The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the ␤2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different ␣ subunit partners of ␤2 (i.e., ␣4 and ␣6), the homo-pentameric ␣7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 g free base/kg/inf) selfadministration was investigated with drug-naive mice deleted (KO) for the ␤2, ␣4, ␣6 and ␣7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, ␤2-VEC mice with the ␤2 subunit re-expressed exclusively in the VTA, ␣4-VEC mice with selective ␣4 re-expression in the VTA, ␣6-VEC mice with selective ␣6 re-expression in the VTA, and ␣7-KO mice promptly self-administer nicotine intravenously, whereas ␤2-KO, ␤2-VEC in the substantia nigra, ␣4-KO and ␣6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of ␣4␤2-and ␣6␤2-subunit containing nicotinic receptors (␣4␤2*-and ␣6␤2*-nAChRs), but not ␣7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

Cholinergic neurotransmission affects decision-making, notably through the modulation of perceptual processing in the cortex. In addition, acetylcholine acts on value-based decisions through as yet unknown mechanisms. We found that nicotinic acetylcholine receptors (nAChRs) expressed in the ventral tegmental area (VTA) are involved in the translation of expected uncertainty into motivational value. We developed a multi-armed bandit task for mice with three locations, each associated with a different reward probability. We found that mice lacking the nAChR β2 subunit showed less uncertainty-seeking than their wild-type counterparts. Using model-based analysis, we found that reward uncertainty motivated wild-type mice, but not mice lacking the nAChR β2 subunit. Selective re-expression of the β2 subunit in the VTA was sufficient to restore spontaneous bursting activity in dopamine neurons and uncertainty-seeking. Our results reveal an unanticipated role for subcortical nAChRs in motivation induced by expected uncertainty and provide a parsimonious account for a wealth of behaviors related to nAChRs in the VTA expressing the β2 subunit.

Background-Modulation of midbrain dopamine neurons by nicotinic acetylcholine receptors (nAChRs) plays an important role in behavior, cognition, motivation and reward. Specifically, nAChRs containing β2 subunits (β2-nAChRs) switch dopamine cells from a resting to an excited state. However, how β2-nAChRs can be modulated and thereby dopamine firing activity be affected is still elusive. Because changes in dopamine cell activity are reflected in the dynamics of micro-circuits generating altered responses to stimuli/inputs, factors regulating their state are fundamental. Among these, endogenous ligands to the nuclear receptor-transcription factor peroxisome proliferator-activated receptors type-alpha (PPARα) have been recently found to suppress nicotine-induced responses of dopamine neurons.

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Individuality is a striking feature of animal behavior. Individual animals differ in traits and preferences which shape their interactions and their prospects for survival. However, the mechanisms underlying behavioral individuation are poorly understood and are generally considered to be genetic-based. Here, we devised a large environment, Souris City, in which mice live continuously in large groups. We observed the emergence of individual differences in social behavior, activity levels, and cognitive traits, even though the animals had low genetic diversity (inbred C57BL/6J strain). We further show that the phenotypic divergence in individual behaviors was mirrored by developing differences in midbrain dopamine neuron firing properties. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animal’s traits and its dopamine firing pattern. Individuality can rapidly change upon social challenges, and does not just depend on the genetic status or the accumulation of small differences throughout development.

Author's contributions CB designed, performed and analyzed most of the experiments. EM performed transcriptomic meta-analyses, behavioral and molecular studies. EP, MDM, MM, SP, SLa, XF, LV performed and analyzed ex vivo patch-clamp electrophysiology. DS, YN, MB, XSD performed human studies and data analysis. ST, FM and PF performed and analyzed in vivo electrophysiology recordings. MAS performed the RNAscope and lipidomics studies. JC helped with surgery and behavioral procedures. CMo helped performing western blots and dissections. CMa designed and performed doppler imaging and fiber photometry experiments. MCad and SC designed and performed self-administration experiments. JHS and CBJ performed the iDISCO analysis. MHT, GG, TSH and SL secured funding. TSH and DS provided scientific guidance and experimental design. SL and GG supervised the whole project, interpreted the data and wrote the manuscript with contribution from all coauthors.

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