Stress-Activated Protein Kinase JNK Modulates Depression-like Behaviors in Mice

Zhou, Xiaokun; Yi, Wenxiang; Zhi, Yiqiang; Yu, Jurui; Lu, Danping; Luo, Zhousong; Yuan, Ling; Chen, Liyu; Xu, Zhiheng; Xu, Dan

doi:10.1007/s12035-023-03209-x

Cited by 5 publications

(5 citation statements)

References 34 publications

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“…Additionally, JNK plays a role in the homeostatic regulation of glucocorticoid receptor transcriptional activity 25,28 . In contrast, when JNK is inhibited in mouse brain, a reduction in anxiety- and depressive-like behaviours is observed 55 , as is the case with JNK inhibitor treatment or genetic deletion 29,56–58 . In contrast, chimeric JNK activation induces depressive-like behaviour and impaired assessment of risk/reward benefit 58,59 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, when JNK is inhibited in mouse brain, a reduction in anxiety- and depressive-like behaviours is observed 55 , as is the case with JNK inhibitor treatment or genetic deletion 29,56–58 . In contrast, chimeric JNK activation induces depressive-like behaviour and impaired assessment of risk/reward benefit 58,59 . In zebrafish brain at the larval stage, JNK1 orthologs ( mapk8a and mapk8b) are expressed 60 , and consistent with behavioural findings in rodents 54 , we find that treatment with structurally independent JNK1 inhibitors SP600125 and JNK-IN-8, induce an AA phenotype with A.U.C.s of 97.9% and 98.3% respectively in the startle period.…”

Section: Discussionmentioning

confidence: 99%

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JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Hong,

Sourander,

Hackl

et al. 2024

Preprint

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Current treatments for anxiety and depression show limited efficacy in many patients indicating that research into new underlying mechanisms is needed. Inhibition of JNK1 has been shown to evoke an anxiolytic-and antidepressant-like phenotype in mice however the downstream effectors that elicit these behavioural effects are unknown. Here we employ a zebrafish (D. Rerio) larvae behavioural assay to identify an antidepressant-/anxiolytic-like phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from behavioural features measured during and after a startle battery in fish exposed to AA drugs (fluoxetine, imipramine, diazepam, lithium chloride, ketamine). We demonstrate that structurally independent JNK inhibitors replicate the AA classification with high accuracy, consistent with findings in mice. We go on to identify signalling hubs downstream from JNK1 by comparing phosphoproteome data from wildtype andJnk1-/-mouse brains, and test these hubs as possible mediators of the AA phenotype in zebrafish larvae. Among these, we find that AKT, GSK-3, 14-3-3ζ/ε and PKCε, when pharmacologically targeted, phenocopy clinically proven AA drugs. This assay shows promise as an early phase screening for compounds with anti-stress-axis/anxiolytic-like properties, and for mode of action analysis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Hong,

Sourander,

Hackl

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Additionally, JNK plays a role in the homeostatic regulation of glucocorticoid receptor transcriptional activity 28 , 31 . In contrast, when JNK is inhibited in mouse brain a reduction in anxiety- and depressive-like behaviours is observed 61 , as is the case with JNK inhibitor treatment or genetic deletion 36 , 62 – 64 . In contrast, chimeric JNK activation induces depressive-like behaviour and impaired assessment of risk/reward benefit 64 , 65 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, when JNK is inhibited in mouse brain a reduction in anxiety- and depressive-like behaviours is observed 61 , as is the case with JNK inhibitor treatment or genetic deletion 36 , 62 – 64 . In contrast, chimeric JNK activation induces depressive-like behaviour and impaired assessment of risk/reward benefit 64 , 65 . In zebrafish brain at the larval stage, JNK1 orthologues ( mapk8a and mapk8b) are expressed 66 , and consistent with behavioural findings in rodents 60 , we find that treatment with structurally independent JNK1 inhibitors SP600125 and JNK-IN-8, induce an AA phenotype with A.U.C.s of 97.9% and 98.3% respectively in the startle period.…”

Section: Discussionmentioning

confidence: 99%

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen

Hong,

Sourander,

Hackl

et al. 2024

Sci Rep

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Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14–3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.

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“…[ 34 ] AP-1 then stimulates the transcription of corticotropin-releasing factor (CRF) mRNA, thereby initiating the activation of the HPA axis. [ 35 ] When stress persists, JNK becomes responsible for phosphorylating c-Jun, which in turn initiates apoptosis. This process is closely associated with apoptosis observed in hippocampal neurons in depression.…”

Section: Classical Signaling Pathwaymentioning

confidence: 99%

Natural products for the treatment of depression: Insights into signal pathways influencing the hypothalamic–pituitary–adrenal axis

Liu,

Meng,

Wang

et al. 2023

Medicine

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Depression, a prevalent psychiatric malady, afflicts a substantial global demographic, engendering considerable disease burden due to its elevated morbidity and mortality rates. Contemporary therapeutic approaches for depression encompass the administration of serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants, albeit these pharmaceuticals potentially induce adverse neurological and gastrointestinal effects. Traditional Chinese Medicine (TCM) natural products proffer the benefits of multi-target, multi-level, and multi-channel depression treatment modalities. In this investigation, we conducted a comprehensive literature review of the past 5 years in PubMed and other databases utilizing the search terms “Depression,” “Natural medicines,” “Traditional Chinese Medicine,” and “hypothalamic–pituitary–adrenal axis.” We delineated the 5 most recent and pertinent signaling pathways associated with depression and hypothalamic–pituitary–adrenal (HPA) axis dysregulation: nuclear factor kappa light-chain-enhancer of activated B cell, brain-derived neurotrophic factor, mitogen-activated protein kinase, cyclic AMP/protein kinase A, and phosphoinositide 3-kinase/protein kinase B. Additionally, we deliberated the antidepressant mechanisms of natural medicines comprising alkaloids, flavonoids, polyphenols, saponins, and quinones via diverse pathways. This research endeavor endeavored to encapsulate and synthesize the progression of TCMs in modulating HPA axis-associated signaling pathways to mitigate depression, thereby furnishing robust evidence for ensuing research in this domain.

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Stress-Activated Protein Kinase JNK Modulates Depression-like Behaviors in Mice

Cited by 5 publications

References 34 publications

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen

Natural products for the treatment of depression: Insights into signal pathways influencing the hypothalamic–pituitary–adrenal axis

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