Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation

In humans and other hierarchical species, social status is tightly linked to variation in health and fitness-related traits. Experimental manipulations of social status in female rhesus macaques suggest that this relationship is partially explained by status effects on immune gene regulation. However, social hierarchies are established and maintained in different ways across species: While some are based on kin-directed nepotism, others emerge from direct physical competition. We investigated how this variation influences the relationship between social status and immune gene regulation in wild baboons, where hierarchies in males are based on fighting ability but female hierarchies are nepotistic. We measured rank-related variation in gene expression levels in adult baboons of both sexes at baseline and in response to ex vivo stimulation with the bacterial endotoxin lipopolysaccharide (LPS). We identified >2,000 rank-associated genes in males, an order of magnitude more than in females. In males, high status predicted increased expression of genes involved in innate immunity and preferential activation of the NF-κB-mediated proinflammatory pathway, a pattern previously associated with low status in female rhesus macaques. Using Mendelian randomization, we reconcile these observations by demonstrating that high status-associated gene expression patterns are precursors, not consequences, of high social status in males, in support of the idea that physiological condition determines who attains high rank. Together, our work provides a test of the relationship between social status and immune gene regulation in wild primates. It also emphasizes the importance of social context in shaping the relationship between social status and immune function.

https://www.pnas.org/content/pnas/115/52/E12163.full.pdf

Dominance rank-associated gene expression is widespread, sex-specific, and a precursor to high social status in wild male baboons.

Background and purpose Developing novel pharmacological targets beyond the monoaminergic system is now a popular strategy for treating depression. PPARα is a nuclear receptor protein that functions as a transcription factor,-regulating gene expression. We have previously reported that both WY14643 and fenofibrate, two pharmacological agonists of PPARα, have antidepressant-like effects in mice, implying that PPARα is a potential antidepressant target. Experimental approach We first used various biotechnological methods to evaluate the effects of chronic stress and fluoxetine on hippocampal PPARα. The viral-mediated genetic approach was then employed to explore whether hippocampal PPARα was an antidepressant target. PPARα inhibitors, PPARα-knockout (KO) mice and PPARα-knockdown (KD) mice were further used to determine the role of PPARα in the antidepressant effects of fluoxetine. Key results Chronic stress significantly decreased mRNA and protein levels of PPARα in the hippocampus, but not other regions, and also fully reduced the recruitment of hippocampal PPARα to the cAMP response element-binding (CREB) promoter. Genetic overexpression of hippocampal PPARα induced significant antidepressant-like actions in mice by promoting CREB-mediated biosynthesis of brain-derived neurotrophic factor. Moreover, fluoxetine notably restored the stress-induced negative effects on hippocampal PPARα. Using PPARα antagonists fully blocked the antidepressant effects of fluoxetine in mice, and similarly, both PPARα-KO and PPARα-KD abolished the effects of fluoxetine. Besides, PPARα-KO and PPARα-KD aggravated depression in mice. Conclusions and implications Hippocampal PPARα is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.14346

Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice.

Stressful experiences are part of everyday life and animals have evolved physiological and behavioral responses aimed at coping with stress and maintaining homeostasis. However, repeated or intense stress can induce maladaptive reactions leading to behavioral disorders. Adaptations in the brain, mediated by changes in gene expression, have a crucial role in the stress response. Recent years have seen a tremendous increase in studies on the transcriptional effects of stress. The input raw data are freely available from public repositories and represent a wealth of information for further global and integrative retrospective analyses. We downloaded from the Sequence Read Archive 751 samples (SRA-experiments), from 18 independent BioProjects studying the effects of different stressors on the brain transcriptome in mice. We performed a massive bioinformatics re-analysis applying a single, standardized pipeline for computing differential gene expression. This data mining allowed the identification of novel candidate stress-related genes and specific signatures associated with different stress conditions. The large amount of computational results produced was systematized in the interactive "Stress Mice Portal".

/pdf/a-gene-expression-atlas-for-different-kinds-of-stress-in-the-3djxhvd63y.pdf

A gene expression atlas for different kinds of stress in the mouse brain.

Humans and animals live in social relationships shaped by actions of approach and avoidance. Both are crucial for normal physical and mental development, survival, and well-being. Active withdrawal from social interaction is often induced by the perception of threat or unpleasant social experience and relies on adaptive mechanisms within neuronal networks associated with social behavior. In case of confrontation with overly strong or persistent stressors and/or dispositions of the affected individual, maladaptive processes in the neuronal circuitries and its associated transmitters and modulators lead to pathological social avoidance. This review focuses on active, fear-driven social avoidance, affected circuits within the mesocorticolimbic system and associated regions and a selection of molecular modulators that promise translational potential. A comprehensive review of human research in this field is followed by a reflection on animal studies that offer a broader and often more detailed range of analytical methodologies. Finally, we take a critical look at challenges that could be addressed in future translational research on fear-driven social avoidance.

/pdf/molecular-and-neurocircuitry-mechanisms-of-social-avoidance-5foz0ej5c2.pdf

Molecular and neurocircuitry mechanisms of social avoidance

Chronic stress is a risk factor for major depression. Social defeat stress is a well-validated murine model of depression. However, little is known about the gene activity dynamics during the development of a depression-like state. We analyzed the effects of social defeat stress of varying duration (10 and 30 days) on the behavioral patterns and prefrontal-cortex transcriptome of C57BL/6 mice. The 10-day exposure to social defeat stress resulted in a high level of social avoidance with no signs of depression-associated behavior. Most animals exposed to 30 days of social defeat stress demonstrated clear hallmarks of depression, including a higher level of social avoidance, increased immobility in the forced swimming test, and anhedonic behavior. The monitoring of transcriptome changes revealed widespread alterations in gene expression on the 10th day. Surprisingly, the expression of only a few genes were affected by the 30th day of stress, apparently due to a reversal of the majority of the early stress-induced changes to the original basal state. Moreover, we have found that glucocorticoid-sensitive genes are clearly stimulated targets on the 10th day of stress, but these genes stop responding to the elevated corticosterone level by the 30th day of stress. The majority of genes altered by the 30-day stress were downregulated, with the most relevant ones participating in chromatin modifications and neuroplasticity (e.g., guanine nucleotide exchange factors of the Rho-family of GTPases). Very different molecular responses occur during short-term and long-term social stress in mice. The early-stress response is associated with social avoidance and with upregulation and downregulation of many genes, including those related to signal transduction and cell adhesion pathways. Downregulation of a few genes, in particular, genes for histone-modifying methyltransferases, is a signature response to prolonged stress that induces symptoms of depression. Altogether, our data show that the development of depression under social stress conditions is correlated with suppression of the overactive molecular response to induced stress, involving gene regulatory resistance to glucocorticoid molecules, potentially via a chromatin remodeling mechanism.

Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice

The effects of two influences, social stress and acute opisthorchiasis, were investigated in inbred C57BL/6J male mice. In the model of social stress, mice were repeatedly attacked and defeated by aggressive outbred ICR male mice and were in continuous sensory contact with an aggressive conspecific mouse in their home cage for 20 days. Acute opisthorchiasis was provoked by invasion of Opisthorchis felineus (50 larvae per animal) on the fourth day after the social stress was induced. Simultaneous action of both factors caused the hypertrophy of adrenal glands, as well as elevated the activity of cathepsins B and L in the spleen. This effect on the activity of the cysteine proteases in the hippocampus and hypothalamus following O. felineus invasion was the predominant result of simultaneous action with social stress. Acute opisthorchiasis, social stress, and their combination caused an increase in the level of blood IL-6 in approximately 30% of the animals. Social stress induced a more pronounced effect on mouse plus-maze behavior than O. felineus invasion. Our results suggest a more severe negative effect of the simultaneous influence of both factors on most of the parameters that were investigated.

Mikhail V. Tenditnik

Papers

Molecular Adaptations to Social Defeat Stress and Induced Depression in Mice

Combined effects of social stress and liver fluke infection in a mouse model.