All his scientific career, Changeux has been faithful to a handful of scientific questions, at molecular, cellular and brain levels. If one needs to seek a unifying theme to all of them, it is the conviction that selection is the basis of life processes, rather than instruction. While started as separate lines of investigations, all the research threads were tied in the recent decades within the study of allosteric mechanisms as a basis of for the involvement of
nicotinic receptors in
cognitive functions.
Allostery During his
PhD studies in the laboratory of
Jacques Monod and
François Jacob, Changeux studied the
allosteric regulations of
enzymes, that is the modulation of their activity by compounds different from their
substrates. This work led to the development of the
model of concerted transitions for
allosteric proteins. The main ideas behind this theory are: 1)
proteins can exist under various conformations in
thermal equilibrium in the absence of regulators. The allosteric regulators merely shift the equilibrium between the conformations, stabilizing the ones for which they display the highest affinity, and 2) all the subunits of a symmetrical multimeric protein exist in the same conformation, the transition taking place in a
concerted fashion. The resulting model explains the observed
cooperativity without a progressive change of biophysical parameters. This conceptual framework is still the principal model used to explain the function of cooperative proteins such as
hemoglobin. In his PhD thesis, Changeux suggested that the recognition and transmission of signals by
membrane, and in particular by
synapses, could use the same mechanisms as the allosteric regulation of enzymes. More than forty years of research would follow, mainly focussed on nicotinic acetylcholine receptors (see below). In 1967, Changeux extended the MWC model to bi-dimensional lattice of
receptors (an idea that would also be developed three decades afterward by
Dennis Bray). He then applied this idea to the post-synaptic membrane of
electric organs (analog to
striated muscle). His team demonstrated the existence of several interconvertible states for the nicotinic receptor, resting, open and desensitized, displaying different affinities for the ligands, such as the endogenous agonist
acetylcholine. The transitions between the states followed different kinetics, and those kinetics plus the differential affinities sufficed to explain the shape of the post-synaptic potential. A full mechanistic model of the nicotinic receptor from striated muscle (or electric organ) was to be provided much later, when Changeux collaborated with Stuart Edelstein, another specialist of allostery, who worked decades on
hemoglobin. In addition to the allosteric modulation of the channel gating by the agonists, many other regulations of the ligand-gated ion channels activity have since been discovered. The modulators bind to a variety of allosteric sites, whether on the agonist binding sites, other binding sites at the subunit interfaces, on the cytoplasmic part of the protein or in the transmembrane domain. The concept of an allosteric pharmacology for ion channels was developed over the years. In addition to the well known
GABAA receptor positive allosteric modulators (such as
benzodiazepines and
barbiturate drugs), one can find antiparasitic drug such as
ivermectin and glutamate receptor modulators used against
Alzheimer's disease such as
aniracetam.
Nicotinic receptor structure bound to the
nicotinic acetylcholine receptor. Adapted from that he was able to identify thanks to the properties of a snake toxin, which was purified by Taiwanese researchers CY Lee and CC Chang. The isolation of the receptor was also later reported by
Ricardo Miledi. The improvements of purification methods developed in the group allowed the proposition that the receptor was a
pentameric protein, a finding quickly confirmed by the team of Arthur Karlin. The group of Changeux was among the firsts to elucidate the primary structure of the subunits of the receptor, in parallel with the group of
Shosaku Numa and
Stephen Heinemann. Throughout the 1980s and 1990s, molecular biology technics were used to decipher the tertiary and quaternary structures of the receptor. The location of the ionic pore was identified, made up of the second transmembrane segment, as shown also later by the groups of Shosaku Numa and Ferdinand Hucho. The molecular basis of ionic selectivity were also identified in the transmembrane domain. The structure of the binding site for the acetylcholine and nicotine was located at the interface between adjacent subunits. The quest of Changeux for the structure of the nicotinic receptor culminated with the publication of the structure, at atomic resolution, of a bacterial homolog in the open and resting conformations supporting the concept of a symmetrical concerted opening for channel gating, in agreement with molecular dynamics simulations.
Stabilization of synapses by neuronal activity In 1973, together with Philippe Courrège and
Antoine Danchin, Changeux proposed a model describing how, during development of the
nervous system, the activity of a network could cause the stabilization or regression of the
synapses involved and illustrated it with the neuromuscular junction. This model is effectively the precursor of the "neural Darwinism" theory further promoted by
Gerald Edelman. Changeux later extended and illustrated further this idea. During the 1970s, he tried to document this phenomenon, either by studying mutant animals or by experimental denervation.
Nicotinic receptor function While until the 1990s, Changeux's group studied the structure of the nicotinic receptor present in
electric organs of electric eel and torpedo, the investigations of the physiological role of those receptors were mostly focussed on two model systems: the nicotinic receptors of the
neuromuscular junction, the synapse linking the
motorneuron to the
skeletal muscle, and the nicotinic receptors of the brain, notably in relation with nicotine addiction. From the mid-1980s, the group studied the compartimentalisation of the muscle cell upon development, as a model of synaptogenesis and in relation with the theoretical work on epigenesis. In particular, the group focussed on the accumulation of nicotinic receptors in the post-synaptic region upon development, concomitant to a switch of receptor identity. They were able to decrypt the different signalling pathways involved in the response to synaptic activity, showing that the accumulation resulted from an inhibition of gene transcription outside the synaptic region due to electrical activity triggering an uptake of calcium and activation of PKC, and a stimulation of gene transcription at the synapse by the calcitonin gene-related peptide (CGRP) activating PKA and the ARIA (heregulin) activating tyrosine kinase cascades. The 1990s saw the progressive shift of interest of Changeux from the neuromuscular junction to the nicotinic receptors expressed in the brain. Among the notable achievements of the group is the discovery that neuronal nicotinic receptors are highly permeable to calcium – which explains the positive effect of nicotinic receptors on the release of many neurotransmitters in the brain. The group also discovered that the nicotinic receptor is regulated by a variety of "allosteric modulators" such as: 1. calcium ions (This was also discovered independently by the group of John Dani), which binding sites were later identified and localized in the extracellular domain, at the interface between subunits (Le Novère et al. 2002); 2. ivermectin); 3. phosphorylation of the cytoplasmic domain which regulate desensitization. By the mid-1990s, Changeux concentrated most of his interest on the function of nicotinic receptors in the basal ganglia and in particular the mesencephalic dopaminergic system. Using mice deleted for nicotinic receptor genes, the group characterised the types of receptor subunits present in the dopaminergic cells and identified the receptors mainly responsible of the dependence to nicotine, formed by the subunits α4, α6 and β2.
Modeling cognition From the mid-1990s, Changeux developed an activity of computational modeling in order to investigate the neuronal bases of cognitive functions. This research was mainly performed in collaboration with
Stanislas Dehaene, now leading the INSERM-CEA Cognitive Neuroimaging Unit. They notably modeled the acquisition of song recognition in birds, the development of numerical abilities, the Wisconsin card sorting task and the Tower of London task. Following the same trend, Dehaene and Changeux further developed a neuronal model for access to consciousness based on a brain-wide recruitment of networks of neurons with long-range axons, referred to as the global neuronal workspace theory. In the past decades, the theory has received significant confirmation from brain imaging and physiological recordings and tentatively extended to non human species such as Drosophila Clinical applications of the GNW model include the understanding of the mechanism of coma, the action of general anesthetics, drug addiction, and neuropsychiatric diseases. Changeux's approach manifests the constant emphasis to establish causal links between the molecular and the cognitive level, thus, raising the fundamental issue of artificial consciousness.
Origins of the human brain Together with Higletag and Goulas, Changeux has attempted to solve the paradox that the cognitive abilities of the human brain, including have expanded dramatically in the course of our recent evolution from nonhuman primates, despite only minor apparent changes at the gene level. Their “connectomic hypothesis” intends, conceptually, to find a minimal set of principles that allow to understand uniquely human brain architecture in terms of a characteristic neuronal network—connectomic—organization as an anatomical and functional phenotype parsimoniously linking the genome and the cognitive levels with major consequences on large-scale network organization and computations of the brain and, ultimately, human cognition, language, and culture in the course of its epigenetic postnatal complexification. ==Professional and non-scientific activities==