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bioRxiv · 10.1101/2025.10.12.681536

A comprehensive characterization of the phospholipid and cholesterol composition of the uncinate fasciculus in the human brain: evidence of age-related alterations

Perlman, K.·Chen, C.·Smith, M.·Kim, J. J.·Turecki, G.·Bazinet, R.·Mechawar, N.
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Abstract

The uncinate fasciculus (UF) is a long-range association fiber tract that serves to connect the anterior temporal lobe with the orbitofrontal cortex. The UF has been implicated via neuroimaging studies in the neurobiological vulnerability to psychiatric disorders posed by a history of childhood abuse (CA), as well as in the psychopathology underlying depressive disorders. Since the myelin sheath is highly enriched in lipids, white matter (WM) dysfunction may reflect alterations in the myelin lipid profile. In fact, our previous work showed that in the anterior cingulate cortex WM, there was a specific effect of CA in the choline glycerophospholipid fatty acids (FA) involved in the synthesis of arachidonic acid. Given that the UF does not exist in rodents, its molecular properties are highly understudied and its lipid composition is virtually unknown. As such, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and measure whether we could detect lipid-related or myelin-constituent gene/protein changes associated with CA and/or depression. Fresh-frozen left hemisphere UF samples were analyzed from individuals with depression who died by suicide with a history of severe CA (DS-CA), individuals with depression who died by suicide without a history of CA (DS), and non-psychiatric control subjects who died naturally or accidentally (CTRL). Phospholipids were separated by thin-layer chromatography. FA and non-derivatized cholesterol were quantified using gas chromatography-flame ionization detection. Relative expression of myelin-constituent genes (PLP1, MAG, CNP, MOG, PLLP, MBP, and MOBP) was measured by RT-qPCR, and levels of myelin-constituent proteins (MAG, MOG, MBP, and PLP) were measured by immunoblotting. We found no robust relationships between depression or CA and any lipid measures, nor in myelin-constituent gene and protein levels. However, in the phospholipids, we observed striking age relationships that varied across fractions, with an overall pattern of increases in monounsaturates and decreases in long chain omega-6 polyunsaturates with age. In tandem, we observed that most myelin-constituent genes and proteins showed decreasing trends with age, with PLP1 and MAG showing significantly decreasing relationships. We hypothesize that the changes in lipid composition and lipid-protein interactions contribute to age-related myelin deficits and declines in cognition. The absence of group differences highlights the importance of regional specificity in molecular studies assessing neurobiological correlates of psychiatric disorders.

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Perlman, K., Chen, C., Smith, M., Kim, J. J., Turecki, G., Bazinet, R., Mechawar, N.. 2025-10-13. A comprehensive characterization of the phospholipid and cholesterol composition of the uncinate fasciculus in the human brain: evidence of age-related alterations. https://doi.org/10.1101/2025.10.12.681536

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