Biology subjects

Hynes, T.

Publications and source records attributed to Hynes, T..

5 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↗

bioRxiv2025

Accumbal cholinergic interneurons regulate decision making or motor impulsivity depending on latent task state

Dopaminergic transmission within the nucleus accumbens is broadly implicated in risk/reward decision making and impulse control, and the rat gambling task (rGT) measures both behaviours concurrently. While the resulting indices of risky choice and impulsivity correlate at the population level, dopaminergic manipulations rarely impact both behaviours uniformly, with changes in choice more likely when dopaminergic transmission is altered during task acquisition. Although the task structure of the rGT remains constant, the importance of accumbal dopamine signals relevant for reward prediction versus impulse control may vary over time; the former should dominate while learning which option maximises sugar pellet profits, while the suppression of premature responses becomes more valuable once a decision-making strategy is set and can be exploited. Cholinergic interneurons (CINs) critically control dopamine release within the striatum, and can also encode latent task states deciphered by the frontal cortex. We theorised that aCINs may set the dopaminergic tone of the accumbens to maximise reward learning or impulse control during task acquisition or performance, respectively. Using chemogenetics, we found some support for this hypothesis: activation and inhibition of aCINs once behaviour was stable increased and decreased motor impulsivity in both sexes but had no effect on choice patterns. In contrast, activating and inhibiting aCINs throughout task acquisition did not alter motor impulsivity, but decreased and increased risky choice respectively. However, the former effect was only seen in males and the latter in females. We conclude by proposing a set of testable predictions regarding interactions between acetylcholine and dopamine that could explain these sex differences.

animal behavior and cognition↗

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↗

bioRxiv2023

Win-paired cues modulate the effect of dopamine neuron sensitization on decision making and cocaine self-administration: divergent effects across sex

Psychostimulant use and engagement with probabilistic schedules of reward both sensitize the mesocorticolimbic dopamine system. Such behaviours may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. To probe these interactions, we sensitized ventral tegmental area (VTA) dopamine neurons via chronic chemogenetic stimulation while rats learned the rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort, we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine, and potentiated phasic excitability of VTA dopamine neurons through in vivo electrophysiological recordings. In the absence of cues, sensitization promoted risk-taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males, while attenuating cue-induced risk-taking in females. While these results provide further confirmation that VTA dopamine neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact which dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision-making on the cued rGT increased as both males and females learned to self-administer cocaine. The combination of dopamine sensitization and win-paired cues while gambling lead to significantly greater cocaine-taking, but these rats did not show any increase in risky choice as a result. Cocaine and heavily-cued gambles may therefore partially substitute for each other once the dopamine system is rendered labile through sensitization, compounding addiction risk across modalities.

animal behavior and cognition↗

bioRxiv2020

Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity

Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may like-wise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues, and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes, therefore we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue-induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine-induced deficits in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest.

animal behavior and cognition↗