Astrocytes regulate cognitive flexibility and neuronal oscillations by releasing S100b

Abstract

Astrocytes are the most numerous cell in the human brain yet their role in behavior and brain functioning has remained incompletely explored. The goal of my dissertation is to examine the role astrocytes play in cognition. Over the course of several experiments, I show that astrocytes not only change due to experiences associated with improved cognition, but that astrocytes themselves are important contributors to cognition. My dissertation research has primarily utilized a task of cognitive flexibility that previous research in rodents, nonhuman primates, and humans suggests requires the medial prefrontal cortex. Here I show that voluntary exercise improves cognitive flexibility in rodents and that this enhancement is associated with increased astrocyte size and increased dendritic spine density in the medial prefrontal cortex. I follow up on these findings to show that impairment of astrocyte functioning in the medial prefrontal cortex, but not the orbitofrontal cortex, results in diminished cognitive flexibility. Next, I demonstrate that reducing the number of astrocytes in the medial prefrontal cortex similarly impairs cognitive flexibility, and that cognitive flexibility can be enhanced by specifically increasing Ca2+ signaling in astrocytes in the medial prefrontal cortex. Finally, I show that this facilitation is likely controlled by the astrocyte-specific protein S100β, and link S100β levels to changes in neuronal synchrony thought to underlie cognitive flexibility. Collectively, my work demonstrates that astrocytes are important contributors to cognitive flexibility.