Biology subjects

Mondoloni, S.

Publications and source records attributed to Mondoloni, S..

10 recordsLinked to original sources

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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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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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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