Astrocytic Regulation in Hippocampal CA2 Mediates the Impact of Sleep Deprivation on Spatial Working Memory

Jingang He¹Yunshuang Ye²Jun Fang²Jie Wang^2*hoiyin Ruijin Cheung^3*

• ¹School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
• ²Department of Neurosurgery, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, shanghai, China
• ³Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine., shanghai, China

Introduction: Chronic sleep deprivation (CSD) is closely associated with significant mood disorders, such as anxiety and depression, and may lead to spatial memory impairment. Spatial memory is a cognitive function closely linked to the hippocampus, with the CA2 region playing a critical role in memory processing. However, the specific mechanisms by which the CA2 region contributes to spatial memory impairment induced by sleep deprivation remain unclear. This study hypothesizes that CSD impairs spatial memory by affecting the metabolic function of astrocytes in the hippocampal CA2 region. Methods: The study used 7-week-old C57BL/6J mice to establish a CSD model via the multi-platform water environment method (MPT). Functional magnetic resonance imaging (fMRI), including ALFF and ReHo analyses, was employed to assess functional changes in brain regions. Metabolic dynamics were studied using ¹ ³ C-labeled glucose and sodium acetate to evaluate the metabolic states of neurons and astrocytes, respectively. Additionally, chemogenetic manipulation (via AAV viral vectors) was used to modulate the activity of astrocytes in the CA2 region, and spatial memory function was assessed through Y-maze behavioral tests. Results: CSD leads to functional abnormalities in the hippocampal CA2 region and spatial memory impairment in mice, as evidenced by increased ALFF and ReHo values in fMRI and decreased performance in the Y-maze test. Additionally, CSD induces metabolic dysregulation and calcium signaling abnormalities in CA2 astrocytes. Inhibition of calcium signaling exacerbates memory impairment, whereas activation of astrocytes can reverse this effect. This is a provisional file, not the final typeset article Conclusion: Metabolic dysfunction and calcium signaling abnormalities in astrocytes of the hippocampal CA2 region are key mechanisms underlying spatial memory impairment caused by CSD. Activation of CA2 astrocytes can restore memory function, providing a novel therapeutic target for cognitive deficits associated with sleep disorders.