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Hernandez, Ivan
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Spring 2025
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2025-04-04
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Abstract
The mechanistic target of rapamycin (mTOR) is a central regulator of several cellular
processes that are required for learning and memory, through the mTOR complex 1 (mTORC1)
signaling pathway. However, little is known about how mTORC1 signaling in the brain is
affected by sex or disease. We previously reported that activation of mTORC1 by 3-benzyl-5-
((2-nitrophenoxy) methyl)–dihydrofuran-2(3H)-one (3BDO) upregulated hippocampal rRNA
expression and enhanced memory on the hippocampal-dependent active place avoidance task
in young wild-type (WT) male mice. Here, we set out to determine if mTORC1 activation by
3BDO could enhance or rescue learning and memory on the active place avoidance task in both
male and female mice from two strains, WT and APP/PS1, a model of Alzheimer’s Disease
(AD). We selected two age groups to analyze: 8–9-months-old, when plaques are established
and deficits in spatial memory begin to appear in APP/PS1 mice, and 12–13-months-old, when
plaques are extensive and memory is severally impaired in APP/PS1 mice. Our data showed that a single dose of 3BDO delivered systemically rescued memory in 8–9-months-old male
APP/PS1 mice but did not significantly affect male WT mice at this age. Further, 3BDO
improved latency during learning for 12–13-months-old male mice overall but did not impact
memory at this age. Surprisingly, in female mice, we found that 3BDO impaired both learning
and memory at 8–9-months-old in WT mice, while having no significant effect on 8–9-month-old
APP/PS1 mice or 12–13-months-old mice of either genotype. After behavioral testing, we
further analyzed the effects of 3BDO administration on mTOR expression by Western blot. In
the dorsal hippocampus, we saw overall less mTOR and phosphorylated mTOR in females
compared to males at 8–9-months-old, but overall more mTOR and phosphorylated mTOR in
females compared to males at 12–13-months-old. These results challenge the current
understanding of how mTORC1 functions in AD and provide a new avenue of research into
potential therapeutics. At the same time, the opposing effects of 3BDO on males and females trained on the same learning and memory task highlight the importance of studying potential sex
differences of emerging therapeutics.
Citation
Sebastian Avila, V (2025). Sex differences in memory modulation by mTORC1 activation [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. http://hdl.handle.net/20.500.12648/16550