Shared Transcriptional Signatures in Major Depressive Disorder and Mouse Chronic Stress Models

Background Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Methods Using western blot analyses and quantitative real-time polymerase chain reaction, we assessed the effects of five-weeks of chronic unpredictable stress exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin, parvalbumin, and calretinin), and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y, vasoactive intestinal peptide, and cholecystokinin) in the prefrontal cortex and hippocampus of rats. We also investigated the effects of corticosterone and dexamethasone exposure on these markers in vitro in primary cortical and hippocampal cultures. Results We found that chronic unpredictable stress induced significant reductions of GAD67 protein levels in both the prefrontal cortex and hippocampus of chronic unpredictable stress-exposed rats but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely somatostatin and neuropeptide Y, in the prefrontal cortex, suggesting these cell types may be selectively vulnerable to chronic stress. Conclusion Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder.

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Molecular mechanism of reward treatment ameliorating chronic stress-induced depressive-like behavior assessed by sequencing miRNA and mRNA in medial prefrontal cortex

10.21203/rs.3.rs-23798/v1 ◽

2020 ◽

Author(s):

Tingting An ◽

Zhenhua Song ◽

Jin-Hui Wang

Keyword(s):

Major Depressive Disorder ◽

Prefrontal Cortex ◽

Depressive Disorder ◽

Molecular Mechanism ◽

Chronic Stress ◽

Medial Prefrontal Cortex ◽

Differentially Expressed ◽

Mild Stress ◽

Major Depressive ◽

Differentially Expressed Mirnas

Abstract Background Major depressive disorder (MDD) is a disease that seriously endangers human health and mental state. Chronic stress and lack of reward may reduce the function of the brain's reward circuits, leading to major depressive disorder. The effect of reward treatment on chronic stress-induced depression-like behaviors and its molecular mechanism in the brain remain unclear.Methods Mice were divided into the groups of control, chronic unpredictable mild stress (CUMS), and CUMS-companion. Mice of CUMS group was performed by CUMS for 4 weeks, and CUMS-companion group was treated by CUMS accompanied with companion. The tests of sucrose preference, Y-maze, and forced swimming were conducted to assess depression-like behaviors or resilience. High-throughput sequencing was used to analyze mRNA and miRNA profiles in the medial prefrontal cortex harvested from control, CUMS-MDD (mice with depression-like behaviors in CUMS group), Reward-MDD (mice with depression-like behaviors in CUMS-companion group), CUMS-resilience (resilient mice in CUMS group), Reward-resilience (resilient mice in CUMS-companion group) mice.Results The results provided evidence that accompanying with companion ameliorated CUMS-induced depression-like behaviors in mice. 45 differentially expressed genes (DEGs) are associated with depression-like behaviors, 8 DEGs are associated with resilience and 59 DEGs are associated with nature reward (companion) were identified. Furthermore, 196 differentially expressed miRNAs were found to be associated with companion. Based on the differentially expressed miRNAs and DEGs data, miRNA-mRNA network was established to be associated with companion.Conclusion Taken together, our data here provided a method to ameliorate depression-like behaviors, and numerous potential drug targets for the prevention or treatment of depression.

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Central and Peripheral Inflammation Link Metabolic Syndrome and Major Depressive Disorder

Physiology ◽

10.1152/physiol.00047.2018 ◽

2019 ◽

Vol 34 (2) ◽

pp. 123-133 ◽

Cited By ~ 21

Author(s):

Kenny L. Chan ◽

Flurin Cathomas ◽

Scott J. Russo

Keyword(s):

Metabolic Syndrome ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Chronic Stress ◽

Immune Cells ◽

Low Grade ◽

Major Depressive ◽

Metabolic Dysregulation ◽

Critical Areas ◽

Behavioral Abnormalities

Metabolic syndrome and major depression are two of the most common and debilitating disorders worldwide, occurring with significant rates of comorbidity. Recent studies have uncovered that each of these conditions is associated with chronic, low-grade inflammation. This is characterized by increased circulating pro-inflammatory cytokines, altered leukocyte population frequencies in blood, accumulation of immune cells in tissues including the brain, and activation of these immune cells. Cytokines that become elevated during obesity can contribute to the progression of metabolic syndrome by directly causing insulin resistance. During chronic stress, there is evidence that these cytokines promote depression-like behavior by disrupting neurotransmitter synthesis and signal transduction. Animal models of obesity and depression have revealed a bi-directional relationship whereby high-fat feeding and chronic stress synergize and exacerbate metabolic dysregulation and behavioral abnormalities. Although far from conclusive, emerging evidence suggests that inflammation in the central and peripheral immune system may link metabolic syndrome to major depressive disorder. In this review, we will synthesize available data supporting this view and identify critical areas for future investigation.

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Evaluation of cognitive diathesis-stress models in predicting major depressive disorder in adolescents.

Journal of Abnormal Psychology ◽

10.1037/0021-843x.110.2.203 ◽

2001 ◽

Vol 110 (2) ◽

pp. 203-215 ◽

Cited By ~ 160

Author(s):

Peter M. Lewinsohn ◽

Thomas E. Joiner ◽

Paul Rohde

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Major Depressive ◽

Stress Models

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Pathophysiology of affective disorders: functional interaction of stress hormones and hippocampal excitation

Journal of Neurophysiology ◽

10.1152/jn.01065.2015 ◽

2017 ◽

Vol 117 (2) ◽

pp. 477-479

Author(s):

M. Adrienne McGinn ◽

Amanda R. Pahng

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Chronic Stress ◽

Affective Disorders ◽

Stress Hormones ◽

Emotional Behavior ◽

Hippocampal Function ◽

Functional Interaction ◽

Major Depressive ◽

New Finding

An important new study by Kvarta, Bradbrook, Dantrassy, Bailey, and Thompson ( J Neurophysiol 114: 1713–1724, 2015) examined the effects of persistent stress and excessive glucocorticoid levels on hippocampal function and emotional behavior in rodents. The authors specifically implicate the temporoammonic pathway as being susceptible to reductions in excitatory function in the context of chronic stress. We discuss the importance of this new finding in the broader context of medication development for major depressive disorder.

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Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients

Translational Psychiatry ◽

10.1038/s41398-021-01733-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kelly J. Heard ◽

Maxim N. Shokhirev ◽

Caroline Becronis ◽

Callie Fredlender ◽

Nadia Zahid ◽

...

Keyword(s):

Major Depressive Disorder ◽

Stem Cell ◽

Depressive Disorder ◽

Chronic Stress ◽

Prolonged Exposure ◽

Negative Impact ◽

Ion Homeostasis ◽

Induced Pluripotent Stem Cell ◽

Major Depressive

AbstractMajor depressive disorder (MDD) is a prevalent psychiatric disorder, and exposure to stress is a robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic exposure to stress-induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, the astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of “chronic stress” using human induced pluripotent stem cell (iPSC)-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. The MDD-specific DEGs are related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.

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P2X7 Receptor as a Potential Target for Major Depressive Disorder

Current Drug Targets ◽

10.2174/1389450122666210120141908 ◽

2021 ◽

Vol 22 ◽

Author(s):

Zeyi Huang ◽

Sijie Tan

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Chronic Stress ◽

Inflammatory Cytokines ◽

P2x7 Receptor ◽

Microglia Activation ◽

Major Depressive ◽

Bbb Permeability ◽

The Brain

Major depressive disorder (MDD) is a common mental disorder. Although the genetic, biochemical, and psychological factors have been related to the development of MDD, it is generally believed that a series of pathological changes in the brain caused by chronic stress is the main cause of MDD. However, the specific mechanisms underlying chronic stress-induced MDD are largely undermined. Recent investigations have found that increased pro-inflammatory cytokines and changes in the inflammatory pathway in the microglia cells in the brain are the potential pathophysiological mechanism of MDD. P2X7 receptor (P2X7R) and its mediated signaling pathway play a key role in microglia activation. The present review aimed to present and discuss the accumulating data on the role of P2X7R in MDD. Firstly, we summarized the research progress in the correlation between P2X7R and MDD. Subsequently, we presented the P2X7R mediated microglia activation in MDD and the role of P2X7R in increased blood-brain barrier (BBB) permeability caused by chronic stress. Lastly, we also discussed the potential mechanism underlying P2X7R expression changes after chronic stress. In conclusion, P2X7R is a key molecule regulating the activation of microglia. Chronic stress activates microglia in the hippocampus by secreting interleukin-1β (IL-1β) and other inflammatory cytokines, and increasing the BBB permeability, thus promoting the occurrence and development of MDD, which indicated that P2X7R might be promising therapeutic target for MDD.

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