Thioredoxin interacting protein mediates corticosterone-induced depressive-like behavior in male mice.

Sleep patterns deteriorate over time in chronic corticosterone-treated rats

The unfixed light pattern contributes to depressive-like behaviors in male mice

Exercise amelioration of depression-like behavior in OVX mice is associated with suppression of NLRP3 inflammasome activation in hippocampus

Background: Depression is a mental disorder that poses a serious threat to human health. Adult hippocampal neurogenesis (AHN) is closely associated with the efficacy of antidepressants. Chronic treatment with corticosterone (CORT), a well-validated pharmacological stressor, induces depressive-like behaviors and suppresses AHN in experimental animals. However, the possible mechanisms of chronic CORT action remain elusive.Methods: A chronic CORT treatment (0.1 mg/mL, drinking water for 4 weeks) was applied to prepare a mouse model of depression. Immunofluorescence was performed to analyze the hippocampal neurogenesis lineage, and immunoblotting, immunofluorescence, electron microscopy, and adeno-associated virus (AAV) expressing a pH-sensitive tandemly tagged light chain 3 (LC3) protein were used to analyze neuronal autophagy. AAV-hSyn-miR30-shRNA was used to knock down autophagy-related gene 5 (Atg5) expression in the neurons.Results: Chronic CORT induces depressive-like behaviors and decreases the expression of neuronal brain-derived neurotrophic factor (BDNF) in the dentate gyrus (DG) of the hippocampus in mice. Moreover, it markedly diminishes the proliferation of neural stem cells (NSCs), neural progenitor cells, and neuroblasts and impairs the survival and migration of newborn immature and mature neurons in the DG, which may be attributed to changes in the cell cycle kinetics and induction of NSCs apoptosis. Furthermore, chronic CORT induces hyperactive neuronal autophagy in the DG, possibly by increasing the expression of ATG5 and causing excess lysosomal degradation of BDNF in neurons. Notably, inhibiting hyperactive neuronal autophagy in the DG of mice by knocking down Atg5 in neurons using RNA interference reverses the decrease of neuronal BDNF expression, rescues AHN, and exerts antidepressant effects.Conclusion: Our findings reveal a neuronal autophagy-dependent mechanism that links chronic CORT to reduced neuronal BDNF levels, AHN suppression and depressive-like behavior in mice. In addition, our results provide insights for treating depression by targeting neuronal autophagy in the DG of the hippocampus.

Depression is one of the most common psychiatric symptoms in Alzheimer's disease (AD), and considerable evidence indicates that major depressive disorder increases the risk of AD.1, 2, 3 To date, however, the molecular mechanisms underlying the clinical association between depression and AD have remained elusive. Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of AD patients and are increasingly recognized as the proximal neurotoxins responsible for synapse failure and memory deficits in AD.4, 5 We have hypothesized that AβOs might be mechanistically linked to behavioral changes in AD. In order to test this hypothesis, mice were given a single intracerebroventricular (i.c.v.) injection of 10 pmol AβOs and were subsequently evaluated in the Porsolt forced swim test (FST) for assessment of depressive-like behavior. Compared with vehicle-injected control mice, AβO-injected mice exhibited a significant increase in immobility in the FST, both 24 h and 8 days after AβO injections (Figure 1a). Similar results were obtained when animals were assessed in the tail suspension test, another classical task to evaluate depressive-like behavior in rodents (Supplementary Figure S1a). AβO-induced immobility in the FST was blocked by anti-depressant (fluoxetine) treatment (Figure 1a). An important feature of depressive disorder is anhedonic behavior, including decreased interest for pleasurable sensorial experiences. Whereas vehicle-injected mice exhibited an expected preference for sucrose solution over plain water, AβO-injected mice did not exhibit such preference, indicating that AβOs instigate anhedonic behavior (Figure 1b). Figure 1 Amyloid-β oligomers (AβOs) induce depressive-like behavior, memory deficits and hippocampal recruitment of microglia and astrocytes in mice. Three-month-old Swiss mice received a single intracerebroventricular (i.c.v.) injection of AβOs ... As memory deficit is the main clinical symptom of AD, we investigated the impact of AβOs on mice memory using the novel object recognition (OR) task. Results showed that 24 h after i.c.v. injection, AβO-treated mice spent equal amounts of time exploring both old (familiar) and new (novel) objects, indicating a deficit in declarative recognition memory, whereas vehicle-injected animals exhibited a significant preference for the novel object (Figure 1c). Treatment with fluoxetine prevented the memory deficit induced by AβOs (Figure 1c). Control measurements showed no changes in spontaneous exploratory or locomotor activities of fluoxetine-, saline-, vehicle- or AβO-injected animals during the training phase of the OR test (Supplementary Figure S1c–e). As the hippocampus is a key anatomical structure for OR memory, we sought to determine whether AβOs injected i.c.v. reached the hippocampus. Indeed, robust AβO immunoreactivity was verified using an anti-oligomer monoclonal antibody (NU4)6 in hippocampi from AβO-injected mice, but not in hippocampi from control vehicle-injected animals (Supplementary Figure S1b). Together, these results indicate that AβOs have an acute impact on memory, learning and mood in mice, and that fluoxetine treatment prevented both cognitive impairment and depressive-like behavior induced by AβOs. The beneficial actions of fluoxetine have been partly ascribed to its anti-inflammatory effect. This led us to ask whether AβOs triggered an inflammatory response in the mouse brain. The brains of mice used in the tests described above were analyzed for levels of pro-inflammatory cytokines after i.c.v. injection of AβOs or vehicle. AβO-injected animals showed significantly elevated brain levels of interleukin-1β and tumor necrosis factor-α compared with vehicle-injected animals (Figure 1d, e). Sections from the hippocampus and cortex of AβO- or vehicle-injected mice were further immunostained for the presence of microglia (anti-Iba-1 antibody) and astrocytes (anti-GFAP antibody). Compared with vehicle-injected animals, AβO-injected mice showed markedly increased immunoreactivities for both Iba-1 and GFAP in the hippocampus and cortex 24 h after injection (Figure 1f–o, and Supplementary Figure 1f–o). The increase in glial cell numbers instigated by AβOs was blocked by fluoxetine treatment of the animals before AβO injection (Figure 1f–o, and Supplementary Figure 1f–o). The current findings establish that AβOs link memory impairment and depressive-like behavior in mice, providing molecular mechanistic support to clinical evidence connecting AD and depressive disorder. The impact of AβOs on mood, learning and memory, and its prevention by fluoxetine, can likely be attributed to the activation of inflammatory pathways (as shown here) and, possibly, to the deregulation of the serotonergic axis. The latter possibility is in line with the observation that pro-inflammatory cytokines impact serotonin metabolism7, 8 and that increased serotonin levels are associated with lower brain Aβ levels in transgenic mouse models of AD and in humans.9 Moreover, 5-HT1A and 5-HT2A receptors have been reported to be reduced in post-mortem AD brain,10 and 5-HT1A receptors have been found to be reduced in vivo in AD.11 Brain disturbances that place a person at risk for developing depression and AD are still largely unknown. By revealing that AβOs underlie both cognitive and depressive-like symptoms in mice, our results suggest a mechanism by which elevated brain levels of AβOs may be linked to changes in cognition and mood in AD.

Xiaoyaosan improves depression-like behaviours in mice with post-stroke depression by modulating gut microbiota and microbial metabolism and regulating P2X7R/NLRP3 inflammasome.

Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration

Depression is a prevalent affective disorder, but its pathophysiology remains unclear. Dysfunction in the gamma-aminobutyric acid (GABA)-ergic system may contribute to its onset. Recently, antidepressants (e.g., brexanolone, zuranolone) targeting the GABA-A receptor were introduced. The zona incerta (ZI), an inhibitory subthalamic region mainly composed of GABAergic neurons, has been implicated in emotional regulation. Deep brain stimulation of the ZI in humans affects anxiety and depression symptoms, while activation of ZI neurons in mice can either worsen or alleviate anxiety. Currently, there is no direct evidence linking GABAergic neurons in the ZI to depression-like behaviors in rodents. To explore the relationship between GABAergic neurons in the ZI and depression-like behaviors in mice. A chronic restraint stress (CRS) model was utilized to induce depression in mice. Whole-cell patch-clamp recordings assessed the excitability changes of GABAergic neurons in the ZI. Additionally, chemogenetic techniques were employed to modulate ZI GABAergic neurons. The performance of the mice in behavioral tests for depression and anxiety was observed. The findings indicated that GABAergic neurons in the ZI were closely associated with depression-like behaviors in mice. Twenty-eight days after the CRS model was established, depression-like and anxiety-like behaviors were observed in the mice. The excitability of GABAergic neurons in the ZI was reduced. Chemogenetic activation of these neurons alleviated CRS-induced depression-like and anxiety-like behaviors. Conversely, inhibition of GABAergic neurons in the ZI led to changes in emotion-related behavioral outcomes in mice. Activity of GABAergic neurons in the ZI was closely associated with depression-like phenotypes in mice, suggesting that these neurons could be a potential therapeutic target for treating depression.

Depression is a very common psychiatric disorder affecting approximately 300 million people worldwide with the prevalence being twice as high in women as in men. Despite intense research efforts in recent decades, the neurobiological basis underlying depression remains incompletely understood. However, the exposure to chronic stress is widely accepted to constitute a precipitating factor for the development of this mental disorder. Several animal models for the investigation of the pathogenetic link between chronic stress and depression exist and have yielded important insights. The present study aimed at comparing two published protocols for the induction of depression-like behavior in mice based on chronic oral glucocorticoid application. Given the gender distribution in the prevalence of depression, the second goal of this study was to reveal possible differences in the behavioral responses of female and male mice to corticosterone (CORT) treatment. CORT treatment was found to modulate depression-like behavior in selected behavioral paradigms in a sex- and protocol-specific manner. These data are of relevance for the experimental design and interpretation of future studies in the field and further highlight the relevance of “sex as biological variable” to be considered an important parameter for experimental planning and interpretation of results.

Previously, a chronic social defeat stress (CSDS) model has been widely-adopted for assessing depressive-like behaviors in animals. However, there is still room for improvement in the CSDS model to safeguard study accuracy and the welfare of lab rodents. Our study team developed a novel, standardized apparatus to induce CSDS in rodents and assessed the model's practical adaptability. An innovative CSDS cage apparatus and water bottle was designed. To evaluate the effectiveness of the newly developed tools, a variety of animal models, including the tail suspension test (TST), sucrose preference test, forced swimming test (FST), novelty-suppressed feeding test, female urine sniffing test, and open field test (OFT), were adopted to assess depressive-like behaviors in mice. Fluoxetine treatment was also administered to observe the reversal effect, as part of the validation. The CSDS cage apparatus resulted in the manifestation of depressive-like behaviors in the model mice. Significant reductions in sucrose preference and urine sniffing time were observed, while the OFT revealed decreased central zone total distance, residence time, and frequency of entry. Moreover, increased immobility was found in the FST and TST. Fluoxetine treatment was found to successfully reverse the modeling effect. The CSDS cage apparatus was validated for enhanced usability and addressed the previous challenges of water bottle leakage and lab rodent welfare issues. The consistent results from multiple behavioral tests also supported real-world application of the apparatus, offering researchers a promising alternative to conventional rodent cages.

The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.

While androgen receptor (AR) and stress may influence the development of the major depressive disorder (MDD), the detailed relationship, however, remains unclear. Here we found loss of AR accelerated development of depressive-like behaviors in mice under chronic mild stress (CMS). Mechanism dissection indicated that AR might function via altering the expression of miR-204-5p to modulate the brain-derived neurotrophic factor (BDNF) expression to influence the depressive-like behaviors in the mice under the CMS. Adding the antiandrogen flutamide with the stress hormone corticosterone can additively decrease BDNF mRNA in mouse hippocampus mHippoE-14 cells, which can then be reversed via down-regulating the miR-204-5p expression. Importantly, targeting this newly identified AR-mediated miR-204-5p/BDNF/AKT/MAPK signaling with small molecules including 7,8-DHF and fluoxetine, all led to alter the depressive-like behavior in AR knockout mice under CMS exposure. Together, results from these preclinical studies conclude that decreased AR may accelerate the stress-induced MDD via altering miR-204-5p/BDNF/AKT/MAPK signaling, and targeting this newly identified signaling may help in the development of better therapeutic approaches to reduce the development of MDD.

Fluoride exposure caused anxiety- and depression-like behavior in mice. Meanwhile, exercise contributes to relieve anxiety and depression. However, the effects of exercise on anxiety- and depression-like behavior in fluorosis mice remain unclear. In the current study, thirty-six Institute of Cancer Research (ICR) female mice were randomly assigned to four groups: control group (C, gavage with distilled water); exercise group (E, gavage with distilled water and treadmill exercise (speed, 10 m/min; time, 30 min/day)); fluoride group (F, gavage with 24 mg/kg sodium fluoride (NaF)); and exercise plus fluoride group (EF, gavage with 24 mg/kg NaF and treadmill exercise). All treatments lasted for 8 weeks. A number of entries into and time spent in the open zone in the elevated zero maze (EZM), resting time in the tail suspension test (TST) and levels of serotonin (5-HT) and gamma-aminobutyric acid (GABA), were significantly altered in F when compared to C. Meanwhile, the anxiety-like behavior in the EZM and the depression-like behavior in the TST were significantly improved in EF when compared to group F. Exercise significantly enhanced fluoride-induced low GABA level, with less effect on the concentration of 5-HT. Moreover, the mRNA and protein expressions of GABA synthesis and transport-related proteins of glutamic acid decarboxylase (GAD) 65 and GAD67 and vesicular GABA transporter (VGAT) were all strikingly decreased in F, while those in EF were increased. In conclusion, exercise ameliorates anxiety- and depression-like behavior in fluorosis mice through increasing the expressions of GABA synthesis and transport-related proteins, rather than 5-HT system.

Chronic corticosterone exposure reduces hippocampal astrocyte structural plasticity and induces hippocampal atrophy in mice

The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice