Divergent modulation of nociception by glutamatergic and GABAergic neuronal subpopulations in the periaqueductal gray

The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception

Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain

Painful bladder syndrome is a debilitating condition that affects 3–6% of women in the United States. Multiple lines of evidence suggest that changes in central nervous system processing are key to the development of chronic bladder pain conditions, but little is known regarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distension-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distension. Additionally, pharmacological blockade or virally-mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA localized effects on responses to bladder distention are associated with changes in extracellular signal regulated kinases 1/2 phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization

(193) Proposal to democratize aspects of the governance of the International Code of Nomenclature for algae, fungi, and plants

descripción no proporcionada por scopu

Myelinating Schwann cells ensheath multiple axons in the absence of E3 ligase component Fbxw7

In the central nervous system (CNS), oligodendrocytes myelinate multiple axons; in the peripheral nervous system (PNS), Schwann cells (SCs) myelinate a single axon. Why are the myelinating potentials of these glia so fundamentally different? Here, we find that loss of Fbxw7, an E3 ubiquitin ligase component, enhances the myelinating potential of SCs. Fbxw7 mutant SCs make thicker myelin sheaths and sometimes appear to myelinate multiple axons in a fashion reminiscent of oligodendrocytes. Several Fbxw7 mutant phenotypes are due to dysregulation of mTOR; however, the remarkable ability of mutant SCs to ensheathe multiple axons is independent of mTOR signaling. This indicates distinct roles for Fbxw7 in SC biology including modes of axon interactions previously thought to fundamentally distinguish myelinating SCs from oligodendrocytes. Our data reveal unexpected plasticity in the myelinating potential of SCs, which may have important implications for our understanding of both PNS and CNS myelination and myelin repair

Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding

An animal\u27s evolutionary success depends on the ability to seek and consume foods while avoiding environmental threats. However, how evolutionarily conserved threat detection circuits modulate feeding is unknown. In mammals, feeding and threat assessment are strongly influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits feeding. Here, we report that the PBN receives dense inputs from two discrete neuronal populations in the bed nucleus of the stria terminalis (BNST), an extended amygdala structure that encodes affective information. Using a series of complementary approaches, we identify opposing BNST-PBN circuits that modulate neuropeptide-expressing PBN neurons to control feeding and affective states. These previously unrecognized neural circuits thus serve as potential nodes of neural circuitry critical for the integration of threat information with the intrinsic drive to feed

Inequitable gains and losses from conservation in a global biodiversity hotspot

A billion rural people live near tropical forests. Urban populations need them for water, energy and timber. Global society benefits from climate regulation and knowledge embodied in tropical biodiversity. Ecosystem service valuations can incentivise conservation, but determining costs and benefits across multiple stakeholders and interacting services is complex and rarely attempted. We report on a 10-year study, unprecedented in detail and scope, to determine the monetary value implications of conserving forests and woodlands in Tanzania’s Eastern Arc Mountains. Across plausible ranges of carbon price, agricultural yield and discount rate, conservation delivers net global benefits (+US$8.2B present value, 20-year central estimate). Crucially, however, net outcomes diverge widely across stakeholder groups. International stakeholders gain most from conservation (+US$10.1B), while local-rural communities bear substantial net costs (-US$1.9B), with greater inequities for more biologically important forests. Other Tanzanian stakeholders experience conflicting incentives: tourism, drinking water and climate regulation encourage conservation (+US$72M); logging, fuelwood and management costs encourage depletion (-US$148M). Substantial global investment in disaggregating and mitigating local costs (e.g., through boosting smallholder yields) is essential to equitably balance conservation and development objectives

A Novel Behavioral Assay for Measuring Cold Sensation in Mice

Behavioral models of cold responses are important tools for exploring the molecular mechanisms of cold sensation. To complement the currently cold behavioral assays and allow further studies of these mechanisms, we have developed a new technique to measure the cold response threshold, the cold plantar assay. In this assay, animals are acclimated on a glass plate and a cold stimulus is applied to the hindpaw through the glass using a pellet of compressed dry ice. The latency to withdrawal from the cooled glass is used as a measure of the cold response threshold of the rodents, and the dry ice pellet provides a ramping cold stimulus on the glass that allows the correlation of withdrawal latency values to rough estimates of the cold response threshold temperature. The assay is highly sensitive to manipulations including morphine-induced analgesia, Complete Freund's Adjuvant-induced inflammatory allodynia, and Spinal Nerve Ligation-induced neuropathic allodynia

Topography-driven isolation, speciation and a global increase of endemism with elevation

Aim: Higher-elevation areas on islands and continental mountains tend to be separated by longer distances, predicting higher endemism at higher elevations; our study is the first to test the generality of the predicted pattern. We also compare it empirically with contrasting expectations from hypotheses invoking higher speciation with area, temperature and species richness. Location: Thirty-two insular and 18 continental elevational gradients from around the world. Methods: We compiled entire floras with elevation-specific occurrence information, and calculated the proportion of native species that are endemic (‘percent endemism’) in 100-m bands, for each of the 50 elevational gradients. Using generalized linear models, we tested the relationships between percent endemism and elevation, isolation, temperature, area and species richness. Results: Percent endemism consistently increased monotonically with elevation, globally. This was independent of richness–elevation relationships, which had varying shapes but decreased with elevation at high elevations. The endemism–elevation relationships were consistent with isolation-related predictions, but inconsistent with hypotheses related to area, richness and temperature. Main conclusions: Higher per-species speciation rates caused by increasing isolation with elevation are the most plausible and parsimonious explanation for the globally consistent pattern of higher endemism at higher elevations that we identify. We suggest that topography-driven isolation increases speciation rates in mountainous areas, across all elevations and increasingly towards the equator. If so, it represents a mechanism that may contribute to generating latitudinal diversity gradients in a way that is consistent with both present-day and palaeontological evidence

High aboveground carbon stock of African tropical montane forests

Tropical forests store 40–50 per cent of terrestrial vegetation carbon1. However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests2. Owing to climatic and soil changes with increasing elevation3, AGC stocks are lower in tropical montane forests compared with lowland forests2. Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4 megagrams of carbon per hectare (95% confidence interval 137.1–164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network4 and about 70 per cent and 32 per cent higher than averages from plot networks in montane2,5,6 and lowland7 forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa8. We find that the low stem density and high abundance of large trees of African lowland forests4 is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to help to guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse9,10 and carbon-rich ecosystems