The urotensin II receptor triggers an early meningeal response and a delayed macrophage-dependent vasospasm after subarachnoid hemorrhage in male mice.

Subarachnoid hemorrhage (SAH) can be associated with neurological deficits and has profound consequences for mortality and morbidity. Cerebral vasospasm (CVS) and delayed cerebral ischemia affect neurological outcomes in SAH patients, but their mechanisms are not fully understood, and effective treatments are limited. Here, we report that urotensin II receptor UT plays a pivotal role in both early events and delayed mechanisms following SAH in male mice.

Lateral flexion of a compliant spine improves motor performance in a bioinspired mouse robot.

A flexible spine is critical to the motion capability of most animals and plays a pivotal role in their agility. Although state-of-the-art legged robots have already achieved very dynamic and agile movement solely relying on their legs, they still exhibit the type of stiff movement that compromises movement efficiency. The integration of a flexible spine thus appears to be a promising approach to improve their agility, especially for small and underactuated quadruped robots that are underpowered because of size limitations.

Embodied bidirectional simulation of a spiking cortico-basal ganglia-cerebellar-thalamic brain model and a mouse musculoskeletal body model distributed across computers including the supercomputer Fugaku.

Embodied simulation with a digital brain model and a realistic musculoskeletal body model provides a means to understand animal behavior and behavioral change. Such simulation can be too large and complex to conduct on a single computer, and so distributed simulation across multiple computers over the Internet is necessary. In this study, we report our joint effort on developing a spiking brain model and a mouse body model, connecting over the Internet, and conducting bidirectional simulation while synchronizing them.

Meta-Reinforcement Learning in Nonstationary and Nonparametric Environments.

Recent state-of-the-art artificial agents lack the ability to adapt rapidly to new tasks, as they are trained exclusively for specific objectives and require massive amounts of interaction to learn new skills. Meta-reinforcement learning (meta-RL) addresses this challenge by leveraging knowledge learned from training tasks to perform well in previously unseen tasks. However, current meta-RL approaches limit themselves to narrow parametric and stationary task distributions, ignoring qualitative differences and nonstationary changes between tasks that occur in the real world.

Deploying and Optimizing Embodied Simulations of Large-Scale Spiking Neural Networks on HPC Infrastructure.

Simulating the brain-body-environment trinity in closed loop is an attractive proposal to investigate how perception, motor activity and interactions with the environment shape brain activity, and vice versa. The relevance of this embodied approach, however, hinges entirely on the modeled complexity of the various simulated phenomena. In this article, we introduce a software framework that is capable of simulating large-scale, biologically realistic networks of spiking neurons embodied in a biomechanically accurate musculoskeletal system that interacts with a physically realistic virtual environment.

The Neurorobotics Platform Robot Designer: Modeling Morphologies for Embodied Learning Experiments.

The more we investigate the principles of motion learning in biological systems, the more we reveal the central role that body morphology plays in motion execution. Not only does anatomy define the kinematics and therefore the complexity of possible movements, but it now becomes clear that part of the computation required for motion control is offloaded to body dynamics (a phenomenon referred to as "Morphological Computation.") Consequentially, a proper design of body morphology is essential to carry out meaningful simulations on motor control of robotic and musculoskeletal systems.

Chemotactic cell migration: the core autophagy protein ATG9A is at the leading edge.

Accumulating data indicate that several components of the macroautophagy/autophagy machinery mediate additional functions, which do not depend on autophagosome biogenesis or lysosomal cargo degradation. In this context, we found that the core autophagy protein ATG9A participates in the chemotactic movement of several cell lines, including highly invasive glioblastoma cells. Accordingly, ATG9A-depleted cells are unable to form large and persistent leading-edge protrusions.

The core autophagy protein ATG9A controls dynamics of cell protrusions and directed migration.

Chemotactic migration is a fundamental cellular behavior relying on the coordinated flux of lipids and cargo proteins toward the leading edge. We found here that the core autophagy protein ATG9A plays a critical role in the chemotactic migration of several human cell lines, including highly invasive glioma cells. Depletion of ATG9A protein altered the formation of large and persistent filamentous actin (F-actin)-rich lamellipodia that normally drive directional migration.

Toward Cognitive Navigation: Design and Implementation of a Biologically Inspired Head Direction Cell Network.

As a vital cognitive function of animals, the navigation skill is first built on the accurate perception of the directional heading in the environment. Head direction cells (HDCs), found in the limbic system of animals, are proven to play an important role in identifying the directional heading allocentrically in the horizontal plane, independent of the animal's location and the ambient conditions of the environment. However, practical HDC models that can be implemented in robotic applications are rarely investigated, especially those that are biologically plausible and yet applicable to the real world.

Robotic Manipulation in Dynamic Scenarios via Bounding-Box-Based Hindsight Goal Generation.

By relabeling past experience with heuristic or curriculum goals, state-of-the-art reinforcement learning (RL) algorithms such as hindsight experience replay (HER), hindsight goal generation (HGG), and graph-based HGG (G-HGG) have been able to solve challenging robotic manipulation tasks in multigoal settings with sparse rewards. HGG outperforms HER in challenging tasks in which goals are difficult to explore by learning from a curriculum, in which intermediate goals are selected based on the Euclidean distance to target goals. G-HGG enhances HGG by selecting intermediate goals from a precomputed graph representation of the environment, which enables its applicability in an environment with stationary obstacles.

Complex Robotic Manipulation via Graph-Based Hindsight Goal Generation.

Reinforcement learning algorithms, such as hindsight experience replay (HER) and hindsight goal generation (HGG), have been able to solve challenging robotic manipulation tasks in multigoal settings with sparse rewards. HER achieves its training success through hindsight replays of past experience with heuristic goals but underperforms in challenging tasks in which goals are difficult to explore. HGG enhances HER by selecting intermediate goals that are easy to achieve in the short term and promising to lead to target goals in the long term.

Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma.

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system.

Ethical and Social Aspects of Neurorobotics.

The interdisciplinary field of neurorobotics looks to neuroscience to overcome the limitations of modern robotics technology, to robotics to advance our understanding of the neural system's inner workings, and to information technology to develop tools that support those complementary endeavours. The development of these technologies is still at an early stage, which makes them an ideal candidate for proactive and anticipatory ethical reflection. This article explains the current state of neurorobotics development within the Human Brain Project, originating from a close collaboration between the scientific and technical experts who drive neurorobotics innovation, and the humanities and social sciences scholars who provide contextualising and reflective capabilities.

Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin.

Research on energy homeostasis has focused on neuronal signaling; however, the role of glial cells has remained little explored. Glial endozepines exert anorexigenic actions by mechanisms which remain poorly understood. In this context, the present study was designed to decipher the mechanisms underlying the anorexigenic action of endozepines and to investigate their potential curative effect on high-fat diet-induced obesity.

Development of Novel -In-Labelled DOTA Urotensin II Analogues for Targeting the UT Receptor Overexpressed in Solid Tumours.

Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis.

Endozepines and their receptors: Structure, functions and pathophysiological significance.

The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP).

Endogenous Expression of ODN-Related Peptides in Astrocytes Contributes to Cell Protection Against Oxidative Stress: Astrocyte-Neuron Crosstalk Relevance for Neuronal Survival.

Astroglial cells are important actors in the defense of brain against oxidative stress injuries. Glial cells synthesize and release the octadecaneuropeptide ODN, a diazepam-binding inhibitor (DBI)-related peptide, which acts through its metabotropic receptor to protect neurons and astrocytes from oxidative stress-induced apoptosis. The purpose of the present study is to examine the contribution of the endogenous ODN in the protection of astrocytes and neurons from moderate oxidative stress.

Ketamine and Etomidate Down-regulate the Hypothalamic-Pituitary-Adrenal Axis in an Endotoxemic Mouse Model.

Background: We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis.

Methods: Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3β-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11β-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD).

The G Protein-Coupled Receptor UT of the Neuropeptide Urotensin II Displays Structural and Functional Chemokine Features.

The urotensinergic system was previously considered as being linked to numerous physiopathological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions. Thus, it turns out that the actions of the urotensin II (UII)/G protein-coupled receptor UT system in animal models are currently not predictive enough in regard to their effects in human clinical trials and that UII analogs, established to target UT, were not as beneficial as expected in pathological situations. Thus, many questions remain regarding the overall signaling profiles of UT leading to complex involvement in cardiovascular and inflammatory responses as well as cancer.

The Autophagy Machinery: A New Player in Chemotactic Cell Migration.

Autophagy is a highly conserved self-degradative process that plays a key role in diverse cellular processes such as stress response or differentiation. A growing body of work highlights the direct involvement of autophagy in cell migration and cancer metastasis. Specifically, autophagy has been shown to be involved in modulating cell adhesion dynamics as well as epithelial-to-mesenchymal transition.

Chemotactic G protein-coupled receptors control cell migration by repressing autophagosome biogenesis.

Chemotactic migration is a fundamental behavior of cells and its regulation is particularly relevant in physiological processes such as organogenesis and angiogenesis, as well as in pathological processes such as tumor metastasis. The majority of chemotactic stimuli activate cell surface receptors that belong to the G protein-coupled receptor (GPCR) superfamily. Although the autophagy machinery has been shown to play a role in cell migration, its mode of regulation by chemotactic GPCRs remains largely unexplored.

Involvement of the Acyl-CoA binding domain containing 7 in the control of food intake and energy expenditure in mice.

Acyl-CoA binding domain-containing 7 (Acbd7) is a paralog gene of the diazepam-binding inhibitor/Acyl-CoA binding protein in which single nucleotide polymorphism has recently been associated with obesity in humans. In this report, we provide converging evidence indicating that a splice variant isoform of the Acbd7 mRNA is expressed and translated by some POMC and GABAergic-neurons in the hypothalamic arcuate nucleus (ARC). We have demonstrated that the ARC ACBD7 isoform was produced and processed into a bioactive peptide referred to as nonadecaneuropeptide (NDN) in response to catabolic signals.