Biology subjects

Changeux, J.-P.

Publications and source records attributed to Changeux, J.-P..

6 recordsLinked to original sources

bioRxiv2026

Host response against SARS-CoV-2 infection is impacted by allosteric modulation of cholinergic and purinergic receptors

The COVID-19 pandemic has caused nearly 8 million deaths and a broad spectrum of clinical manifestations driven by dysregulated host inflammation, notably involving key signalling proteins IL-6, CXCL10, and CXCL5. We previously demonstrated that ivermectin (IVM) improves clinical outcomes and reduces the IL-6/IL-10 ratio in the lungs of SARS-CoV-2-infected hamsters. Here, combining high-throughput confocal microscopy and transcriptomics in human cell co-cultures and a hamster model, we dissected how IVM modulates host cells responses via 7nAChR and purinergic receptors. In vitro, IVM acted independently of 7nAChR, instead triggering a P2X4-dependent drop in intracellular ATP, rapidly upregulating CXCL10 in macrophages, and suppressing CXCL5 and IL-6. In vivo, however, 7nAChR antagonists abolished IVMs clinical benefit, as did the P2X4 blocker BX430; moreover, whereas the orthosteric agonist EVP-6124 was ineffective, the positive allosteric modulators (PAMs) IVM and GAT-107 reduced lung pathology and anosmia. Thus, IVM operates through a dynamic, context-dependent interplay: P2X4 drives early innate responses in cellular systems including macrophages, whereas the situation in vivo is more complex with 7nAChR being essential for tissue protection. These data position selective PAMs and the CXCL10/CXCL5 axis as promising targets for host-directed therapy in COVID-19.

pathology↗

bioRxiv2022

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 transition of the glycine receptor fluorescently labeled at the extracellular-transmembrane interface by voltage-clamp fluorimetry (VCF). Fluorescence reports a glycine-elicited conformational transition that precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger the full fluorescence signal while weakly activating the channel. Molecular dynamic simulations of a partial agonist bound-closed Cryo-EM structure show a highly dynamic personality: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties that recapitulate VCF data. Data thus illuminate a progressive gating transition towards activation, displaying structural plasticity with novel implication concerning the mechanism of action of allosteric effectors.

biophysics↗

bioRxiv2022

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 socio-cultural 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. The first sensorimotor level handles local nonconscious processing, here during a visual classification task. The second level or cognitive level globally integrates the information from multiple local processors via long-ranged connections and synthesizes it in a global, but still nonconscious manner. The third and cognitively highest level handles the information globally and consciously. It is based on the Global Neuronal Workspace (GNW) theory and is referred to as conscious level. We use trace and delay conditioning tasks to, respectively, challenge the second and third levels. Results first highlight the necessity of epigenesis through selection and stabilization of synapses at both local and global scales to allow the network to solve the first two tasks. At the global scale, dopamine appears necessary to properly provide credit assignment despite the temporal delay between perception and reward. At the third level, the presence of interneurons becomes necessary to maintain a self-sustained representation within the GNW in the absence of sensory input. Finally, while balanced spontaneous intrinsic activity facilitates epigenesis at both local and global scales, the balanced excitatory-inhibitory ratio increases performance. Finally, we discuss the plausibility of the model in both neurodevelopmental and artificial intelligence terms.

neuroscience↗

bioRxiv2021

Inhibitory control of synaptic signals preceding motor action in mouse frontal cortex

Preparatory activity in the frontal cortex preceding movement onset is thought to represent a neuronal signature of motor planning. However, how excitatory and inhibitory synaptic inputs to frontal neurons are integrated during movement preparation remains unclear. Here we address this question by performing in vivo whole-cell patch-clamp recordings in the secondary motor cortex (MOs) of head-fixed mice moving on a treadmill. We find that both superficial and deep principal neurons show slowly increasing (~10 s) membrane potential and spike rate ramps preceding the onset of spontaneous, self-paced running periods. By contrast, in animals trained to perform a goal-directed task, both membrane potential and spike ramps are characterized by larger amplitudes and accelerated kinetics during preparation of goal-driven movement. To determine the role of local inhibitory neurons in shaping these task-dependent preparatory signals, we chemogenetically suppressed the activity of specific interneuron subpopulations in untrained animals. Inactivation of parvalbumin-positive (PV+) interneurons leads to depolarized membrane potential ramps with increased amplitudes during preparation of movement, while inactivation of somatostatin-positive (SOM+) interneurons abolishes membrane potential ramps. A computational model of the local MOs circuit shows that SOM+-mediated inhibition of PV+ interneurons in conjunction with recurrent connectivity among the principal neurons can reproduce slow ramping signals, while plasticity of excitatory synapses on SOM+ interneurons can explain the acceleration of these signals in trained animals. Together, our data reveal that local inhibitory neurons play distinct roles in controlling task-dependent preparatory ramping signals when MOs neurons integrate external inputs during motor planning. HighlightsO_LIPrincipal neurons in MOs show slow preparatory membrane potential and firing rate ramps preceding the onset of spontaneous, self-paced running periods. C_LIO_LIIn animals trained to perform a goal-directed task, both membrane potential and spike ramps are faster and larger in amplitude. C_LIO_LIInactivation of PV+ interneurons disinhibits MOs principal neurons and increases the amplitude of membrane potential ramps, while inactivation of SOM+ interneurons abolishes membrane potential ramps. C_LIO_LIOur modeling results suggest that the concerted action of external inputs and local inactivation shapes task-dependent preparatory motor signals in MOs neurons. C_LI

neuroscience↗

bioRxiv2020

Anti-COVID-19 efficacy of ivermectin in the golden hamster

The devastating coronavirus disease 2019 (COVID-19) pandemic, due to SARS-CoV-2, has caused more than 47 million confirmed cases and more than 1.2 million human deaths around the globe1, and most of the severe cases of COVID-19 in humans are associated with neurological symptoms such as anosmia and ageusia, and uncontrolled inflammatory immune response2-5. Among therapeutic options6-8, the use of the anti-parasitic drug ivermectin (IVM), has been proposed, given its possible anti-SARS-CoV-2 activity9. Ivermectin is a positive allosteric modulator of the -7 nicotinic acetylcholine receptor10, which has been suggested to represent a target for the control of Covid-19 infection11, with a potential immunomodulatory activity12. We assessed the effects of IVM in SARS-CoV-2-intranasally-inoculated golden Syrian hamsters. Even though ivermectin had no effect on viral load, SARS-Cov-2-associated pathology was greatly attenuated. IVM had a sex-dependent and compartmentalized immunomodulatory effect, preventing clinical deterioration and reducing olfactory deficit in infected animals. Importantly, ivermectin dramatically reduced the Il-6/Il-10 ratio in lung tissue, which likely accounts for the more favorable clinical presentation in treated animals. Our data support IVM as a promising anti-COVID-19 drug candidate.

immunology↗

bioRxiv2020

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

Transmitter receptors constitute a key component of the molecular machinery for inter-cellular 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 distil these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization, and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density), excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density) and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.

neuroscience↗