Nicotine stimulates ventral tegmental area (VTA) dopaminergic neurons, producing a rewarding effect that drives tobacco consumption. The interpeduncular nucleus (IPN) is thought to become engaged at high nicotine doses to limit drug intake, but its response dynamics are unknown. We developed a chemogenetic approach using a "suicide" antagonist that selectively attaches to designer β4 nicotinic acetylcholine receptors (nAChRs) in genetically modified mice, enabling sustained and pharmacologically specific antagonism. Local infusion in the IPN revealed that nicotine, even at low doses, simultaneously activates and inhibits two distinct populations of IPN neurons, with β4-containing nAChRs mediating only the activation response. Blocking nicotine-induced IPN activation enhanced VTA responses and increased the drug's rewarding effect in a conditioned place preference paradigm. Moreover, optogenetic inhibition of IPN projections to the laterodorsal tegmental nucleus (LDTg) replicated these behavioral effects. Our findings indicate that the IPN acts as a regulatory brake on the nicotine reward circuit via the LDTg.

The mechanisms underlying social organization in mice have predominantly been studied in male colonies, where sociability predicts higher rank and high-ranked individuals show greater anxiety. Here, we demonstrate that groups of isogenic female mice also form stable social hierarchies. Our data indicate that females destined for high rank already exhibit greater sociability and possibly higher anxiety before group formation, and these traits remain consistent afterwards. We further investigated the influence of sex by creating mixed-sex colonies, which revealed a similar hierarchical structure, with both males and females having equal chances of becoming high- or low-ranked. We previously found reduced dopamine neuron activity in high-ranked males; in contrast, high-ranked females show the opposite pattern. Furthermore, while glucocorticoid receptor signaling in dopaminoceptive neurons restricts high rank in males, this effect is absent in females. Overall, these results highlight sex-specific mechanisms that contribute to social ranking and related behavioral traits in mice. ### Competing Interest Statement The authors have declared no competing interest. Fondation pour la Recherche Médicale, DEQ20140329552 Fédération pour la Recherche sur le Cerveau Labex ByoPsy French National Cancer Institute, TABAC-19_020

Nicotine activates ventral tegmental area (VTA) dopaminergic (DA) neurons projecting to the nucleus accumbens (NAc) to drive its reinforcing effects. Simultaneously, nicotine inhibits those projecting to the amygdala (Amg) to mediate anxiety-like behavior through a process that remains unknown. Here, we show that in male mice, 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-like behavior.

Nicotine exposure during adolescence has emerged as a significant risk factor for later psychiatric disease. Notably, adolescence is a critical period for the maturation of acetylcholine and dopamine systems, neuromodulators which tightly regulate cognitive, motivational and emotional behaviors known to contribute to psychiatric vulnerability. This review explores whether long-lasting modifications in these neuromodulatory systems following adolescent nicotine exposure underlie the increased vulnerability to mental health disorders. We discuss evidence that nicotine in adolescence leads to enduring molecular, cellular alterations by perturbing the normal trajectory of cholinergic and dopamine systems, and link these changes with potential adverse behavioral outcomes in adulthood. We propose that persistent alterations in acetylcholine and dopamine signaling caused by adolescent nicotine exposure may contribute to the heightened risk for psychiatric disorders including substance abuse, anxio-depressive disorders, and schizophrenia for which deficits in a large spectrum of motivational domains are highly prevalent. The interaction between nicotine and these developing neurotransmitter systems during adolescence raises important questions about the mechanisms driving these changes. Finally, we discuss limitations in the current research and subsequently identify open questions in the field which will help drive forward research on the psychiatric consequences of adolescent nicotine use. Understanding these maladaptations could pave the way for targeted therapeutic strategies to mitigate the adverse effects of adolescent nicotine exposure on brain development and subsequent psychiatric outcomes.

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. ### Competing Interest Statement The authors have declared no competing interest.

BACKGROUND:Tobacco use significantly impacts reward-driven behavior, leading to comorbidities across a lifetime. While the addictive properties of nicotine are well studied, its effects on cellular mechanisms beyond drug-seeking behaviors remain elusive. Here, we investigated the circuit alterations that parallel drug-related behaviors. METHODS:Male mice were chronically exposed to nicotine in their drinking water for 6 weeks. Then, we combined behavioral measures in operant and non-operant tasks to evaluate changes in motivation while utilizing chemogenetics to selectively modulate cholinergic inputs to the ventral tegmental area (VTA). We combined patch clamp with optogenetics and in vivo electrophysiological recordings to provide a comprehensive cellular analysis of nicotine's impact. Functional assessments were paralleled with high-resolution array tomography to monitor structural adaptations. RESULTS:Chronic nicotine dampened the cholinergic modulation of VTA dopamine neuron activity, leading to an exaggerated motivation for food reward seeking. Selective chemogenetic enhancement of cholinergic tone from the laterodorsal tegmentum (LDT) to the VTA restored normal motivational control, while silencing of this projection triggered the opposite effect. We reveal structural and functional deficits in the synaptic integration of excitatory inputs from the lateral habenula (LHb) onto LDT cholinergic neurons projecting to the VTA that correlate with observed behavioral alterations. We identify specific cellular and synaptic changes that underlie nicotine-induced dysregulation of motivation. CONCLUSIONS:Chronic nicotine consumption alters motivation for natural rewards by disrupting top-down control of the LHb onto the LDT-VTA cholinergic axis. Our work highlights previously unrecognized contributors to nicotine's impact on mental health.

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 behavioral profiles 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 male 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, the profiles mice developed while isolated in the test area correlated 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 interindividual variability in behavior to gain insight into the mechanisms of decision-making and addiction.

Efficient decision-making requires two key processes: learning values from actions and identifying a set of relevant actions to learn from in a given context. While dopamine (DA) is a well-known substrate for signaling reward prediction errors (RPEs) from selected actions to adjust behavior, the process of establishing and switching between action representations is still poorly understood. To address this gap, we used fiber photometry and computational modelling in a three-armed bandit task where mice learned to seek rewards delivered through three successive rule sets, displaying distinct strategies in each rule. We show that DA dynamically reflected RPEs computed from different task features, revealing context-specific internal representations. Our findings demonstrate that mice not only learned and updated action values but also action representations, adapting the features from which they learn across rules for flexible adjustment of their decision strategy. ### Competing Interest Statement The authors have declared no competing interest.

Salience attributed to stimuli predicting rewarding or aversive outcomes is critical for adaptive behavior. Dopamine (DA)-neurons play a central role in this process by modulating responses to both rewarding and aversive cues. DA-neurons are tightly and readily modulated by DA D2 autoreceptors (autoD2Rs), but their role in regulating responses to aversive stimuli remains unclear. In this study, we investigated the role of autoD2R in regulating the activity of VTA DA-neurons in response to salient aversive stimuli. Using Drd2Slc6a3 mice, in which Drd2 is selectively deleted in DA-neurons, we observed enhanced excitatory and inhibitory responses of VTA DA-neurons to aversive stimuli, suggesting that autoD2R acts as a critical regulatory brake. Importantly, this modulation occurred independently of either the pacemaker activity of DA-neurons or their coupling to the non-selective sodium leak channel NALCN. Behaviorally, Drd2Slc6a3 male mice showed enhanced discrimination between threat-predicting and non-predicting cues that persisted during extinction learning, highlighting a sex-biased role of autoD2R in threat processing. Our results provide new mechanistic insights through which autoD2R influence behavioral responses to aversive stimuli, with implications for understanding neuropsychiatric disorders characterized by maladaptive threat processing. ### Competing Interest Statement The authors have declared no competing interest.

Phasic variations in dopamine levels are interpreted as a teaching signal reinforcing rewarded behaviors. However, behavior also depends on the motivational, neuromodulatory effect of phasic dopamine. In this study, we reveal a neurodynamical principle that unifies these roles in a recurrent network-based decision architecture embodied through an action-perception loop with the task space, the MAGNet model. Dopamine optogenetic conditioning in mice was accounted for by an embodied network model in which attractors encode internal goals. Dopamine-dependent synaptic plasticity created "latent" attractors, to which dynamics converged, but only locally. Attractor basins were widened by dopamine-modulated synaptic excitability, rendering goals accessible globally, i.e. from distal positions. We validated these predictions optogenetically in mice: dopamine neuromodulation suddenly and specifically attracted animals toward rewarded locations, without off-target motor effects. We thus propose that motivational dopamine reveals dopamine-built attractors representing potential goals in a behavioral landscape. The reason why manipulating dopamine (DA) activity can affect both action latency, action direction, and movement vigor, but only in certain animal states and behavioral settings is not fully understood. Here, the authors propose that DA signaling builds and reveals latent attractors representing potential goals. They validate their model predictions: activation of dopamine neurons exerts context- and state-dependent effects on mouse movements.

BACKGROUND:Social status in humans, generally reflected by socioeconomic status, has been associated, when constrained, with heightened vulnerability to pathologies including psychiatric diseases. Social hierarchy in mice translates into individual and interdependent behavioral strategies of animals within a group. The rules leading to the emergence of a social organization are elusive, and detangling the contribution of social status from other factors, whether environmental or genetic, to normal and pathological behaviors remains challenging.METHODS:We investigated the mechanisms shaping the emergence of a social hierarchy in isogenic C57BL/6 mice raised in groups of 4 using conditional mutant mouse models and chemogenetic manipulation of dopamine midbrain neuronal activity. We further studied the evolution of behavioral traits and the vulnerability to psychopathological-like phenotypes according to the social status of the animals.RESULTS:Higher sociability predetermined higher social hierarchy in the colony. Upon hierarchy establishment, higher-ranked mice showed increased anxiety and better cognitive abilities in a working memory task. Strikingly, the higher-ranked mice displayed a reduced activity of dopaminergic neurons within the ventral tegmental area, paired with a decreased behavioral response to cocaine and a decreased vulnerability to depressive-like behaviors following repeated social defeats. The pharmacogenetic inhibition of this neuronal population and the genetic inactivation of glucocorticoid receptor signaling in dopamine-sensing brain areas that resulted in decreased dopaminergic activity promoted accession to higher social ranks.CONCLUSIONS:Dopamine activity and its modulation by the stress response shapes social organization in mice, potentially linking interindividual and social status differences in vulnerability to psychopathologies.

How nicotine acts on developing neurocircuitry in adolescence to promote later addiction vulnerability remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescent (PND 21-28) male mice was sufficient to produce a marked vulnerability to nicotine in adulthood (PND 60 + ), associated with disrupted functional connectivity in dopaminergic circuits. These mice showed persistent adolescent-like behavioral and physiological responses to nicotine, suggesting that nicotine exposure in adolescence prolongs an immature, imbalanced state in the function of these circuits. Chemogenetically resetting the balance between the underlying dopamine circuits unmasked the mature behavioral response to acute nicotine in adolescent-exposed mice. Together, our results suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies. How nicotine impacts the adolescent development of neural circuitry is not fully understood. Here authors show that early adolescent nicotine exposure in male mice blocked the maturation of nicotine-evoked dopamine signaling, causing an immature, vulnerable behavioral response in adult mice. Restoring their adult-like nicotine-evoked signaling unmasks a mature behavioral response in male mice.

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 considerable heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in nicotine consumption 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 β4-containing nicotinic acetylcholine receptors of IPN neurons as molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate for individual variabilities and adaptations in nicotine consumption.

The neural mechanisms by which animals initiate goal-directed actions, choose between options, or explore opportunities remain unknown. Here, we develop a spatial gambling task in which mice, to obtain intracranial self-stimulation rewards, 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 firings in the ventral tegmental area (VTA), orbitofrontal cortex (OFC), and prefrontal cortex (PFC) that co-encodes and co-determines self-initiation and choices. This sequence appeared with learning as an uncued realignment of spontaneous dynamics. Interactions between the structures varied with the reward context, particularly the uncertainty associated with the different options. We suggest that self-generated choices arise from a distributed circuit based on an OFC-VTA core determining whether to wait for or initiate actions, while the PFC is specifically engaged by reward uncertainty in action selection and pace.

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.

Individuals differ in their traits and preferences, which shape their interactions, their prospects for survival and their susceptibility to diseases. These correlations are well documented, yet the neurophysiological mechanisms underlying the emergence of distinct personalities and their relation to vulnerability to diseases are poorly understood. Social ties, in particular, are thought to be major modulators of personality traits and psychiatric vulnerability, yet the majority of neuroscience studies are performed on rodents in socially impoverished conditions. Rodent micro-society paradigms are therefore key experimental paradigms to understand how social life generates diversity by shaping individual traits. Dopamine circuitry is implicated at the interface between social life experiences, the expression of essential traits, and the emergence of pathologies, thus proving a possible mechanism to link these three concepts at a neuromodulatory level. Evaluating inter-individual variability in automated social testing environments shows great promise for improving our understanding of the link between social life, personality, and precision psychiatry - as well as elucidating the underlying neurophysiological mechanisms.

Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

Within the peripheral olfactory process, odorant metabolizing enzymes are involved in the active biotransformation of odorants, thus influencing the intensity and quality of the signal, but little evidence exists in humans. Here, we characterized the fast nasal metabolism of the food aroma pentane-2,3-dione in vivo and identified two resulting metabolites in the nasal-exhaled air, supporting the metabolizing role of the dicarbonyl/l-xylulose reductase. We showed in vitro, using the recombinant enzyme, that pentane-2,3-dione metabolism was inhibited by a second odorant (e.g., butanoic acid) according to an odorant-odorant competitive metabolic mechanism. Hypothesizing that such mechanism exists in vivo, pentane-2,3-dione, presented with a competitive odorant, both at subthreshold concentrations, was actually significantly perceived, suggesting an increase in its nasal availability. Our results, suggesting that odorant metabolizing enzymes can balance the relative detection of odorants in a mixture, in turn influencing the intensity of the signal, should be considered to better manage flavor perception in food.

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 in mice the impact of chronic nicotine on midbrain dopamine neuron activity and its consequence on the trade-off between exploitation and exploration. Model-based and archetypal analysis revealed substantial inter-individual variability in decision-making strategies, with mice passively exposed to nicotine shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of dopamine neurons using optogenetics, and found that photo-stimulated mice adopted a behavioral phenotype similar to that of mice exposed to chronic nicotine. Our results reveal a key role of tonic midbrain dopamine in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects the exploration/exploitation balance and decision-making.