¹Université Libre de Bruxelles (ULB), Neurophy Lab, Brussels, Belgium, ²Institut de Génomique Fonctionnelle, UMR 5203 CNRS – U 1191 INSERM, Montpellier, France, ³Université Libre de Bruxelles (ULB)/ WELBIO, WEL Research Institute, Neurophy Lab, Brussels, Belgium

Background: Decision-making is a fundamental cognitive process emerging from the mesocorticolimbic loop, where the striatum plays a critical role in evaluating actions based on expected values. The striatum is anatomically divided into regions with distinct functions: the dorsomedial striatum (DMS) manages goal-directed actions, the dorsolateral striatum (DLS) governs habit formation, and the nucleus accumbens (NAc) handles reward and motivation. Within these regions, two main populations of striatal projection neurons (SPNs)—direct (dSPN) and indirect (iSPN)—interact to influence behavior, yet their specific roles in risk seeking and individual decision-making strategies remain poorly understood.

Aims & Objectives: This study aimed to characterize individual decision-making strategies in mice using a rodent-adapted Iowa Gambling Task (IGT) and to determine how these strategies are modulated by specific striatal subpopulations. The researchers sought to move beyond simple "safe vs. risky" dichotomies by identifying archetypal behavioral profiles and testing how chemogenetic manipulation of dSPNs and iSPNs in different striatal subregions (DMS, DLS, and NAc) affects these profiles.

Method: We used a mouse gambling task where animals chose between four nose-poke holes (P1–P4) associated with different reward magnitudes and punishment (time-out) probabilities. P1 and P2 were "safe" options with higher long-term returns, while P3 and P4 were "risky". Individual variability was analyzed using archetypal analysis and a reinforcement-learning model to identify stable cognitive traits. Finally, chemogenetic tools (DREADDs) were employed to selectively increase the excitability of dSPNs and iSPNs in the DMS, DLS, or NAc to observe effects on choice behavior.

Results: Archetypal analysis identified three stable decision-making strategies: Optimizers (prioritizing advantageous options), Risk-averse (preferring certain, small rewards), and Explorers (lower attentional control and fewer trials). Chemogenetic results showed that only DMS manipulations substantially altered decision-making. Specifically, increasing DMS dSPN activity decreased risk aversion across all mice. In contrast, increasing DMS iSPN activity only decreased safe choices in "Optimizer" mice by reducing their sensitivity to large gains (reward saturation). Manipulations in the NAc had lesser effects, while DLS manipulations only impacted motivation without affecting choice.

Discussion & Conclusions: This study demonstrates that striatal subpopulations regulate decision-making in a strategy-dependent manner, identifying the dorsomedial striatum (DMS) as a critical hub for maintaining instrumental preferences under risk. Crucially, the behavioral impact of manipulating dSPNs and iSPNs is mediated by an individual’s baseline cognitive profile—whether they are "Optimizers," "Risk-averse," or "Explorers." From a clinical perspective, this necessitates a shift in how we approach decision-related disorders such as pathological gambling and addiction. Rather than viewing these conditions as global deficits, they should be framed as specific shifts in the neural parameters governing goal-directed choice. By identifying the biological and social factors that influence these "meta-learning" rules, research can move toward a translational model of precision psychiatry. Such a framework offers a promising pathway for developing personalized therapeutic interventions—ranging from targeted pharmacological treatments to cognitive behavioral therapies—tailored to an individual’s specific neuro-cognitive strategy.