Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation.

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear.

The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level.

The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo-electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites.

[Working with François Gros at the Institut Pasteur: allostery, the nicotinic receptor and the biology of the future].

Working with François Gros was a privileged moment in my scientific life, enabling me to appreciate a scientific personality whose generosity knew no bounds and whose vision of science was far ahead of its time.

About the compatibility between the perturbational complexity index and the global neuronal workspace theory of consciousness.

This paper investigates the compatibility between the theoretical framework of the global neuronal workspace theory (GNWT) of conscious processing and the perturbational complexity index (PCI). Even if it has been introduced within the framework of a concurrent theory (i.e.

A natural cortical axis connecting the outside and inside of the human brain.

What structural and connectivity features of the human brain help to explain the extraordinary human cognitive abilities? We recently proposed a set of relevant connectomic fundamentals, some of which arise from the size scaling of the human brain relative to other primate brains, while others of these fundamentals may be uniquely human. In particular, we suggested that the remarkable increase of the size of the human brain due to its prolonged prenatal development has brought with it an increased sparsification, hierarchical modularization, as well as increased depth and cytoarchitectonic differentiation of brain networks. These characteristic features are complemented by a shift of projection origins to the upper layers of many cortical areas as well as the significantly prolonged postnatal development and plasticity of the upper cortical layers.

Louis Pasteur, molecular dissymmetry, therapeutic chemistry and neuropharmacology.

Louis Pasteur is celebrated as the founding father of microbiology. But he was a chemist by training and discovered molecular dissymmetry experimentally. All his life, his constant preoccupation will be to apply the method and strategies of the fundamental sciences to living processes, "from the molecule to the brain".

Paleoanthropology of cognition: an overview on Hominins brain evolution.

Recent advances in neurobiology, paleontology, and paleogenetics allow us to associate changes in brain size and organization with three main "moments" of increased behavioral complexity and, more speculatively, language development. First, Australopiths display a significant increase in brain size relative to the great apes and an incipient extension of postnatal brain development. However, their cortical organization remains essentially similar to that of apes.

Illumination of a progressive allosteric mechanism mediating the glycine receptor activation.

Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating mechanism of the glycine receptor fluorescently labeled at the extracellular-transmembrane interface by voltage-clamp fluorometry (VCF). Fluorescence reports a glycine-elicited conformational change that precedes pore opening.

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway.

Glycine receptors (GlyRs) are ligand-gated ion channels mediating signal transduction at chemical synapses. Since the early patch-clamp electrophysiology studies, the details of the ion permeation mechanism have remained elusive. Here, we combine molecular dynamics simulations of a zebrafish GlyR-α1 model devoid of the intracellular domain with mutagenesis and single-channel electrophysiology of the full-length human GlyR-α1.

Multilevel development of cognitive abilities in an artificial neural network.

Several neuronal mechanisms have been proposed to account for the formation of cognitive abilities through postnatal interactions with the physical and sociocultural environment. Here, we introduce a three-level computational model of information processing and acquisition of cognitive abilities. We propose minimal architectural requirements to build these levels, and how the parameters affect their performance and relationships.

Differential mechanisms underlie trace and delay conditioning in Drosophila.

Two forms of associative learning-delay conditioning and trace conditioning-have been widely investigated in humans and higher-order mammals. In delay conditioning, an unconditioned stimulus (for example, an electric shock) is introduced in the final moments of a conditioned stimulus (for example, a tone), with both ending at the same time. In trace conditioning, a 'trace' interval separates the conditioned stimulus and the unconditioned stimulus.

Inhibitory control of synaptic signals preceding locomotion in mouse frontal cortex.

The frontal cortex is essential for organizing voluntary movement. The secondary motor cortex (MOs) is a frontal subregion thought to integrate internal and external inputs before motor action. However, how excitatory and inhibitory synaptic inputs to MOs neurons are integrated preceding movement remains unclear.

Nicotinic receptors: From protein allostery to computational neuropharmacology.

We propose an extension and further development of the Monod-Wyman-Changeux model for allosteric transitions of regulatory proteins to brain communications and specifically to neurotransmitters receptors, with the nicotinic acetylcholine receptor (nAChR) as a model of ligand-gated ion channels. The present development offers an expression of the change of the gating isomerization constant caused by pharmacological ligand binding in terms of its value in the absence of ligands and several "modulation factors", which vary with orthosteric ligand binding (agonists/antagonists), allosteric ligand binding (positive allosteric modulators/negative allosteric modulators) and receptor desensitization. The new - explicit - formulation of such "modulation factors", provides expressions for the pharmacological attributes of potency, efficacy, and selectivity for the modulatory ligands (including endogenous neurotransmitters) in terms of their binding affinity for the active, resting, and desensitized states of the receptor.

Dynamic Cellular Cartography: Mapping the Local Determinants of Oligodendrocyte Transcription Factor 2 (OLIG2) Function in Live Cells Using Massively Parallel Fluorescence Correlation Spectroscopy Integrated with Fluorescence Lifetime Imaging Microscopy (mpFCS/FLIM).

Compartmentalization and integration of molecular processes through diffusion are basic mechanisms through which cells perform biological functions. To characterize these mechanisms in live cells, quantitative and ultrasensitive analytical methods with high spatial and temporal resolution are needed. Here, we present quantitative scanning-free confocal microscopy with single-molecule sensitivity, high temporal resolution (∼10 μs/frame), and fluorescence lifetime imaging capacity, developed by integrating massively parallel fluorescence correlation spectroscopy with fluorescence lifetime imaging microscopy (mpFCS/FLIM); we validate the method, use it to map in live cell location-specific variations in the concentration, diffusion, homodimerization, DNA binding, and local environment of the oligodendrocyte transcription factor 2 fused with the enhanced Green Fluorescent Protein (OLIG2-eGFP), and characterize the effects of an allosteric inhibitor of OLIG2 dimerization on these determinants of OLIG2 function.

Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin.

The devastating pandemic due to SARS-CoV-2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID-19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard doses of ivermectin (IVM), an anti-parasitic drug with potential immunomodulatory activities through the cholinergic anti-inflammatory pathway, prevent clinical deterioration, reduce olfactory deficit, and limit the inflammation of the upper and lower respiratory tracts in SARS-CoV-2-infected hamsters.

The natural axis of transmitter receptor distribution in the human cerebral cortex.

Transmitter receptors constitute a key component of the molecular machinery for intercellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distill these observations into key organizational principles.

A Connectomic Hypothesis for the Hominization of the Brain.

Cognitive abilities of the human brain, including language, have expanded dramatically in the course of our recent evolution from nonhuman primates, despite only minor apparent changes at the gene level. The hypothesis we propose for this paradox relies upon fundamental features of human brain connectivity, which contribute to a characteristic anatomical, functional, and computational neural phenotype, offering a parsimonious framework for connectomic changes taking place upon the human-specific evolution of the genome. Many human connectomic features might be accounted for by substantially increased brain size within the global neural architecture of the primate brain, resulting in a larger number of neurons and areas and the sparsification, increased modularity, and laminar differentiation of cortical connections.

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications.

SARS-CoV-2 epidemics raises a considerable issue of public health at the planetary scale. There is a pressing urgency to find treatments based upon currently available scientific knowledge. Therefore, we tentatively propose a hypothesis which hopefully might ultimately help save lives.

Golden Anniversary of the Nicotinic Receptor.

The high-resolution structure of the nicotinic acetylcholine receptor from Torpedo electric tissue in association with the snake toxin α-bungarotoxin (Rahman et al., 2020) is presented 50 years after its identification as the first neurotransmitter receptor and ligand-gated ion channel.

Do Nicotinic Receptors Modulate High-Order Cognitive Processing?

Recent studies provided strong evidence that deficits in cholinergic signaling cause disorders of cognition and affect conscious processing. Technical advances that combine molecular approaches, in vivo recordings in awake behaving animals, human brain imaging, and genetics have strengthened our understanding of the roles of nicotinic acetylcholine receptors (nAChRs) in the modulation of cognitive behavior and network dynamics. Here, we review the emergent role of nAChRs in high-order cognitive processes and discuss recent work implicating cholinergic circuits in cognitive control, including conscious processing.

Discovery of the First Neurotransmitter Receptor: The Acetylcholine Nicotinic Receptor.

The concept of pharmacological receptor was proposed at the turn of the 20th century but it took almost 70 years before the first receptor for a neurotransmitter was isolated and identified as a protein. This review retraces the history of the difficulties and successes in the identification of the nicotinic acetylcholine receptor, the first neurotransmitter receptor to be identified.

The Glycine Receptor Allosteric Ligands Library (GRALL).

Motivation: Glycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of chemically diverse compounds that are able to modulate GlyR function both positively and negatively have been reported, which provides useful information for the development of pharmacological strategies and models for the allosteric modulation of these ion channels.

Results: Based on existing literature, we have collected 218 unique chemical entities with documented modulatory activities at homomeric GlyR-α1 and -α3 and built a database named GRALL.