The Sex-Dependent Effects of Psychedelics on Myelination in APOE4 Mice

Myelin abnormalities are linked to neuropsychiatric disorders, and psychedelics are being explored as potential treatments. A mutation in the APOE4 gene disrupts cholesterol regulation in oligodendrocytes, impairing myelination. This work investigates how the psychedelic compound DOI affects myelination in male and female APOE4 mice. Preliminary results show a significant increase in myelin basic protein (MBP) in the CA1 and CA2 brain regions of female APOE4 mice after DOI administration, correlating with reduced anxiety-related behaviors. No similar effect was observed in males. These findings reveal sex-specific biological mechanisms in brain degeneration and suggest potential for developing sex-specific therapeutics for myelin-related disorders.

Study at a glance

Abstract

Several studies have linked myelin abnormalities with neuropsychiatric disorders; others have implicated psychedelics as a potential therapeutic for such conditions. One risk factor for these demyelinating disorders is a mutation in the Apolipoprotein E gene known as APOE4. This variant impedes the cholesterol regulation of oligodendrocytes responsible for the myelination, or insulation, of neurons when compared to the wild-type phenotype. In this work, I advance knowledge of cellular pathways involved in the progression of APOE4-related diseases and elucidate the effects of psychedelics on the brain. Myelin sheaths are vital for maintaining neural pathways, and healthy oligodendrocytes serve as a prerequisite for axonal integrity. Further, the Kaufer Lab has observed significant behavioral differences between male and female APOE4 mice following psychedelic treatment with 2,5-Dimethoxy-4-iodoamphetamine, or DOI, a serotonin receptor ligand. The sex-dependent mechanisms influencing symptom differences and treatment outcomes in AD are unclear, and could be key to developing successful therapeutics for myelin-related issues. I hypothesize that administration of DOI will increase the myelination activity of oligodendrocytes in female APOE4 mice compared with their male counterparts or controls. Preliminary results show a significant increase in MBP in the CA1, or short-term, and CA2, or long term, areas in only female APOE4 mice post-introduction of DOI to the system. This aligns with behavioral data indicating fewer anxiety-related behaviors in female APOE4 mice after DOI administration. These findings reveal distinct biological mechanisms in male and female brain degeneration and suggest potential for sex-specific therapeutics.