Hippocampal miR-34a/SIRT1 and BDNF Responses Following Adolescent Stress: Differential Effects of Ketamine and Fluoxetine.
Feyza Dönmez, Gülin Özdamar Ünal, Kuyaş Hekimler Öztürk, Duygu Kumbul, Eltaf Doğan
Turk psikiyatri dergisi = Turkish journal of psychiatry 2026 DOI: 10.5080/u27776 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experimental animal study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Male Wistar albino rats, 4 weeks old at start |
| Interventions | Fluoxetine Ketamine |
| Dose | Fluoxetine 10 mg/kg, i.p.; ketamine 10 mg/kg, i.p. |
| Duration | 6-week chronic unpredictable mild stress; fluoxetine and ketamine administered during the last 3 weeks; behavioral assessments at weeks 3 and 6 |
| Measures | Sucrose preference test (SPT), open field test (OFT), forced swim test (FST), ELISA for BDNF protein, RT-PCR for miR-34a, SIRT1, and NLRP3 gene expression |
| Topics | Depression Ketamine Esketamine |
| Keywords | Early life stress Fluoxetine Mir-34a sirt1. |
| Key findings | Adolescent chronic unpredictable mild stress induced depression-like behaviors and decreased hippocampal BDNF while increasing miR-34a. Fluoxetine reversed the miR-34a increase and raised SIRT1 and BDNF levels; ketamine improved behavior but did not significantly alter BDNF, SIRT1, or miR-34a. No significant group differences in NLRP3 expression were observed. The authors argue that fluoxetine's effects are associated with the miR-34a/SIRT1/BDNF axis, whereas ketamine may act through different, possibly extra-hippocampal mechanisms. |
Abstract
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. 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. 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. 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.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cites 7
- The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive‐like rats Acta Physiologica October 22, 2018
- Subcutaneous ketamine reduces suicide risk and improves functioning in depression: A proof-of-concept study. Psychiatry Research July 1, 2024
- Chronic oral ketamine prevents anhedonia and alters neuronal activation in the lateral habenula and nucleus accumbens in rats under chronic unpredictable mild stress. Neuropharmacology February 20, 2023
- Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test PLoS One April 15, 2019
- Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects European Psychiatry June 1, 2015
and 2 more in the library