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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE290477 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation. In order to identify genes differentially regulated between 3- and 16-month old mice upon fear conditioning we subjected 3- and 16-month old mice to fear conditioning (4 mice each group, total 8 mice) . Mice of the same age that were handled but not subjected to any of the employed behavior paradigms served as control (4 mice 3-month old and 4 mice 16-month old, total 8 mice). During fear conditioning mice are subjected to a novel context followed by a mild electric foot-shock (context-shock exposure). In order to identify genes that are differentially regulated upon fear conditioning and are specific to associative learning we also tested the hippocampal gene-expression profile of 3-month old mice subjected to the same context-exposure that is not followed by a foot-shock (Context-exposure) (4 mice) or receive an immediate foot shock once they are placed in the context and only afterwards are allowed to explore the context (shock-context exposure) (4 mice). In order to identify genes that are regulated upon fear conditioning and are specific to associative learning we compared the hippocampal gene-expression profile of mice subjected to fear conditioning (context-shock), context or shock-context exposure regarding to their age-matched control mice (3 month old) mentioned above (control). Hippocampi from each mice were tested resulting to 24 samples which were separately hybridized (OneColor Array Design).

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

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