Identification of parvalbumin interneurons as cellular substrate of fear memory persistence

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR {beta}3L(185L) to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders

Serum peptide reactivities may distinguish neuromyelitis optica subgroups and multiple sclerosis

Objective: To assess in an observational study whether serum peptide antibody reactivities may distinguish aquaporin-4 (AQP4) antibody (Ab)–positive and -negative neuromyelitis optica spectrum disorders (NMOSD) and relapsing-remitting multiple sclerosis (RRMS). Methods: We screened 8,700 peptides that included human and viral antigens of potential relevance for inflammatory demyelinating diseases and random peptides with pooled sera from different patient groups and healthy controls to set up a customized microarray with 700 peptides. With this microarray, we tested sera from 66 patients with AQP4-Ab-positive (n = 16) and AQP4-Ab-negative (n = 19) NMOSD, RRMS (n = 11), and healthy controls (n = 20). Results: Differential peptide reactivities distinguished NMOSD subgroups from RRMS in 80% of patients. However, the 2 NMOSD subgroups were not well-discriminated, although those patients are clearly separated by their antibody reactivities against AQP4 in cell-based assays. Elevated reactivities to myelin and Epstein-Barr virus peptides were present in RRMS and to AQP4 and AQP1 peptides in AQP4-Ab-positive NMOSD. Conclusions: While AQP4-Ab-positive and -negative NMOSD subgroups are not well-discriminated by peptide antibody reactivities, our findings suggest that peptide antibody reactivities may have the potential to distinguish between both NMOSD subgroups and MS. Future studies should thus concentrate on evaluating peptide antibody reactivities for the differentiation of AQP4-Ab-negative NMOSD and MS

Murine GRPR and Stathmin Control in Opposite Directions both Cued Fear Extinction and Neural Activities of the Amygdala and Prefrontal Cortex

Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction

NCAM180 Regulates Ric8A Membrane Localization and Potentiates β-Adrenergic Response

Cooperation between receptors allows integrated intracellular signaling leading to appropriate physiological responses. The Neural Cell Adhesion Molecule (NCAM) has three main isoforms of 120, 140 and 180 kDa, with adhesive and signaling properties, but their respective functions remains to be fully identified. Here we show that the human NCAM180 intracellular domain is a novel interactor of the human guanosine exchange factor (GEF) Ric8A using the yeast two hybrid system and immunoprecipitation. Furthermore, NCAM, Ric8A and Gαs form a tripartite complex. Colocalization experiments by confocal microscopy revealed that human NCAM180 specifically induces the recruitment of Ric8A to the membrane. In addition, using an in vitro recombinant system, and in vivo by comparing NCAM knock-out mouse brain to NCAM heterozygous and wild type brains, we show that NCAM expression dose dependently regulates Ric8A redistribution in detergent resistent membrane microdomains (DRM). Previous studies have demonstrated essential roles for Ric8 in Gα protein activity at G protein coupled receptors (GPCR), during neurotransmitter release and for asymmetric cell division. We observed that inhibition of Ric8A by siRNA or its overexpression, decreases or increases respectively, cAMP production following β-adrenergic receptor stimulation. Furthermore, in human HEK293T recombinant cells, NCAM180 potentiates the Gαs coupled β-adrenergic receptor response, in a Ric8A dependent manner, whereas NCAM120 or NCAM140 do not. Finally, in mouse hippocampal neurons expressing endogenously NCAM, NCAM is required for the agonist isoproterenol to induce cAMP production, and this requirement depends on Ric8A. These data illustrate a functional crosstalk between a GPCR and an IgCAM in the nervous system

On the heating mix of ITER (invited paper)

This paper considers the heating mix of ITER for the two main scenarios. Presently, 73MWof absorbed power are foreseen in the mix 20/33/20 for ECH, NBI and ICH. Given a sufficient edge stability, Q = 10 the goal of scenario 2 can be reached with 40MW power irrespective of the heating method but depends sensitively inter alia on the H-mode pedestal temperature, the density profile shape and on the characteristics of impurity transport. ICH preferentially heats the ions and would contribute specifically with Q 0.5, and strong off-axis current drive (CD). The findings presented here are based on revised CD efficiencies γ for ECCD and a detailed benchmark of several CD codes. With ECCD alone, the goals of scenario 4 can hardly be reached. Efficient off-axisCDis only possible with NBI.With beams, inductive discharges with fni > 0.8 can be maintained for 3000 s. The conclusion of this study is that the present heating mix of ITER is appropriate. It provides the necessary actuators to induce in a flexible way the best possible scenarios. The development risks of NBI at 1MeV can be reduced by operation at 0.85MeV

Aerodynamic investigations of ventilated brake discs.

The heat dissipation and performance of a ventilated brake disc strongly depends on the aerodynamic characteristics of the flow through the rotor passages. The aim of this investigation was to provide an improved understanding of ventilated brake rotor flow phenomena, with a view to improving heat dissipation, as well as providing a measurement data set for validation of computational fluid dynamics methods. The flow fields at the exit of four different brake rotor geometries, rotated in free air, were measured using a five-hole pressure probe and a hot-wire anemometry system. The principal measurements were taken using two-component hot-wire techniques and were used to determine mean and unsteady flow characteristics at the exit of the brake rotors. Using phase-locked data processing, it was possible to reveal the spatial and temporal flow variation within individual rotor passages. The effects of disc geometry and rotational speed on the mean flow, passage turbulence intensity, and mass flow were determined. The rotor exit jet and wake flow were clearly observed as characterized by the passage geometry as well as definite regions of high and low turbulence. The aerodynamic flow characteristics were found to be reasonably independent of rotational speed but highly dependent upon rotor geometry

Scientists' warning to humanity on insect extinctions

Here we build on the manifesto ‘World Scientists’ Warning to Humanity, issued by the Alliance of World Scientists. As a group of conservation biologists deeply concerned about the decline of insect populations, we here review what we know about the drivers of insect extinctions, their consequences, and how extinctions can negatively impact humanity. We are causing insect extinctions by driving habitat loss, degradation, and fragmentation, use of polluting and harmful substances, the spread of invasive species, global climate change, direct overexploitation, and co-extinction of species dependent on other species. With insect extinctions, we lose much more than species. We lose abundance and biomass of insects, diversity across space and time with consequent homogenization, large parts of the tree of life, unique ecological functions and traits, and fundamental parts of extensive networks of biotic interactions. Such losses lead to the decline of key ecosystem services on which humanity depends. From pollination and decomposition, to being resources for new medicines, habitat quality indication and many others, insects provide essential and irreplaceable services. We appeal for urgent action to close key knowledge gaps and curb insect extinctions. An investment in research programs that generate local, regional and global strategies that counter this trend is essential. Solutions are available and implementable, but urgent action is needed now to match our intentions.Peer reviewe

Solutions for humanity on how to conserve insects

The fate of humans and insects intertwine, especially through the medium of plants. Global environmental change, including land transformation and contamination, is causing concerning insect diversity loss, articulated in the companion review Scientists' warning to humanity on insect extinctions. Yet, despite a sound philosophical foundation, recognized ethical values, and scientific evidence, globally we are performing poorly at instigating effective insect conservation. As insects are a major component of the tapestry of life, insect conservation would do well to integrate better with overall biodiversity conservation and climate change mitigation. This also involves popularizing insects, especially through use of iconic species, through more media coverage, and more inclusive education. Insect conservationists need to liaise better with decision makers, stakeholders, and land managers, especially at the conceptually familiar scale of the landscape. Enough evidence is now available, and synthesized here, which illustrates that multiple strategies work at local levels towards saving insects. We now need to expand these locally-crafted strategies globally. Tangible actions include ensuring maintenance of biotic complexity, especially through improving temporal and spatial heterogeneity, functional connectivity, and metapopulation dynamics, while maintaining unique habitats, across landscape mosaics, as well as instigating better communication. Key is to have more expansive sustainable agriculture and forestry, improved regulation and prevention of environmental risks, and greater recognition of protected areas alongside agro-ecology in novel landscapes. Future-proofing insect diversity is now critical, with the benefits far reaching, including continued provision of valuable ecosystem services and the conservation of a rich and impressive component of Earth's biodiversity.Peer reviewe