scholarly journals Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Ksenia Musaelyan ◽  
Selin Yildizoglu ◽  
James Bozeman ◽  
Andrea Du Preez ◽  
Martin Egeland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Chronic Stress ◽  
Molecular Mechanisms ◽  
Dendritic Tree ◽  
Hippocampal Neurogenesis ◽  
Stress Disorders ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Neurogenic Niche

Abstract Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.

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 Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

2020 ◽  
Author(s):  
Evgenia Salta ◽  
Hannah Walgrave ◽  
Sriram Balusu ◽  
Elke Vanden Eynden ◽  
Sarah Snoeck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Memory Decline ◽  
Human Neural Stem Cells ◽  
Neurogenic Niche

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

scholarly journals Stress Modifies the Expression of Glucocorticoid-Responsive Genes by Acting at Epigenetic Levels in the Rat Prefrontal Cortex: Modulatory Activity of Lurasidone

2021 ◽  
Vol 22 (12) ◽  
pp. 6197
Author(s):  
Paola Brivio ◽  
Giulia Sbrini ◽  
Letizia Tarantini ◽  
Chiara Parravicini ◽  
Piotr Gruca ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Chronic Stress ◽  
Chronic Mild Stress ◽  
Male Rats ◽  
Mild Stress ◽  
Experimental Conditions ◽  
Glucocorticoid Responsive Element ◽  
Responsive Element

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45β, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45β and Gilz gene expression and lurasidone normalized the Gadd45β modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45β gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45β expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.

Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury

2021 ◽  
Vol 28 ◽  
Author(s):  
Lucas Alexandre Santos Marzano ◽  
Fabyolla Lúcia Macedo de Castro ◽  
Caroline Amaral Machado ◽  
João Luís Vieira Monteiro de Barros ◽  
Thiago Macedo e Cordeiro ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Cognitive Outcomes ◽  
Adult Hippocampal Neurogenesis ◽  
The Brain

: Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

Sexual activity counteracts the suppressive effects of chronic stress on adult hippocampal neurogenesis and recognition memory

2013 ◽  
Vol 1538 ◽  
pp. 26-40 ◽  
Author(s):  
Jong-In Kim ◽  
Jae Won Lee ◽  
Young Ah Lee ◽  
Dong-Hun Lee ◽  
Nam Soo Han ◽  
...  
Keyword(s):  
Recognition Memory ◽  
Sexual Activity ◽  
Chronic Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis

scholarly journals Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression

2021 ◽  
Vol 13 ◽  
Author(s):  
Katarzyna M. Grochowska ◽  
Julia Bär ◽  
Guilherme M. Gomes ◽  
Michael R. Kreutz ◽  
Anna Karpova
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Protein Transport ◽  
Pyramidal Neurons ◽  
Temporal Integration ◽  
Dendritic Tree ◽  
Nuclear Gene ◽  
Receptor Activation ◽  
Excitatory Input ◽  
Splice Isoforms

Pyramidal neurons exhibit a complex dendritic tree that is decorated by a huge number of spine synapses receiving excitatory input. Synaptic signals not only act locally but are also conveyed to the nucleus of the postsynaptic neuron to regulate gene expression. This raises the question of how the spatio-temporal integration of synaptic inputs is accomplished at the genomic level and which molecular mechanisms are involved. Protein transport from synapse to nucleus has been shown in several studies and has the potential to encode synaptic signals at the site of origin and decode them in the nucleus. In this review, we summarize the knowledge about the properties of the synapto-nuclear messenger protein Jacob with special emphasis on a putative role in hippocampal neuronal plasticity. We will elaborate on the interactome of Jacob, the signals that control synapto-nuclear trafficking, the mechanisms of transport, and the potential nuclear function. In addition, we will address the organization of the Jacob/NSMF gene, its origin and we will summarize the evidence for the existence of splice isoforms and their expression pattern.

scholarly journals Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Meltem Weger ◽  
Daniel Alpern ◽  
Antoine Cherix ◽  
Sriparna Ghosal ◽  
Jocelyn Grosse ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dna ◽  
Prefrontal Cortex ◽  
Mitochondrial Dysfunction ◽  
Chronic Stress ◽  
Mitochondrial Gene ◽  
Brain Regions ◽  
Mitochondrial Gene Expression ◽  
Data Set ◽  
A Genome

Abstract Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

scholarly journals JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

2016 ◽  
Vol 23 (2) ◽  
pp. 362-374 ◽  
Author(s):  
H Mohammad ◽  
F Marchisella ◽  
S Ortega-Martinez ◽  
P Hollos ◽  
K Eerola ◽  
...  
Keyword(s):  
Hippocampal Neurogenesis ◽  
Autonomous Control ◽  
Adult Hippocampal Neurogenesis ◽  
Neurogenic Niche
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