bioRxiv Science⌕ Search

Biology subjects

Calderhead, L.

Publications and source records attributed to Calderhead, L..

3 recordsLinked to original sources

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↗

Insight into differing decision-making strategies that underlie cognitively effort-based decision making using computational modeling in rats

RationaleThe rat Cognitive Effort Task (rCET), a rodent model of cognitive rather than physical effort, requires animals to choose between an easy or hard visuospatial discrimination, with a correct hard choice more highly rewarded. Like in humans, there is stable individual variation in choice behavior. In previous reports, animals were divided into two groups - workers and slackers - based on their mean preference for the harder option. Although these groups differed in their response to pharmacological challenges, the rationale for using this criterion for grouping was not robust. MethodsWe collated experimental data from multiple cohorts of male and female rats performing the rCET, and used a model-based framework combining drift diffusion modeling with cluster analysis to identify the decision-making processes underlying variation in choice behavior. ResultsWe verified that workers and slackers are statistically different groups, but also found distinct intra-group profiles. These subgroups exhibited dissociable performance during the attentional phase, linked to distinct decision-making profiles during choice. Reanalysis of previous pharmacology data using this model-based framework showed that serotonergic drug effects were explained by changes in decision boundaries and non-decision times, whilst scopolamines effects were driven by changes in decision starting points and rates of evidence accumulation. ConclusionsModeling revealed the decision-making processes that are associated with cognitive effort costs, and how these differ across individuals. Reanalysis of drug data provided insight into the mechanisms through which different neurotransmitter systems impact cognitively effortful attention and decision-making processes, with relevance to multiple psychiatric disorders.

neuroscience↗

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↗