Foxq1 activates CB2R with oleamide to alleviate POCD

Area of Science:

• Neuroscience
• Gerontology
• Molecular Biology

Background:

• Postoperative cognitive dysfunction (POCD) is a significant clinical concern, especially in the elderly population.
• Social isolation is hypothesized to contribute to the development of POCD.
• Multiomics approaches can elucidate complex biological mechanisms.

Purpose of the Study:

• To investigate the mechanisms underlying POCD development in aged mice using social isolation and multiomics.
• To explore the roles of the Foxq1 gene, oleamide, and cannabinoid receptor type 2 (CB2R) in POCD.
• To identify potential therapeutic targets for mitigating POCD.

Main Methods:

• Aged mice were subjected to social isolation (ISO) or paired housing (PH) and underwent tibial surgery to model POCD.
• Interventions included oleamide administration, CB2R antagonist AM630, and Foxq1 adeno-associated virus (AAV) vector delivery to the hippocampus.
• Cognitive function was assessed using Y-maze, open field, and novel object recognition tests; inflammatory markers were measured.

Main Results:

• Social isolation intensified cognitive deficits and elevated inflammatory markers post-surgery.
• Integrative transcriptomic and metabolomic analyses revealed elevated oleamide in paired-housed mice, linked to the Foxq1 gene.
• Oleamide and Foxq1 overexpression improved cognitive performance and reduced inflammation, effects blocked by the CB2R antagonist AM630.

Conclusions:

• The Foxq1 gene and oleamide play crucial roles in alleviating POCD, potentially through CB2R-mediated pathways.
• These factors modulate neuroinflammation and reduce pro-inflammatory cytokines, enhancing cognitive function post-surgery.
• The Foxq1-oleamide-CB2R axis represents a promising therapeutic target for preventing or treating POCD.