Dexmedetomidine Inhibits Fear Memory Consolidation via the Astrocyte-Specific Srebf1-Phgdh Pathway in the Prelimbic Prefrontal Cortex

Background Post-traumatic stress disorder (PTSD) is a common mental disorder for which effectiveinterventions remain limited. Therefore, we set out to study whether anestheticdexmedetomidine could mitigate fear memory consolidation, part of PTSD, in mice andexplored underlying mechanisms. Methods Adult C57BL/6 male mice received dexmedetomidine (40 μg kg-1, i.p.) immediately following fear conditioning. An auditory-cued memory test in a different context wasconducted next day. RNA sequencing and neuromolecular analyses of prelimbicprefrontal cortex were performed. Molecular pathways were validated using specific gene knockdown, coupled with detailed phenotype analysis. Results Dexmedetomidine significantly reduced freezing time in mice during the auditory-cued memory test compared to control condition (15 [11.73] % vs. 59.67 [14.46] %,P=0.0018) and decreased concentrations of synaptic-related proteins (10.69 [1.27]vs. 7.97 [1.29], P<0.0001) and levels of dendritic spine density. Additionally, dexmedetomidine alleviated anxiety-like behavior and sensorimotor gating function impairment in mice after fear conditioning. These effects correlated with reduced nuclear translocation of sterol regulatory element-binding protein 1 (Srebf1) in astrocytes, but not neurons nor microglia, within the prelimbic prefrontal cortex of mice, leading to downregulation of phosphoglycerate dehydrogenase (Phgdh), a downstream target gene. Specific knockdown of Srebf1 or Phgdh in astrocytes without the treatment of dexmedetomidine inhibited fear memory consolidation and the associated synaptic plasticity in mice. Conclusions Dexmedetomidine mitigated PTSD-like behavior in mice by inhibiting fear memory consolidation through the astrocyte-specific Srebf1-Phgdh pathway in the prelimbic prefrontal cortex. These findings will promote more research toward to understanding of using anesthetic to treat PTSD and the underlying mechanism