scholarly journals Increasing Adult Hippocampal Neurogenesis Promotes Resilience in a Mouse Model of Depression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 972
Author(s):  
Barbara Planchez ◽  
Natalia Lagunas ◽  
Anne-Marie Le Guisquet ◽  
Marc Legrand ◽  
Alexandre Surget ◽  
...  
Keyword(s):  
Mouse Model ◽  
Water Maze ◽  
Chronic Mild Stress ◽  
Tail Suspension Test ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Maze Procedure ◽  
Mild Stress ◽  
Protective Effects ◽  
Stress Resilience

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.

scholarly journals The impact of gut microbiota on depressive-like behaviors and adult hippocampal neurogenesis requires the endocannabinoid system

2019 ◽  
Author(s):  
Grégoire Chevalier ◽  
Eleni Siopi ◽  
Laure Guenin-Macé ◽  
Maud Pascal ◽  
Thomas Laval ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Endocannabinoid System ◽  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Microbiota Composition ◽  
The Impact

SUMMARYDepression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota, but causality remains yet to be established. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that the UCMS mice display phenotypic alterations — characterized by an altered gut microbiota composition, a reduced adult hippocampal neurogenesis and a depressive-like behaviors — which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota on adult neurogenesis and behavior in naïve recipient mice were alleviated by selectively enhancing the central eCB tone or by adding arachidonic acid, a fatty acid precursor of eCB ligands, to the diet. In the gut of both UCMS donors and recipients, the microbiota composition was characterized by a relative decrease in Lactobacilli abundance, and complementation of the UCMS recipient microbiota with a strain of the Lactobacilli genus was sufficient to restore normal eCB brain levels, hippocampal neurogenesis and to alleviate depressive-like behaviors. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota dysbiosis generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

scholarly journals Ginsenoside Rb1 Induces a Pro-Neurogenic Microglial Phenotype via PPARγ Activation in Male Mice Exposed to Chronic Mild Stress

2021 ◽  
Author(s):  
Zili You ◽  
Lijuan Zhang ◽  
Minmin Tang ◽  
Xiaofang Xie ◽  
Qiuying Zhao ◽  
...  
Keyword(s):  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Immunofluorescence Staining ◽  
Mild Stress ◽  
Ginsenoside Rb1 ◽  
Male Mice ◽  
Antidepressant Effects

Abstract BackgroundAnti-inflammatory approaches are emerging as a new strategy for treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examined whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. MethodsThe antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by molecular markers and morphological properties, analyzed by RT-qPCR, western blotting and immunofluorescence staining. Effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro were detected using immunofluorescence staining. ResultsBehavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examinationdemonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were reversed by PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells.ConclusionsThese findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

scholarly journals Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPARγ activation in male mice exposed to chronic mild stress

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lijuan Zhang ◽  
Minmin Tang ◽  
Xiaofang Xie ◽  
Qiuying Zhao ◽  
Nan Hu ◽  
...  
Keyword(s):  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Immunofluorescence Staining ◽  
Mild Stress ◽  
Ginsenoside Rb1 ◽  
Male Mice ◽  
Antidepressant Effects

Abstract Background Anti-inflammatory approaches are emerging as a new strategy for the treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive-like behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examine whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. Methods The antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by pro- and anti-inflammatory cytokine expression and morphological properties, analyzed by RT-qPCR, western blotting, and immunofluorescence staining. The effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro was detected using immunofluorescence staining. Results Behavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examination demonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were effectively reversed by the PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells. Conclusions These findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

scholarly journals Changes in the functional connectome and behavior after exposure to chronic stress and increasing neurogenesis

2020 ◽  
Author(s):  
Luka Culig ◽  
Patrick E. Steadman ◽  
Justin W. Kenney ◽  
Sandra Legendre ◽  
Frédéric Minier ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Granule Cells ◽  
Brain Networks ◽  
Chronic Mild Stress ◽  
Protective Role ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Brain Circuitry ◽  
Newborn Neurons

AbstractAddition of new neurons to the dentate gyrus might change the activity of neural circuitry in the areas which the hippocampus projects to. The size of the hippocampus and the number of adult newborn granule cells are decreased by unpredictable chronic mild stress (UCMS). Additionally, one of the notable effects of chronic stress is the induction of ΔFosB, an unusually stable transcription factor which accumulates over time in several brain areas. This accumulation has been observed in many animal models of depression and it could have a protective role against stress, but no studies so far have explored how a specific increase in neurogenesis might regulate the induction and which brain networks might be predominately affected.We attempted to investigate the role of increasing adult hippocampal neurogenesis on stress-related behavior and the functional brain circuitry involved in mice exposed to UCMS. We used iBax mice, in which the pro-apoptotic gene Bax can be selectively ablated in neural stem cells, therefore inducibly enhancing survival of newborn neurons after tamoxifen administration. The animals were exposed to UCMS for 9 weeks and treated with tamoxifen in week 3 after the beginning of UCMS. In week 8, they were submitted to a battery of behavioral tests to assess depressive-like and anxiety-like behavior. In week 9, blood was collected to assess basal corticosterone levels, and the animals were sacrificed and their brain collected for ΔFosB immunohistochemistry. Brain-wide maps of ΔFosB expression were constructed and graph theoretical analyses were used to study the changes in brain networks after stress.UCMS induced negative correlations between the lateral entorhinal cortex and both the hippocampal structures and the nucleus accumbens in the VEH-treated mice, which were not present in other groups. Ranking nodes by degree reveals a strong thalamic-cortical signature in both non-stress (NS) groups. Exposure to UCMS seems to induce activity in thalamic areas and cerebral nuclei, with a different signature in the UCMS TAM group, which seems to completely “disengage” the neocortex and has most of its nodes with the most connections in the thalamic areas.

scholarly journals Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease

2020 ◽  
Vol 58 (1) ◽  
pp. 204-216
Author(s):  
Martina Stazi ◽  
Oliver Wirths
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Recognition Task ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Behavioral Deficits ◽  
Neuron Loss ◽  
Beneficial Effects ◽  
Memantine Treatment

AbstractMemantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer’s disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.

scholarly journals The Effects of Gene-Environment Interactions Between Cadmium Exposure and Apolipoprotein E4 on Memory in a Mouse Model of Alzheimer’s Disease

2019 ◽  
Author(s):  
Liang Zhang ◽  
Hao Wang ◽  
Glen M Abel ◽  
Daniel R Storm ◽  
Zhengui Xia
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Health Concern ◽  
Apoe Ε4 ◽  
Gene Environment ◽  
Cd Exposure

Abstract Cadmium (Cd) is a heavy metal of great public health concern. Recent studies suggested a link between Cd exposure and cognitive decline in humans. The ε4 allele, compared with the common ε3 allele, of the human apolipoprotein E gene (ApoE) is associated with accelerated cognitive decline and increased risks for Alzheimer’s disease (AD). To investigate the gene-environment interactions (GxE) between ApoE-ε4 and Cd exposure on cognition, we used a mouse model of AD that expresses human ApoE-ε3 (ApoE3-KI [knock-in]) or ApoE-ε4 (ApoE4-KI). Mice were exposed to 0.6 mg/l CdCl2 through drinking water for 14 weeks and assessed for hippocampus-dependent memory. A separate cohort was sacrificed immediately after exposure and used for Cd measurements and immunostaining. The peak blood Cd was 0.3–0.4 µg/l, within levels found in the U.S. general population. All Cd-treated animals exhibited spatial working memory deficits in the novel object location test. This deficit manifested earlier in ApoE4-KI mice than in ApoE3-KI within the same sex and earlier in males than females within the same genotype. ApoE4-KI but not ApoE3-KI mice exhibited reduced spontaneous alternation later in life in the T-maze test. Finally, Cd exposure impaired neuronal differentiation of adult-born neurons in the hippocampus of male ApoE4-KI mice. These data suggest that a GxE between ApoE4 and Cd exposure leads to accelerated cognitive impairment and that impaired adult hippocampal neurogenesis may be one of the underlying mechanisms. Furthermore, male mice were more susceptible than female mice to this GxE effect when animals were young.

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