Single-nucleus transcriptomic analysis reveals the relationship between gene expression in oligodendrocyte lineage and major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common mental illness that affects millions of people worldwide and imposes a heavy burden on individuals, families and society. Previous studies on MDD predominantly focused on neurons and employed bulk homogenates of brain tissues. This paper aims to decipher the relationship between oligodendrocyte lineage (OL) development and MDD at the single-cell resolution level. METHODS: Here, we present the use of a guided regularized random forest (GRRF) algorithm to explore single-nucleus RNA sequencing profiles (GSE144136) of the OL at four developmental stages, which contains dorsolateral prefrontal cortex of 17 healthy controls (HC) and 17 MDD cases, generated by Nagy C et al. We prioritized and ordered differentially expressed genes (DEGs) based on Nagy et al., which could predominantly discriminate cells in the four developmental stages and two adjacent developmental stages of the OL. We further screened top-ranked genes that distinguished between HC and MDD in four developmental stages. Moreover, we estimated the performance of the GRRF model via the area under the curve value. Additionally, we validated the pivotal candidate gene Malat1 in animal models. RESULTS: We found that, among the four developmental stages, the onset development of OL (OPC2) possesses the best predictive power for distinguishing HC and MDD, and long noncoding RNA MALAT1 has top-ranked importance value in candidate genes of four developmental stages. In addition, results of fluorescence in situ hybridization assay showed that Malat1 plays a critical role in the occurrence of depression. CONCLUSIONS: Our work elucidates the mechanism of MDD from the perspective of OL development at the single-cell resolution level and provides novel insight into the occurrence of depression.

Effects of testosterone dose on depression-like behavior among castrated adult male rats.

Previous research has shown a decrease in serum testosterone levels in male patients with depression. In recent years, the results of testosterone replacement therapy (TRT) to improve depression have been mixed. Using the classic CUMS model, we induced depressive-like behaviors in rats and observed a decrease in their serum testosterone levels along with an increase in androgen receptor expression in the hippocampus. We then performed castration and sham surgery on male rats and found that testosterone deprivation led to the manifestation of depressive-like behavior that could be ameliorated by TRT. Through a repeated measures experiment consisting of five blocks over a period of 25 days, we discovered that the reduction in depressive-like behavior in testosterone-deprived rats began 22 days after drug administration (0.5 and 0.25 mg/rat). Furthermore, rats in 0.5mgT group showed the most significant improvements. Subsequently, this dose was used in CUMS rats and reduced the occurrence of depressive-like behaviors. Our study has demonstrated the complex interplay between depression and testosterone, as well as the intricate dose-response relationship between TRT and reduction in depression. Our research supports the use of TRT to alleviate depression, but dosage and duration of treatment are critical factors in determining efficacy.

Tunicamycin induces depression-like behaviors in male rats, accompanied by initiated chaperon-mediated autophagy and decreased synaptic protein expression in the hippocampus.

BACKGROUND AND AIM: Endoplasmic reticulum (ER) stress participates in the occurrence and development of depression, but the underlying mechanism is not fully understood. This study aimed to investigate the behavioral performance and intracerebral molecular changes in an ER stress model of male rats. METHODS: Intrahippocampal injection of tunicamycin (TM) was performed on male rats as a model of ER stress. The body weight was determined, and behavioral tests, including sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST), were performed to evaluate depressive and anxiety-like phenotypes within 8 days after injection. The levels of chaperone-mediated autophagy (CMA), synaptic proteins, and neuroinflammation related factors in this model were measured via real-time quantitative PCR and Western blot analysis. RESULTS: Intrahippocampal injection of TM (2 or 1 µg) induced depression-like behaviors in rats, as indicated by the reduced body weight, sucrose preference in SPT, central time in OFT, and increased immobility time in FST. The mRNA and protein levels of GRP78, ATF4, CHOP, LAMP2A, IL-1ß, IL-6, and TNF-α were significantly increased, while the expressions of MEF2D, PSD95, SYN, p-CREB (Ser133), and BDNF were significantly decreased in the hippocampus in the model group compared with the sham group. CONCLUSIONS: These results confirmed that intrahippocampal injection of TM was a valid method to induce an ER stress rat model with depression-like behaviors accompanied by decreased synaptic protein expression and neuroinflammation. The alteration in CMA-related proteins in this ER stress depression model indicated the involvement of CMA in the development of depression.

Social isolation after chronic unpredictable mild stress perpetuates depressive-like behaviors, memory deficits and social withdrawal via inhibiting ERK/KEAP1/NRF2 signaling.

BACKGROUND: Social withdrawal in patients with depression can aggravate depressive symptoms. However, few studies focus on the behavioral changes of social isolation after CUMS. NRF2 had been reported to be down-regulated after CUMS. But whether NRF2 participates in behavioral changes induced by social isolation after CUMS remains unclear. This study aims to develop a new model combined social isolation with CUMS, and investigate whether such behavioral changes are related to NRF2 signaling. METHODS: This study included two stages. In Stage 1, rats were subjected to 4-week CUMS and CUMS-susceptible rats were selected. In Stage 2, the CUMS-susceptible rats received 4-week social isolation or social support. Behavioral tests were carried out to observe behavioral changes, including sucrose preference test, forced swimming test, open field test, novel object recognition and social interaction test. QRT-PCR, western blot and immunofluorescence staining detected the ERK/KEAP1/NRF2 signaling. RESULTS: CUMS-susceptible rats exhibited depressive-like behaviors accompanied by the down-regulated ERK/KEAP1/NRF2 signaling in hippocampus. In Stage 2, compared with 4-week social support (group CUMSG), 4-week social isolation (group CUMSI) perpetuated the depressive-like behaviors, memory deficits and social withdrawal in CUMS-susceptible rats, as well as lower levels of p-ERK, NRF2, p-NRF2, HO-1 and NQO1, and the higher levels of KEAP1 in hippocampus. CONCLUSION: These findings suggested that social isolation after CUMS perpetuated depressive-like behaviors, memory deficits and social withdrawal via inhibiting ERK/KEAP1/NRF2 signaling. This study provided molecular evidence for the effects of post-stress social isolation on mental health, and the antioxidant stress signaling might be a target to rescue these.