Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus–pituitary–adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.NWOMicrobial Biotechnolog

Hypoxic blackwater events suppress the emergence of zooplankton from wetland sediments

The increased incidence of severe hypoxic ‘blackwater’ (high dissolved organic carbon, DOC) events as a consequence of river regulation and other river management practices poses a threat to the management of many river-floodplain systems. However, there is still a lack of fundamental knowledge regarding the effects of hypoxic blackwater events on the aquatic biota. Zooplankton occupy a central position in river-floodplain food webs, as consumers of algae, fungi and bacteria, and as potential prey items for fish, waterbirds, amphibians and macroinvertebrates. We investigated the impact of hypoxic blackwater events on river-floodplain zooplankton assemblages by examining the effects of varying DOC and dissolved oxygen concentrations on zooplankton emerging from the sediments of two floodplain wetlands in the southern Murray–Darling Basin, Australia. Hypoxic conditions significantly reduced the taxon richness and abundance of zooplankton emerging from the sediments of each wetland, whereas DOC concentration alone had no consistent effects. The effects of hypoxia on zooplankton were partially reversed when oxygen concentrations were returned to normal values within 3 weeks. These findings suggest that hypoxic blackwater events can reduce the availability of food resources to planktivorous biota through their reductions in zooplankton abundance; although these resources may be restored reasonably quickly if oxygenated conditions are returned within a short time

Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Background and Purpose: Endocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood.Experimental Approach: Using an array of cellular, endocrine and behavioural readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signalling to the generation of a stress response.Key Results: The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243 and NAPE PLD inhibitor LEI401 all uniformly increased Fos in the PVN, unmasked stress-linked behaviours, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress-like behavioural changes produced by disruption of eCB signalling.Conclusions and Implications: These data indicate that under resting conditions, constitutive eCB signalling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN.Molecular Physiolog

Scaling of divertor power footprint width in RF-heated type-III ELMy H-mode on the EAST superconducting tokamak

Dedicated experiments for the scaling of divertor power footprint width have been performed in the ITER-relevant radio-frequency (RF)-heated H-mode scheme under the lower single null, double null and upper single null divertor configurations in the Experimental Advanced Superconducting Tokamak (EAST) under lithium wall coating conditioning. A strong inverse scaling of the edge localized mode (ELM)-averaged power fall-off width with the plasma current (equivalently the poloidal field) has been demonstrated for the attached type-III ELMy H-mode as $\lambda_{q} \propto I_{{\rm p}}^{-1.05}$ by various heat flux diagnostics including the divertor Langmuir probes (LPs), infra-red (IR) thermograph and reciprocating LPs on the low-field side. The IR camera and divertor LP measurements show that \lambda_{q,{\rm IR}} \approx {\lambda_{q,{\rm div\mbox{-}LPs}}}/{1.3}=1.15B_{{\rm p,omp}}^{-1.25} , in good agreement with the multi-machine scaling trend during the inter-ELM phase between type-I ELMs or ELM-free enhanced Dα (EDA). H-mode. However, the magnitude is nearly doubled, which may be attributed to the different operation scenarios or heating schemes in EAST, i.e., dominated by electron heating. It is also shown that the type-III ELMs only broaden the power fall-off width slightly, and the ELM-averaged width is representative for the inter-ELM period. Furthermore, the inverse Ip (Bp) scaling appears to be independent of the divertor configurations in EAST. The divertor power footprint integral width, fall-off width and dissipation width derived from EAST IR camera measurements follow the relation, λint cong λq + 1.64S, yielding $\lambda_{\rm int}^{{\rm EAST}} =(1.39\pm 0.03)\lambda_{q}^{{\rm EAST}} +(0.97\pm 0.35)\,{\rm mm}$ . Detailed analysis of these three characteristic widths was carried out to shed more light on their extrapolation to ITER