Interleukin-4 is a participant in the regulation of depressive-like behavior

Wachholz, Simone; Knorr, Alexandra; Mengert, Leonie; Plümper, Jennifer; Sommer, Rainer; Juckel, Georg; Friebe, Astrid

doi:10.1016/j.bbr.2017.03.020

Cited by 40 publications

(29 citation statements)

References 43 publications

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“…Theoretically, anti inflammatory factors would be expected to reduce 5-HT levels in the brain due to their role in suppression of pro-inflammatory factor expression. Indeed, IL4 reduces the 5-HT or SERT levels (Mossner et al, 2001;Pannell et al, 2014;Park et al, 2015;Wachholz et al, 2017), supporting our findings. Therefore, in adult zebrafish brain, AD conditions elicit an inflammatory regulation by IL4 on serotonin, which translates into a neurotransmitter response in a specific neuronal subtype that directly regulates a subpopulation of NSCs.…”

Section: Discussionsupporting

confidence: 89%

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Bhattarai

Coşacak

Mashkaryan

et al. 2019

Preprint

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It was recently suggested that supplying the brain with new neurons could counteract Alzheimer's disease. This provocative idea requires further testing in experimental models where the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in Alzheimer's disease and could help to understand the mechanisms to be harnessed for develop new neurons in diseased mammalian brains. Here, by performing singlecell transcriptomics, we found that Amyloid toxicity-induced Interleukin-4 induces NSC proliferation and neurogenesis by suppressing the tryptophan metabolism and reducing the production of Serotonin. NSC proliferation was suppressed by Serotonin via downregulation of BDNF-expression in Serotoninresponsive periventricular neurons. BDNF enhances NSC plasticity and neurogenesis via NGFRA/NFkB signaling in zebrafish but not in rodents. Collectively, our results suggest a complex neuron-glia interaction that regulates regenerative neurogenesis after Alzheimer's disease conditions in zebrafish. Key findings-Amyloid-induced Interleukin-4 suppresses Serotonin (5-HT) production in adult zebrafish brain -5-HT affects htr1-expresing neurons and suppresses bdnf expression -BDNF enhances plasticity in neural stem cells via NGFRA/NFkB signaling -BDNF/NGFRA signaling is a neuro-regenerative mechanism in zebrafish but not in mammals.

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Section: Discussionsupporting

confidence: 89%

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Bhattarai

Coşacak

Mashkaryan

et al. 2019

Preprint

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“…Upregulation of IL4 in the hippocampus protected mice from stress-induced depressive-like behaviors, consistent with the finding that IL4 overexpression has antidepressant effects 21 . Our transcriptome analysis showed that CMS leads to decreased expression of genes related to immune regulation (Arg1, Irf7, Irf9, etc.)…”

Section: Discussionsupporting

confidence: 89%

“…In our study we found that the levels of IL4 were decreased in the hippocampus of HS mice, but increased in LS mice. Vulnerability to chronic stress is associated with dysregulation of pro-and anti-inflammatory cytokines, in particular an ineffective IL4 pathway 21 . The reduction of IL4 levels can render individuals more vulnerable to stress and more likely to engage in depressive-like behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…Interleukin 4 (IL4) is a multifunctional cytokine expressed in the brain and is involved in the regulation of inflammatory responses and physiological processes of the central nervous system (CNS) [17][18][19] . IL4 deficiency weakens the resilience against stress-induced depression, while increasing IL4 levels can alleviate depressive-like behaviors [20][21][22][23] . Studies have shown that IL4 can reprogram microglia toward an Arg1 + phenotype for maintaining brain homeostasis, neuroprotection and tissue repair [24][25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

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IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

Zhang

Rong

Zhang

et al. 2020

Preprint

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Running title: IL4-driven microglia modulate neurogenesis and stress resilience In Brief:Zhang et al. show that IL4-induced Arg1 + microglia restore hippocampal neurogenesis and promote resilience against stress in mice by increasing BDNF levels. Targeting microglia with immunomodulatory factors may be a strategy for treating mood disorders.2 Highlights:1. Vulnerability to stress in mice is associated with reduced IL4 signaling in the hippocampus 2. Brain-derived IL4 promotes adult hippocampal neurogenesis and stress resistance by driving Arg1 + microglia 3. IL4-driven Arg1 + microglia enhance hippocampal neurogenesis via a BDNF-dependent pathway 3 Abstract Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific groups of microglia and is functionally implicated in behavioral responses to stress. However, the role of microglia in modulating hippocampal neurogenesis in stress responses remains poorly understood. Here we investigated the effects of IL4-driven Arg1 + microglia in the restoration of hippocampal neurogenesis and conferment of stress resilience. We found that low IL4 levels in the hippocampus of mice was associated with greater stress vulnerability and, conversely, overexpression of IL4 in the hippocampus induced a large number of Arg1 + microglia and ameliorated stress-induced depressive-like behaviors. Knockdown of microglial IL4 receptors in the hippocampus of mice exacerbated the stress-induced inflammatory response and abolished the antidepressant effects of IL4 overexpression. Enhancement or inhibition of IL4 signaling in hippocampal microglia modulated neurogenesis, and blockade of neurogenesis abolished the resilience to stress-induced depression. We further show that IL4-activated microglia is associated with upregulation of BDNF levels and neurogenesis. Taken together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis in response to chronic stress, helping protect against depressive-like symptoms. These findings identify the modulation of a specific microglial phenotype as a treatment strategy for mood disorders.

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“…Less research on disrupted behavior after an acute or chronic activation of the immune system in adult animals has been conducted. Nevertheless, there is evidence that even in adulthood activation of the immune system can induce depressive-like behavior and anxiety (Remus and Dantzer 2016; Wachholz et al 2017). So far no reports on adult immune activation and mania-associated behaviors in animal models exist.…”

Section: Introductionmentioning

confidence: 99%

Animal models for bipolar disorder: from bedside to the cage

Beyer

Freund

2017

Int J Bipolar Disord

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Bipolar disorder is characterized by recurrent manic and depressive episodes. Patients suffering from this disorder experience dramatic mood swings with a wide variety of typical behavioral facets, affecting overall activity, energy, sexual behavior, sense of self, self-esteem, circadian rhythm, cognition, and increased risk for suicide. Effective treatment options are limited and diagnosis can be complicated. To overcome these obstacles, a better understanding of the neurobiology underlying bipolar disorder is needed. Animal models can be useful tools in understanding brain mechanisms associated with certain behavior. The following review discusses several pathological aspects of humans suffering from bipolar disorder and compares these findings with insights obtained from several animal models mimicking diverse facets of its symptomatology. Various sections of the review concentrate on specific topics that are relevant in human patients, namely circadian rhythms, neurotransmitters, focusing on the dopaminergic system, stressful environment, and the immune system. We then explain how these areas have been manipulated to create animal models for the disorder. Even though several approaches have been conducted, there is still a lack of adequate animal models for bipolar disorder. Specifically, most animal models mimic only mania or depression and only a few include the cyclical nature of the human condition. Future studies could therefore focus on modeling both episodes in the same animal model to also have the possibility to investigate the switch from mania-like behavior to depressive-like behavior and vice versa. The use of viral tools and a focus on circadian rhythms and the immune system might make the creation of such animal models possible.

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Interleukin-4 is a participant in the regulation of depressive-like behavior

Cited by 40 publications

References 43 publications

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis

Animal models for bipolar disorder: from bedside to the cage

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