Biology subjects

Belin, D.

Publications and source records attributed to Belin, D..

18 recordsLinked to original sources

bioRxiv2026

Serial, as opposed to parallel, insular-prefrontal cortex processing determines the tendency to make risky decisions

Adaptive decision-making under ambiguity requires constant integration of reward- and loss-related information to guide behaviour. In humans and rodents, not all individuals maximise gains in decision-making tasks, such as the Iowa Gambling task or its rodent version, the Rat Gambling task (rGT). While the prefrontal and insular cortices have each been shown independently to support optimal probabilistic decision-making, how they interact functionally to shape individual differences in performance remains unclear. Here, we investigated the consequences of bilateral baclofen/muscimol-mediated inactivation of the prelimbic cortex (PLC) or the anterior insular cortex (AIC) vs. their functional disconnection on the performance of Sprague Dawley rats identified as safe (SDMs) or risky decision makers (RDMs) in the RGT. AIC inhibition decreased advantageous choice in SDMs, whereas it increased win-stay responding in RDMs. In contrast, PLC inhibition primarily affected lose-shift behaviour, reducing sensitivity to losses in SDMs while enhancing adaptive switching in RDMs. Functionally disconnecting the PLC from the AIC, which had no effect on the performance of SDMs, improved decision-making in RDMs by increasing loss-guided behavioural adaptation. Together, these findings identify parallel versus serial AIC-PLC processing as a potential neural mechanism underlying the tendency some individuals have to make suboptimal decisions.

neuroscience↗

bioRxiv2026

Predator avoidance promotes inter-bacterial symbiosis with myxobacteria in polymicrobial communities

Myxobacteria are predatory soil bacteria with the largest known bacterial genomes, rich in biosynthetic gene clusters for specialized metabolites. Despite their ecological importance as potential keystone taxa in soil food webs, there is a disconnect between laboratory-isolated myxobacteria and abundant Myxococcota detected in environmental metagenomic studies. Here, we report the isolation and characterization of stable myxobacterial swarm consortia from rhizospheric soil, consisting of myxobacteria associated with novel Microvirga species. Using metagenomic sequencing, we assembled metagenome-assembled genomes (MAGs) for four consortia, revealing phylogenetically distinct yet stably associated bacterial partnerships. Comparative genomics identified evidence of horizontal gene transfer, including acyl-homoserine lactone (AHL) synthases and ankyrin repeat (ANKYR) proteins shared between consortium members, and genome-scale metabolic modeling predicted complementary auxotrophies. Remarkably, time-lapse microscopy revealed that Archangium exhibited markedly reduced predation toward its Microvirga companion (0.7% predation rate) compared to non-symbiotic Myxococcus xanthus (14.9% predation rate), while maintaining robust predatory capacity against Escherichia coli prey. These findings indicate that predation avoidance and metabolic complementarity can drive stable inter-bacterial symbiosis in predatory myxobacterial communities, providing foundational insights into previously overlooked myxobacterial partnerships that may be prevalent in natural soil ecosystems.

microbiology↗

bioRxiv2025

The spike tip protein of bacteriophage T4

Contractile injection systems (CISs) - bacteriophage tails, tailocins, and bacterial type VI secretion systems - penetrate the envelope of the target cell by employing a contractile sheath-rigid tube mechanism. The membrane-attacking end of the tube carries a spike-shaped complex that ends with a spike tip. In bacteriophage P2, the spike and spike tip proteins are fused, and we used this phage to show that sheath contraction results in the translocation of the spike into the periplasm of the host cell. In bacteriophage T4, the spike and spike tip proteins are encoded by different genes. We show that the ORFan gene 5.4 codes for the spike tip protein of bacteriophage T4. Using an amber nonsense mutation, we show that the gp5.4 protein is dispensable for bacteriophage T4 particle assembly but essential for bacteriophage fitness and infection of bacteria with truncated lipopolysaccharides.

molecular biology↗

bioRxiv2024

Compulsion derived from incentive cocaine-seeking habits is associated with a downregulation of the dopamine transporter in striatal astrocytes

The development of compulsive cue-controlled -incentive- drug-seeking habits, a hallmark of substance use disorder, is predicated on an intrastriatal shift in the locus of control over behaviour from a nucleus accumbens (Nac) core - dorsomedial striatum network to a Nac core - anterior dorsolateral striatum (aDLS) network. Such shift parallels striatal adaptations to chronic drug, including cocaine self-administration, marked by dopamine transporter (DAT) alterations originating in the ventral striatum that spread eventually to encompass the aDLS. Having recently shown that heroin self-administration results in a pan-striatal reduction in astrocytic DAT that precedes the development of aDLS dopamine-dependent incentive heroin-seeking habits we tested the hypothesis that similar adaptations occurr following cocaine exposure. We compared DAT protein levels in whole tissue homogenates, and astrocytes cultured from ventral and dorsal striatal territories of drug naive male Sprague Dawley rats to those of rats with a history of cocaine-taking or an aDLS dopamine-dependent incentive cocaine-seeking habit. Cocaine exposure resulted in a decrease in whole tissue and astrocytic DAT across all territories of the striatum. We further demonstrated that compulsive, i.e., punishment-resistant, incentive cocaine-seeking habits were associated with a reduction in DAT mRNA levels in the Nac shell, but not the Nac core-aDLS incentive habit system. Together with the recent evidence of heroin-induced downregulation of striatal astrocytic DAT, these findings suggest that alterations in astrocytic DAT may represent a common mechanism underlying the development of compulsive incentive drug-seeking habits across drug classes.

neuroscience↗

bioRxiv2024

Noradrenergic and Pavlovian underpinnings of compulsive versus adaptive coping strategies

BackgroundLoss of control over coping strategies can result in the development of impulsive/compulsive spectrum disorders (ICSDs) such as obsessive-compulsive disorder or trichotillomania. Rats, like humans, show individual differences in their tendency to engage in and maintain control over coping behaviours. While most rats exposed to a schedule-induced polydipsia (SIP) procedure develop controlled, moderate, polydipsic coping, some vulnerable individuals engage in excessive, compulsive drinking, or hyperdipsia. The development of hyperdipsia depends in part on noradrenergic mechanisms, as it is prevented by the noradrenaline reuptake inhibitor, atomoxetine in highly impulsive vulnerable rats. However, whether noradrenergic mechanisms also underlie the expression of well-established hyperdipsia, or if other traits, such as the ICSD-relevant sign-tracking, confer vulnerability to its development, are unknown. MethodsIn two longitudinal studies in male Sprague-Dawley rats, we investigated whether well-established hyperdipsia is influenced by atomoxetine and whether its development is predicted by sign-tracking. ResultsSign-tracking was associated with faster acquisition of SIP and the development of high or compulsive levels of SIP. Chronic atomoxetine both exacerbated hyperdipsia and increased the mRNA levels of the markers of cellular activity and plasticity c-fos and zif268, across the dorsal striatum, as revealed by qPCR assays. Atomoxetine also altered the transcriptomic landscape of the nucleus accumbens shell and the pattern of cFos and zif268 expression in the amygdalo-striatal system. ConclusionsThese results provide new insight into the biobehavioural basis of compulsive behaviours, revealing a differential noradrenergic control of the development and expression of compulsive coping, the latter involving recruitment of distinct striatal processes.

animal behavior and cognition↗

bioRxiv2023

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modelling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

neuroscience↗

bioRxiv2022

Neurobehavioral precursors of compulsive cocaine-seeking in dual fronto-striatal circuits

Only some individuals using drugs recreationally eventually become addicted, and persist in drug seeking and taking despite adverse consequences. The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. We report that in drug naive rats the future tendency to develop compulsive cocaine seeking is characterised by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula and nucleus accumbens. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.

neuroscience↗

bioRxiv2022

The development of compulsive coping behaviors depends on the engagement of dorsolateral striatum dopamine-dependent mechanisms

Humans greatly differ in how they cope with stress, a natural behavior learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduces distress. Some individuals, in particular those that use alcohol to self-medicate, tend to lose control over such coping behaviors, which become excessive and compulsive. However, the psychological and neural mechanisms underlying this individual vulnerability have not been elucidated. Here we tested the hypothesis that the development of compulsive adjunctive behaviors stems from the functional engagement of the dorsolateral striatum (DLS) dopamine-dependent habit system after a prolonged history of adjunctive responding. We measured in longitudinal studies in male Sprague Dawley rats the sensitivity of early established vs compulsive polydipsic water or alcohol drinking to a bilateral infusion of the dopamine receptor antagonist -flupentixol into the anterior DLS (aDLS). While most rats acquired a polydipsic drinking response with water, others only did so with alcohol. Whether reliant on water or alcohol, the acquisition of this coping response was insensitive to aDLS dopamine receptor blockade. In contrast, after prolonged experience, adjunctive drinking became dependent on the aDLS dopamine-dependent habit system at a time it was compulsive in vulnerable individuals. These data suggest that habits may develop out of negative reinforcement and that the engagement of their underlying striatal system is necessary for the manifestation of adjunctive behaviors. Significance statementHarnessing the individual variability that rodents, like humans, show to engage in adaptive or maladaptive coping strategies, which can result in the development of compulsive disorders, here we demonstrate that the functional engagement of the dorsolateral striatum-dependent habit system precipitates the transition to compulsion in rats that have acquired a polydipsic adjunctive drinking response with water or alcohol as a means to cope with distress. The results of this study not only provide evidence for the emergence of instrumental habits under negative reinforcement, but they also reveal that compulsive behaviors that originate from the loss of control over coping strategies are mediated by the dorsolateral striatum-dependent habit system.

neuroscience↗

bioRxiv2022

The individual vulnerability to develop compulsive adjunctive behavior is associated with the recruitment of activity-regulated cytoskeleton-associated protein (Arc) within the Locus Coeruleus

Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviors and their ensuing compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline dependent system in stress and related excessive behaviors, we hypothesised that neuroplastic changes in the LC may be involved in the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behavior, and the subsequent development of compulsion in vulnerable individuals. Thus, male Sprague Dawley rats were characterised for their tendency, or not, to develop compulsive polydipsic drinking in a schedule-induced polydipsia (SIP) procedure before their fresh brains were harvested. A new quantification tool for RNAscope assays revealed that the development of compulsive adjunctive behavior was associated with a low mRNA copy number of the plasticity marker Arc in the LC which appeared to be driven by specific adaptations in an ensemble of tyrosine hydroxylase (TH)+, zif268-neurons. This ensemble was specifically engaged by the expression of compulsive adjunctive behavior, not by stress, because its functional recruitment was not observed in individuals that no longer had access to the water bottle before sacrifice while it consistently correlated with the levels of polydipsic water drinking only when it had become compulsive. Together these findings suggest that downregulation of Arc mRNA levels in a population of a TH+zif268-LC neurons represents a signature of the tendency to develop compulsive coping behaviors.

neuroscience↗

bioRxiv2022

Electrophysiological signature of the interplay between habits and inhibition in response to smoking-related cues in individuals with a smoking habit: an ERP study

The rigid, stimulus-bound nature of drug seeking that characterizes Substance-use disorder (SUD) has been related to a dysregulation of motivational and early attentional reflexive and inhibitory reflective systems. However, the mechanisms by which these systems are engaged by drug-paired conditioned stimuli CSs) when they promote the enactment of seeking habits in individuals with a SUD have not been elucidated. The present study aimed behaviorally and electrophysiologically to characterize the nature of the interaction between the reflexive and reflective systems recruited by CSs in individuals with a smoking habit. For this, we measured the behavioral performance and associated ERPs of 20 individuals with a smoking habit and 20 controls, who never smoked regularly, in a modified Go/NoGo task during which smoking-related CSs, appetitive, and neutral pictures, presented either in first-person or as a third-person visual perspective were displayed 250 ms before the Go/NoGo cue. We show that smoking-related cues selectively influence early incentive motivation-related attentional bias (N2 after picture onset), motor readiness and behavioral inhibition (Go-P3, NoGo-P3 and Pc) of individuals with a smoking habit only when presented from a first-person perspective. These data together identify the neural signature of the aberrant engagement of the reflexive and reflective systems during the recruitment of an incentive habit by CSs presented as if they had been response-produced, i.e., as conditioned reinforcers.

neuroscience↗

bioRxiv2021

Addicted or not? A new machine learning-assisted tool for the diagnosis of addiction-like behavior in individual rats

BackgroundOver the last few decades there is a progressive transition from a categorical to a dimensional approach to psychiatric disorders. Especially in case of substance use disorders, the increased interest in the individual vulnerability to transition from controlled to compulsive drug seeking and taking warrants the development of novel dimension-based objective diagnostic or stratification tools. Here we drew on a multidimensional preclinical model of addiction, namely the 3-criteria model, previously developed to identify the neurobehavioural basis of the individual vulnerability to switch from control to compulsive drug taking, to test the potential interest of a machine-learning assisted classifier objectively to identify individual subjects as vulnerable or resistant to addiction. MethodsLarge behavioural datasets from several of our previous studies on addiction-like behaviour for cocaine or alcohol were fed to a variety of machine-learning algorithms (each consisting of an unsupervised-clustering method combined with a supervised-prediction algorithm) to develop a classifier that identifies resilient and vulnerable rats with high precision and reproducibility irrespective of the cohort to which they belong. ResultsA classifier based on K-median or K-mean-clustering (for cocaine or alcohol, respectively) followed by Artificial Neural Networks emerged as a highly reliable and accurate tool to predict if a single rat is vulnerable or resilient to addiction. Thus, each of the rats previously characterized as displaying 0 criterion (i.e., resilient) or 3 criteria (i.e., vulnerable) in individual cohorts were correctly labelled by this classifier. ConclusionThe present machine-learning-based classifier objectively labels single individuals as resilient or vulnerable to develop addiction-like behaviour in multisymptomatic preclinical models of cocaine or alcohol addiction-like behaviour in rats. This novel dimension-based classifier thereby increases the heuristic value and generalizability of these preclinical models while providing proof of principle for the deployment of similar tools for the future of diagnosis of psychiatric disorders.

neuroscience↗

bioRxiv2021

Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats.

The inflexible pursuit of drug-seeking and great tendency to relapse that characterize addiction has been associated with the recruitment of the dorsolateral striatum-dependent habit system. However, the mechanisms by which maladaptive drug-seeking habits influence subsequent relapse are obscure. Here, we show that rats with a long history of cocaine-seeking, controlled by drug-paired cues and mediated by the habit system, show highly exacerbated drug-seeking at relapse that is not mediated by cocaine withdrawal. This heightened tendency to relapse is underpinned by transient engagement of the dorsomedial striatum goal-directed system and reflects emergent negative urgency resulting from the prevention of enacting the seeking habit during abstinence. These results reveal a novel mechanism underlying the pressure to relapse and indicate a target for preventing it. One Sentence SummaryInstrumental deprivation triggers flexibility in the well-established cue-controlled cocaine-seeking behaviour.

neuroscience↗

bioRxiv2020

Individual differences in the engagement of habitual control over alcohol seeking predicts the development of compulsive alcoholseeking and drinking

Excessive drinking is an important behavioural characteristic of alcohol addiction, but not the only one. Individuals addicted to alcohol crave alcoholic beverages, spend time seeking alcohol despite negative consequences, and eventually drink to intoxication. With prolonged use, control over alcohol seeking devolves to anterior dorsolateral striatum, dopamine-dependent mechanisms implicated in habit learning and individuals in whom alcohol-seeking relies more on these mechanisms are more likely to persist in seeking alcohol despite the risk of punishment. Here, we tested the hypothesis that the development of habitual alcohol-seeking predicts the development of compulsive seeking and that, once developed, it is associated with compulsive alcohol drinking. Male alcohol-preferring rats were pre-exposed intermittently to a two-bottle choice procedure, and trained on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed punishment-resistant seeking behaviour. The associative basis of their seeking responses was probed with an outcome-devaluation procedure, early or late in training. After seeking behaviour was well established, subjects that had developed greater resistance to outcome-devaluation (were more habitual) were more likely to show punishment-resistant (compulsive) alcohol seeking. These individuals also drank more alcohol, despite quinine adulteration, even though having similar alcohol preference and intake before and during instrumental training. They were also less sensitive to changes in the contingency between seeking responses and alcohol outcome, providing further evidence of recruitment of the habit system. We therefore provide direct behavioural evidence that compulsive alcohol seeking emerges alongside compulsive drinking in individuals that have preferentially engaged the habit system.

neuroscience↗

bioRxiv2020

AraC mutations that suppress inactivating mutations in the C-terminal domain of the RpoA subunit of Escherichia coli RNA polymerase

In E. coli, transcriptional activation is often mediated by the C-terminal domain of RpoA, the subunit of RNA polymerase. Mutations that prevent activation of the arabinose PBAD promoter are clustered in a small region of the -CTD domain around K271. To determine the target(s) of RpoA in the PBAD promoter, we have isolated suppressors of rpoA -CTD mutations. The suppressors map to the N-terminal domain of AraC, the main transcriptional regulator of ara gene expression. No mutation was found in the large DNA regulatory region between araC and PBAD, suggesting that, in this system, RpoA does not activate transcription through its direct DNA binding. One class of araC mutations result in substitutions in the core of the N-terminal domain suggesting that they may affect its conformation. Another class of suppressors define genetically a domain that potentially interacts with the C-terminal domain of RpoA. Surprisingly, in rpoA+ strains lacking CRP, the araC mutations largely restore arabinose gene expression, suggesting that they somehow strengthen the AraC:-CTD interaction. Thus, the N-terminal domain of AraC exhibits at least three activities: dimerization, arabinose binding and transcriptional activation via RpoA. ImportanceGene expression is most often controlled at the level of transcription by regulators that interact with RNA polymerase. The C-terminal domain of Escherichia coli RpoA is attached to the core enzyme by a flexible linker and serves as a hub that interacts with many regulators and even with DNA sites to activate transcription. Mutations in a RpoA subdomain interfere with activation of the main arabinose promoter by AraC, the regulator that either activates or represses expression of the arabinose operons. We define here genetically the target of RpoA in the main arabinose promoter. Suppressors of most RpoA mutations map to the N-terminal domain of AraC that promotes its dimerization and binds to arabinose, the inducer. Thus, our results identify a third function for this AraC domain. Some suppressors define a potential binding site for RpoA, while others, at internal residues, probably affect the conformation of the AraC domain.

molecular biology↗

bioRxiv2020

Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala

While most individuals with access to alcohol drink it recreationally, about 5 % lose control over their intake and progressively develop an alcohol use disorder (AUD), characterised by compulsive alcohol drinking accompanied by decreased interest in alternative sources of reinforcement. The neural and molecular mechanisms underlying the vulnerability to switch from controlled to compulsive alcohol intake have not been fully characterized, so limiting the development of new treatments for AUD. It has recently been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking. Here, we tested the hypothesis that the GABAB receptor agonist baclofen, which decreases GABA release, specifically decreases compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration or the availability of an alternative ingestive reinforcer, saccharin. In these rats, that were characterised by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala represent an endophenotype of AUD and that the associated compulsive alcohol drinking characteristic is sensitive to baclofen.

neuroscience↗

bioRxiv2020

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse

The anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex since in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a state-dependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects. Thus, we investigated in outbred rats the effects of bilateral excitotoxic lesions of AIC, induced both prior to or after long-term exposure to extended access heroin self-administration, on the development and maintenance of escalated heroin intake and the subsequent vulnerability to relapse following abstinence. Compared to sham-surgeries, pre-exposure AIC lesions had no effect on the development of loss of control over heroin intake, but lesions made after a history of escalated heroin intake potentiated escalation and also enhanced responding at relapse. These data show that the AIC inhibits or limits the loss of control over heroin intake and propensity to relapse, in marked contrast to its influence on the loss of control over cocaine intake.

neuroscience↗

bioRxiv2020

The Basolateral amygdala --> Nucleus Accumbens core circuit mediates the conditioned reinforcing effects of cocaine-paired cues on cocaine seeking.

Individuals addicted to cocaine spend much of their time foraging for the drug. Pavlovian drug-associated conditioned stimuli exert a major influence on the initiation and maintenance of drug seeking often long into abstinence, especially when presented response-contingently, acting as conditioned reinforcers that bridge delays to drug use. The acquisition of cue-controlled cocaine seeking has been shown to depend on functional interactions between the basolateral amygdala (BLA) and the core of the nucleus accumbens (NAcC). However, the precise neuronal circuits underlying the acquisition of cue-controlled cocaine seeking behaviour have not been elucidated. Here we used a projection-specific Cre-dependent DREADD-mediated causal approach to test the hypothesis that the direct projections from the BLA to the NAcC are required for the acquisition of cue-controlled cocaine seeking behaviour. In Sprague Dawley rats with cre-mediated expression of the inhibitory DREADD Hm4Di in the NAcC projecting BLA neurons, treatment with CNO, but not vehicle, selectively prevented the impact of cocaine-associated conditioned reinforcement on cocaine seeking under a second-order schedule of reinforcement. This effect was attributable to the chemogenetic inhibition of the NAcC projecting BLA neurons as it was reversible, and absent in CNO-treated rats expressing an empty control virus. In contrast, chemogenetic inhibition of the anterior insula, which receives collateral projections from NAcC projecting BLA neurons, was without effect. These data demonstrate that the acquisition of cue-controlled cocaine seeking that depends on the conditioned reinforcing effects of cocaine cues require activity in the direct projections from the basolateral amygdala to the nucleus accumbens core.

neuroscience↗

bioRxiv2020

Environment-dependent behavioral traits and experiential factors shape addiction vulnerability

The transition from controlled drug use to drug addiction depends on an interaction between a vulnerable individual, their environment and a drug. Here we tested the hypothesis that conditions under which individuals live influence behavioral vulnerability traits and experiential factors operating in the drug taking environment to determine the vulnerability to addiction. The role of behavioural vulnerability traits in mediating the influence of housing conditions on the tendency to acquire cocaine self-administration was characterised in 48 rats housed in either an enriched (EE) or a standard (SE) environment. Then, the influence of these housing conditions on the individual vulnerability to develop addiction-like behaviour for cocaine or alcohol was measured in 72 EE or SE rats after several months of cocaine self-administration or intermittent alcohol drinking, respectively. The determining role of negative experiential factors in the drug taking context was further investigated in 48 SE rats that acquired alcohol drinking as a self-medication strategy. The environment influenced the acquisition of drug intake through its effect on behavioral markers of resilience to addiction. In contrast, the initiation of drug taking as a coping strategy or in a negative state occasioned by the contrast between enriched housing conditions and a relatively impoverished drug taking setting, facilitated the development of compulsive cocaine and alcohol intake. These data demonstrate that addiction vulnerability depends on environmentally determined experiential factors, suggesting that initiating drug use through negative reinforcement-based self-medication facilitates the development of addiction in vulnerable individuals. Significance StatementThe factors that underlie an individuals vulnerability to switch from controlled, recreational drug use to addiction are not well understood. We showed that in individuals housed in enriched conditions, the experience of drugs in the relative social and sensory impoverishment of the drug taking context, and the associated change in behavioural traits of resilience to addiction, exacerbate the vulnerability to develop compulsive drug intake. We further demonstrated that the acquisition of alcohol drinking as a mechanism to cope with distress increases the vulnerability to develop compulsive alcohol intake. Together these results demonstrate that experiential factors in the drug taking context shape the vulnerability to addiction.

neuroscience↗