SYSTEM XC- AS A MOLECULAR MECHANISM FOR EVOLUTIONARY NEW FORMS OF ADVANCED COGNITION.

Human cognitive abilities are deeply rooted in evolutionary building blocks that maximize computation while maintaining efficiency. These abilities are not without evolutionary signatures; conserved processes like vision have undergone continual phylogenetic adjustments to better serve ecological niches. Conversely, more sophisticated forms of cognition may have required evolutionary innovations to transform existing neuronal processing to expand computational abilities. One such innovation is system xc- (Sxc), a cystine-glutamate antiporter predominantly localized to astrocytes that emerged in deuterostomes (e.g., vertebrates) after their divergence from protostomes over 550 million years ago. Previous evidence suggests that genetically modified rats that lack functional Sxc (MSxc) exhibit enhanced cocaine-seeking behavior. In this study, we deconstructed drug-seeking into its component behaviors, categorizing them as reliant on evolutionary conserved or newly evolved cognitive processes. Our results reveal that Sxc function is dispensable for conserved processes like visual, emotional, and hedonic processing, but critical for advanced, evolutionary new cognitive functions, particularly impulse control and decision making. Notably, we demonstrate a temporally specific reliance on Sxc during the learning phase of optimal decision-making, but not in maintaining established strategies. This is an important addition to our current understanding of astrocytes in non-homeostatic functions, indicating their critical role in computationally demanding phases of learning and memory. Unraveling evolutionary innovations like Sxc not only deepens our understanding of cognitive evolution but also paves the way for revolutionary, precision- targeted therapies in neuropsychiatric disorders, potentially transforming treatment paradigms and patient outcomes.