Biology subjects

Hrelja, K.

Publications and source records attributed to Hrelja, K..

3 recordsLinked to original sources

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↗

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↗