Objective: Early life stress is a well-established risk factor for
psychiatric disorders in adulthood; however, the underlying molecular
mechanisms remain unclear. This study investigated the effects of
chronic unpredictable mild stress (CUMS) starting in adolescence on
anxiety- and depression-like behaviors, as well as on hippocampal miR-
34a, SIRT1, BDNF, and NLRP3 levels in rats treated with ketamine or
fluoxetine.
Methods: A total of 40 Wistar albino rats (4 weeks old) were divided into
four groups: Control, CUMS, CUMS + fluoxetine (FLU), and CUMS
+ ketamine (KETA). Chronic unpredictable mild stress was applied for
6 weeks, while fluoxetine (10 mg/kg, i.p.) and ketamine (10 mg/kg, i.p.)
were administered during the last 3 weeks. Behavioral assessments were
performed at weeks 3 and 6 using the sucrose preference test (SPT),
open field test (OFT), and forced swim test (FST). Hippocampal BDNF
protein levels were measured by ELISA, and miR-34a, SIRT1, and
NLRP3 gene expression levels were analyzed by RT-PCR.
Results: Both fluoxetine and ketamine improved CUMS-induced
depression-like behaviors. Chronic unpredictable mild stress decreased
hippocampal BDNF levels and increased miR-34a expression.
Fluoxetine reversed the increase in miR-34a and elevated SIRT1
expression and BDNF levels. In contrast, although ketamine improved
behavioral outcomes, it did not significantly alter hippocampal BDNF
or SIRT1 levels and did not reduce miR-34a expression. No significant
differences in NLRP3 expression were observed among the groups.
Conclusion: Adolescent CUMS induces depression-like behaviors
by affecting the hippocampal miR-34a/SIRT1/BDNF axis. While
the antidepressant effects of fluoxetine are associated with this axis,
ketamine may exert its behavioral effects through different and possibly
extra-hippocampal mechanisms. miR-34a may serve as a potential
biomarker for depression related to early life stress.
Keywords: Depression, early life stress, fluoxetine, ketamine, miR-34a,
SIRT1