Twining, R. C. | Search bioRxiv

bioRxiv2025

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.

neuroscience↗

bioRxiv2022

Genetic Disruption of System xc- Mediated Glutamate Release from Astrocytes Increases Negative-Outcome Behaviors While Preserving Basic Brain Function in Rat

The impact of CNS disorders is exacerbated by the difficulty in developing safe, effective glutamatergic therapeutics. Synaptic glutamate transmission is vital for neural physiology throughout the brain, which contributes to the vast therapeutic potential and safety risk of glutamatergic therapeutics. Here, we created a genetically modified rat (MSxc) to survey the range of brain functions impacted by the loss of glutamate release from astrocytes involving system xc- (Sxc). Eliminating Sxc activity was not lethal and did not alter growth patterns, activity states, novel object recognition or performance of other simple tasks. In contrast, MSxc rats differed from WT in Pavlovian Conditioned Approach and cocaine self-administration/reinstatement paradigms. Both WT and MSxc rats readily learned that a cue predicted food delivery during Pavlovian Conditioned Approach training. However, WT rats were more likely to approach the food tray (i.e., goal tracking) whereas MSxc rats were more likely to approach the food-predicted cue (i.e., sign tracking) even when this behavior was punished. In the self-administration/reinstatement paradigm, MSxc rats had higher levels of cocaine-primed drug seeking in the absence of altered extinction or cocaine self-administration. These data demonstrate that Sxc-mediated glutamate release from astrocytes regulates non-reinforced and negative-outcome behaviors without altering simple learning or other forms of basic brain function.

neuroscience↗