the Antarctic Ice Sheet (AIS) can continue for centuries. Unfortunately, the short observational record cannot resolve the tipping ...points, rate of change, and timescale of responses. Iceberg-rafted debris data from Iceberg Alley identify eight retreat phases after the Last Glacial Maximum that each destabilized the AIS within a decade, contributing to global sea-level rise for centuries to a millennium, which subsequently re-stabilized equally rapidly. This dynamic response of the AIS is supported by (i) a West Antarctic blue ice record of ice-elevation drawdown >600 m during three such retreat events related to globally recognized deglacial meltwater pulses, (ii) step-wise retreat up to 400 km across the Ross Sea shelf, (iii) independent ice sheet modeling, and (iv) tipping point analysis. Our findings are consistent with a growing body of evidence suggesting the recent acceleration of AIS mass loss may mark the beginning of a prolonged period of ice sheet retreat and substantial global sea level rise.
Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through ...which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT
) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF
) in mice. Specifically, 5-HT
projections to the BNST, via actions at 5-HT
receptors (5-HT
Rs), engage a CRF
inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF
inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF
R, also known as CRHR1), given that CRF
R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT
→CRF
circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.
Sex differences in pain severity, response, and pathological susceptibility are widely reported, but the neural mechanisms that contribute to these outcomes remain poorly understood. Here we show ...that dopamine (DA) neurons in the ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DR) differentially regulate pain-related behaviors in male and female mice through projections to the bed nucleus of the stria terminalis (BNST). We find that activation of vlPAG/DRDA+ neurons or vlPAG/DRDA+ terminals in the BNST reduces nociceptive sensitivity during naive and inflammatory pain states in male mice, whereas activation of this pathway in female mice leads to increased locomotion in the presence of salient stimuli. We additionally use slice physiology and genetic editing approaches to demonstrate that vlPAG/DRDA+ projections to the BNST drive sex-specific responses to pain through DA signaling, providing evidence of a novel ascending circuit for pain relief in males and contextual locomotor response in females.
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•vlPAG/DRDA to BNST activation promotes anti-nociception in male mice•vlPAG/DRDA to BNST activation promotes locomotion in female mice•Membrane-gated currents driven by optically evoked DA release differ by sex•Dopamine is required for vlPAG/DR-driven anti-nociception
Yu et al. demonstrate that dopamine neurons in the periaqueductal gray/dorsal raphe target the bed nucleus of the stria terminalis to reduce pain sensitivity in male mice and increase locomotion in female mice. Dopamine signaling is required for sex-specific expression of these adaptive behaviors.
Stamen development is governed by a conserved genetic pathway, within which the role of hormones has been the subject of considerable recent research. Our understanding of the involvement of ...gibberellin (GA) signalling in this developmental process is further advanced than for the other phytohormones, and here we review recent experimental results in rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) that have provided insight into the timing and mechanisms of GA regulation of stamen development, identifying the tapetum and developing pollen as major targets. GA signalling governs both tapetum secretory functions and entry into programmed cell death via the GAMYB class of transcription factor, the targets of which integrate with the established genetic framework for the regulation of tapetum function at multiple hierarchical levels.
The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that regulates motivated behavior and affective states and plays an integral role in the development of ...alcohol-use disorder (AUD). The dorsal subdivision of the BNST (dBNST) receives dense dopaminergic input from the ventrolateral periaqueductal gray (vlPAG)/dorsal raphe (DR). To date, no studies have examined the effects of chronic alcohol on this circuit. Here, we used chronic intermittent ethanol exposure (CIE), a well-established rodent model of AUD, to functionally interrogate the vlPAG/DR-BNST dopamine (DA) circuit during acute withdrawal. We selectively targeted vlPAG/DR
neurons in tyrosine hydroxylase-expressing transgenic adult male mice. Using
electrophysiology, we found hyperexcitability of vlPAG/DR
neurons in CIE-treated mice. Further, using optogenetic approaches to target vlPAG/DR
terminals in the dBNST, we revealed a CIE-mediated shift in the vlPAG/DR-driven excitatory-inhibitory (E/I) ratio to a hyperexcitable state in dBNST. Additionally, to quantify the effect of CIE on endogenous DA signaling, we coupled optogenetics with fast-scan cyclic voltammetry to measure pathway-specific DA release in dBNST. CIE-treated mice had significantly reduced signal half-life, suggestive of faster clearance of DA signaling. CIE treatment also altered the ratio of vlPAG/DR
-driven cellular inhibition and excitation of a subset of dBNST neurons. Overall, our findings suggest a dysregulation of vlPAG/DR to BNST dopamine circuit, which may contribute to pathophysiological phenotypes associated with AUD.
The dorsal bed nucleus of the stria terminalis (dBNST) is highly implicated in the pathophysiology of alcohol-use disorder and receives dopaminergic inputs from ventrolateral periaqueductal gray/dorsal raphe regions (vlPAG/DR). The present study highlights the plasticity within the vlPAG/DR to dBNST dopamine (DA) circuit during acute withdrawal from chronic ethanol exposure. More specifically, our data reveal that chronic ethanol strengthens vlPAG/DR-dBNST glutamatergic transmission while altering both DA transmission and dopamine-mediated cellular inhibition of dBNST neurons. The net result is a shift toward a hyperexcitable state in dBNST activity. Together, our findings suggest chronic ethanol may promote withdrawal-related plasticity by dysregulating the vlPAG/DR-dBNST DA circuit.
Understanding preferences for veterinary vaccines in low and middle-income countries is important for increasing vaccination coverage against infectious diseases, especially when the consumer is ...responsible for choosing between similar vaccines. Over-the-counter sales of vaccines without a prescription gives decision-making power to consumers who may value vaccine traits differently from national or international experts and vaccine producers and distributers. We examine consumer preferences for La Sota and I-2 Newcastle disease vaccines in Tanzania to understand why two vaccines co-exist in the market when I-2 is considered technically superior because of its thermotolerance. Household survey and focus group results indicate consumers perceive both vaccines to be effective, use the two vaccines interchangeably when the preferred vaccine is unavailable, and base preferences more on administration style than thermotolerance. Considering the consumers' perspectives provides a way to increase vaccination coverage by targeting users with a vaccine that fits their preferences.
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