Biology subjects

Mourot, A.

Publications and source records attributed to Mourot, A..

17 recordsLinked to original sources

bioRxiv2026

Focal drug uncaging for the precise control of endogenous nicotinic receptors in behaving mice

Nicotinic acetylcholine receptors shape diverse brain functions, including reward, aversion, and pain, but dissecting their roles in vivo requires drug delivery with spatiotemporal precision that conventional pharmacology cannot provide. Here we establish in vivo photopharmacology of endogenous nicotinic receptors: two complementary, highly-potent agonists, administered systemically in an inactive caged form, are photoreleased locally in target brain circuits of behaving wild-type mice. Despite irreversible photochemistry, photoactivation can be repeated over many trials on a minute timescale, for hours following a single injection. Local uncaging evokes circuit-specific dopamine release, drives place preference from the ventral tegmental area and aversion from the interpeduncular nucleus, and, in pain circuits, reveals a pronociceptive effect masked when the same agonists are given systemically. By controlling where and when nicotinic signaling acts, this approach exposes circuit-specific drug effects invisible to conventional pharmacology, and outlines a general strategy for on-demand control of endogenous receptors in vivo.

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bioRxiv2026

An optonanobody for reversible photoactivation of recombinant and native α7 nicotinic

Photopharmacology which enables the precise optical control of endogenous receptor activity, represents a powerful approach in neuroscience. However, photochromic diffusible ligands often exhibit limited subtype specificity, while alternative strategies for controlling specific receptor subtypes require genetic modification. Here, to achieve high subtype selectivity without the need of receptor engineering, we introduce a genetically independent strategy for optical control of endogenous receptors based on highly selective and chemically-defined photoswitchable nanobodies. By covalently coupling a light-sensitive azobenzene agonist to a high-affinity nanobody targeting 7 nicotinic acetylcholine receptor (nAChR), we engineered MalAzoCh-C4, an optonanobody that confers reversible, light-dependent activation of native 7 receptors. In Xenopus oocytes, MalAzoCh-C4 enables wavelength-controlled modulation of recombinant 7 receptors, with enhanced activity in trans configuration. In acute hippocampal slices, application of MalAzoCh-C4 produces robust photocontrol of endogenous 7 nAChRs in interneurons, sufficient to modulate action potential firing. This strategy combines nanobody specificity with the temporal resolution of photopharmacology, establishing optonanobodies as a platform for control of native neuronal receptors.

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bioRxiv2025

Dopaminergic mechanisms of dynamical social specialization in mouse microsocieties

Social organization and division of labor are fundamental to animal societies, but how do these structures emerge from individual interactions, and what role does neuromodulation play in shaping them? Using behavioral tracking in a semi-natural environment, neural recordings, and computational models integrating reinforcement and social learning, we show that groups of three isogenic mice spontaneously develop specialized roles while solving a foraging task requiring individual decisions under social constraints. Moreover, these roles are shaped by dopaminergic activity in the ventral tegmental area. Strikingly, despite minor sex-differences in behavior when mice were tested alone, male triads formed stable worker-scrounger relationships driven by competition, whereas female triads adopted uniform, cooperative strategies. Model analysis revealed how intra- and inter-sex parameter differences in resource exploitation, combined with contingent and dynamic social interactions, drive behavioral specialization and labor division. Most notably, it highlighted how contingency, amplified by competition, magnifies individual differences and shapes social profiles. The plastic, adaptive nature of social organization within triads was confirmed by manipulating dopaminergic cell activity, which reshaped social roles and altered group structure. Our findings support a feedback loop where social context shapes neural states, which in turn reinforce behavioral specialization and stabilize social structures.

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bioRxiv2024

Nicotine engages a VTA-NAc feedback loop to inhibit amygdala-projecting dopamine neurons and induce anxiety.

Nicotine activates ventral tegmental area (VTA) dopaminergic (DA) neurons projecting to the nucleus accumbens (NAc) to drive its reinforcing effects. Simultaneously, it inhibits those projecting to the amygdala (Amg) to mediate anxiety through a process that remains unknown. Here we show that NAc- and Amg-projecting DA neurons respond with similar polarities to ethanol and nicotine, suggesting a shared network-based mechanism underlying the inhibitory effect of these otherwise pharmacologically-distinct drugs. Selective activation of NAc-projecting DA neurons, using genetic or optogenetic strategies, produced inhibition of Amg-projecting DA neurons, through a GABAergic feedback loop. Furthermore, optogenetically silencing this feedback loop prevented nicotine from inducing both inhibition of DA neurons and anxiety-like behavior. Therefore, nicotine-induced inhibition of the VTA-Amg DA pathway results from a VTA-NAc inhibitory feedback loop, mediating anxiety.

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bioRxiv2024

Dopamine reveals adaptive learning of actions representation

Flexible decision-making requires not only updating values, but redefining which features constitute an action in a given context. We recorded nucleus accumbens (NAc) dopamine release while mice navigated a three-target intracranial self-stimulation foraging task in which outcomes were evaluated under three distinct reward delivery rules. Despite a constant motor repertoire, dopamine transients reorganized across contingencies and generalized linear models revealed context-dependent dopamine signal reflecting action direction, recent outcome-history, or target identity. Reinforcement-learning model comparison showed that these signatures are best explained by distinct reward prediction errors (RPEs) defined over different state-action representations, rather than a single fixed model-free scheme. A single deep reinforcement-learning agent trained by temporal-difference learning, recapitulated both the rule-specific policies and the corresponding dopamine signature. These results identify NAc dopamine as a dynamic readout of representation learning, remapping prediction errors onto the task features that define successful action as contingencies change.

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bioRxiv2023

Nicotine in adolescence freezes dopamine circuits in an immature state

Nicotine use during adolescence is largely associated with negative long-term outcomes, including addiction to nicotine in adulthood. How nicotine acts on developing neurocircuitry in adolescence remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescence was sufficient for adult mice to show a marked vulnerability to nicotine. Brain-wide activity mapping showed that these mice had an enhanced response to an acute nicotine injection and widespread disruption of functional connectivity in comparison to controls, particularly within dopaminergic networks. Neurophysiological analysis further revealed that their ventral tegmental area (VTA) dopamine neurons show an immature basal plasticity signature and an adolescent-like imbalance in nicotine-induced activity between nucleus accumbens (NAc) and amygdala (AMG)-projecting pathways, known to respectively produce the reinforcing and anxiogenic effects of nicotine. The anxiogenic effect of nicotine is abolished in adult mice treated with nicotine in adolescence, strongly resembling the normal phenotype of young mice. Together these results suggest that nicotine exposure in adolescence somehow "froze" both their neural circuit and behavioral reaction to nicotine, carrying an adolescent-like vulnerability to the drug into adulthood. Finally, we are able to "thaw" the behavioral response to acute nicotine in adolescent-exposed mice by chemogenetically resetting the balance between the underlying NAc- and AMG-projecting dopamine circuits, restoring a mature anxiety-like response to acute nicotine. Together, our results highlight how diverse dopamine pathways can be impacted by experience in adolescence, and further suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies.

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bioRxiv2023

Individual variations in reward-seeking adaptability emerge among isogenic mice living in a micro-society and predict their response to nicotine

Individual animals differ in their traits and preferences, which shape their social interactions, survival, and susceptibility to disease, including addiction. Nicotine use is highly heterogenous, and has been linked to the expression of personality traits. Although these relationships are well-documented, we have limited understanding of the neurophysiological mechanisms that give rise to distinct personalities and their connection to nicotine susceptibility. To address this question, we conducted a study using a semi-natural and social environment called "Souris-City" to observe the long-term behavior of individual mice. Souris-City provided both a communal living area and a separate test area where mice engaged in a reward-seeking task isolated from their peers. Mice developed individualistic reward-seeking strategies when choosing between water and sucrose in the test compartment, which, in turn, predicted how they adapted to the introduction of nicotine as a reinforcer. Moreover, mouse profiles in isolation also extended to correlate with their behavior within the social environment, linking decision-making strategies to the expression of behavioral traits. Neurophysiological markers of adaptability within the dopamine system were apparent upon nicotine challenge, and were associated with specific profiles. Our findings suggest that environmental adaptations influence behavioral traits and sensitivity to nicotine by acting on dopaminergic reactivity in the face of nicotine exposure, potentially contributing to addiction susceptibility. These results further emphasize the importance of understanding inter-individual variability in behavior to gain insight into the mechanisms of decision making and addiction.

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bioRxiv2023

The interpeduncular nucleus blunts the rewarding effect of nicotine

Nicotine, by stimulating ventral tegmental area (VTA) dopaminergic neurons, has a rewarding effect that drives tobacco consumption. In turn, the interpeduncular nucleus (IPN) is thought to become activated at high nicotine doses to restrict drug intake. However, the dynamics of the IPN response to nicotine and its impact on the rewarding effect of the drug remain unknown. To address this issue, we have developed a genetically-modified mouse model, in which a "suicide" antagonist of nicotinic acetylcholine receptors (nAChRs) selectively attaches to a designer {beta}4 nAChR subunit. By locally infusing this antagonist in the IPN, we achieved pharmacologically-specific and sustained antagonism of nAChRs containing the {beta}4 subunit. By combining this chemogenetic method with in vivo electrophysiology, we show that even at low doses, nicotine activates and inhibits two different populations of IPN neurons, and that {beta}4-containing nAChRs are only involved in the activation response. Furthermore, blocking the response to nicotine selectively in the IPN increased both the sensitivity of the VTA to the drug and its rewarding effect in a conditioned place preference paradigm. These findings indicate that the IPN is engaged across a large range of nicotine doses and acts as a regulatory brake on the nicotine reward circuit.

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bioRxiv2022

Dopamine builds and reveals reward-associated latent behavioral attractors

Phasic variations in dopamine levels are interpreted as a teaching signal reinforcing rewarded behaviors. However, behavior also depends on the online, neuromodulatory effect of phasic dopamine signaling. Here, we unravel a new neurodynamical principle that reconciles these roles. In a biophysical recurrent network-based decision architecture, we showed that dopamine-mediated synaptic plasticity stabilized neural assemblies representing rewarded locations as latent, local attractors. Dopamine-modulated synaptic excitability activated these attractors online, and they became accessible as internal goals, even from remote animal positions. We experimentally validated these predictions in mice, using optogenetics, by demonstrating that online dopamine signaling specifically attracts animals toward rewarded locations, without off-target motor effects. We therefore propose that online dopamine signaling reveals potential goals by widening and deepening the basin of dopamine-built attractors representing rewards.

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bioRxiv2022

Self-generation of goal-directed choices in a distributed dopaminergic andprefrontal circuit

Goal-directed choices that are not triggered by external cues arise from internal representations of the outcomes. The use of a stimulus to specify when to act, which option to take, or whether to explore, has led to consider the reward circuit as a feedforward set of modules carrying independent computations. Here, we develop an uncued task in which mice self-determine the initiation, direction, vigor and pace of their actions based on their knowledge of the outcomes. Using electrophysiological recordings, pharmacology and optogenetics, we identify a sequence of oscillations and firing in the ventral tegmental area (VTA), orbitofrontal (OFC) and prefrontal cortices (PFC) that co-encodes and co-determines self-initiation and choices. This sequence appeared with learning as an unguided realignment of spontaneous dynamics. The interactions between the structures depended on the reward context, in particular regarding the uncertainty associated with the different options. We suggest that self-generated choices arise from a distributed circuit based on an OFC-VTA core setting whether to wait or to initiate actions, while the PFC is specifically engaged by reward uncertainty to participate in both the selection and pace of actions. HighlightsO_LISelf-paced actions arise from contextual reorganization of mesocortical dynamics. C_LIO_LIVTA, PFC and OFC complementarily encode predictions and errors about outcomes. C_LIO_LIDistributed firing-then-oscillations dynamics set the goal, initiation and pace of actions. C_LIO_LIVTA and PFC antagonistically promote and inhibit motivation by reward uncertainty. C_LI

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bioRxiv2021

Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus.

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified {beta}4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.

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bioRxiv2021

Chronic nicotine increases midbrain dopamine neuron activity and biases individual strategies towards reduced exploration in a foraging task.

Long-term exposure to nicotine alters brain circuits and induces profound changes in decision-making strategies, affecting behaviors both related and unrelated to drug seeking and consumption. Using an intracranial self-stimulation reward-based foraging task, we investigated the impact of chronic nicotine on the trade-off between exploitation and exploration, and the role of ventral tegmental area (VTA) dopamine (DA) neuron activity in decision-making unrelated to nicotine-seeking. Model-based and archetypal analysis revealed a substantial inter-individual variability in decision-making strategies, with mice passively exposed to chronic nicotine visiting more frequently options associated with higher reward probability and therefore shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of VTA DA neurons using optogenetics, and found that photo-stimulated mice had a behavioral phenotype very close to that of mice exposed to nicotine, suggesting that the dopaminergic control of the exploration/exploitation balance is altered under nicotine exposure. Our results thus reveal a key role of tonic midbrain DA in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects decision-making.

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bioRxiv2020

Distinct dopamine circuits transmit the reinforcing and anxiogenic effects of nicotine

Nicotine, the addictive component of tobacco, stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces negative emotional states such as anxiety, yet through an unknown circuitry. Here we show that nicotine at reinforcing doses drives opposite functional responses on two distinct populations of VTA DA neurons with anatomically segregated projections: it activates those that project to the nucleus accumbens (NAc) while it inhibits those that project to the amygdala nuclei (Amg). We further show that nicotine, by acting on {beta}2 subunit-containing nicotinic acetylcholine receptors of the VTA, mediates both reinforcement and anxiety. Finally, using optogenetic experiments we dissociate the roles of the VTA-NAc excitation and VTA-Amg inhibition in reinforcement and anxiety-like behavior, respectively. We thus propose that the positive and negative behavioral outcomes of nicotine consumption involve distinct subpopulations of VTA DA neurons with opposite responses to nicotine.

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bioRxiv2020

Probing the ionotropic activity of the orphan glutamate delta 2 receptor with genetically-engineered photopharmacology.

Glutamate delta (GluD) receptors belong to the ionotropic glutamate receptor family, yet whether they actually form functional and physiologically-relevant ion channels in neurons remains a debated question. Here we used a chemo-genetic approach to engineer specific and photo-reversible pharmacology in the orphan GluD2 receptor. We incorporated a cysteine mutation in the cavity located above the putative ion channel pore, for site-specific conjugation with a photoswitchable ligand. We first showed that, in the constitutively-open GluD2 Lurcher mutant, current could be rapidly and reversibly decreased with light. We then transposed the cysteine mutation to the native receptor, to demonstrate with absolute pharmacological specificity that metabotropic glutamate receptor signaling opens the GluD2 ion channel in heterologous expression system. Our results assess the functional relevance of GluD2 ion channel and introduce an optogenetic tool that will provide a novel and powerful means for probing GluD2 ionotropic contribution to neuronal physiology.

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bioRxiv2019

Mice adaptively generate choice variability in a deterministic task

Can our choices just be driven by chance? To investigate this question, we designed a deterministic setting in which mice reinforce non-repetitive choice sequences, and modeled it using reinforcement learning. Mice progressively increased their choice variability using a memory-free, pseudo-random selection, rather than by learning complex sequences. Our results demonstrate that a decision-making process can self-generate variability and randomness even when the rules governing reward delivery are not stochastic.

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bioRxiv2018

Somatic nicotinic acetylcholine receptors control the activity of dopamine neurons and reward-related behaviors.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in vivo. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through somatic {beta}2-containing ({beta}2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.

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bioRxiv2017

Social interactions impact on the dopaminergic system and drive individuality

Individuality is a ubiquitous and well-conserved feature among animal species. The behavioral patterns of individual animals affect their respective role in the ecosystem and their prospects for survival. Even though some of the factors shaping individuality have been identified, the mechanisms underlying individuation are poorly understood and are generally considered to be genetics-based. Here we devised a large environment where mice live continuously, and observed that individuality, measured by both social and individual traits, emerged and settled within the group. Midbrain dopamine neurons underwent neurophysiological adaptations that mirrored this phenotypic divergence in individual behaviors. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animals personality and its dopaminergic signature. These results indicate that individuality can rapidly evolve upon social challenges, and does not just depend on the genetic or epigenetic initial status of the animal.

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