Dysregulation of Neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress

Dang, Ruili; Cai, Hualin; Zhang, Ling; Liang, Donglou; Lv, Chuanfeng; Guo, Yujin; Yang, Ranyao; Zhu, Yuan; Jiang, Pei

doi:10.1016/j.physbeh.2015.11.023

Cited by 38 publications

(27 citation statements)

References 38 publications

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“…68 However, in the chronic unpredicatable stress (CUS) model of depression in rats, NRG1 protein was significantly increased in the PFC. 69 This increased PFC NRG1 expression parallels the results found in our BDNF +/− model and implies increased PFC Nrg1 expression may contribute to the observed depressive-like phenotype in our model.…”

Section: Discussionsupporting

confidence: 87%

BDNF^+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

Martis

Wiborg

Holmes

et al. 2019

Genes Brain and Behavior

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Major depressive disorder (MDD) is a leading contributor to the global burden of disease. However, the causal relationship of risk factors, such as genetic predisposition or experience of augmented stress, remain unknown. Numerous studies in humans and rodents have implicated brain‐derived neurotrophic factor (BDNF) in MDD pathology, as a genetic risk factor and a factor regulated by stress. Until now, the majority of preclinical studies have employed genetically modified mice as their model of choice. However, mice display a limited behavioural repertoire and lack expression of circulating BDNF, which is present in rats and humans. Therefore, heterozygous BDNF (BDNF+/−) rats were tested for affective behaviours and accompanying expression of key genes associated with affective disorders in the brain. We found that BDNF+/− rats, which have reduced BDNF levels in brain and plasma, displayed symptoms of anhedonia, a core symptom of MDD, and anxiety‐like behaviour, but no behavioural despair or cognitive impairments. This was accompanied by changes in the expression of genes that are implicated in modulation of the stress response and affective disorders. Hence, glucocorticoid receptor, neuregulin 1 and disrupted‐in‐schizophrenia 1 gene expression were upregulated in the prefrontal cortex of BDFN+/− rats, whereas FK506 binding protein 5 levels were decreased in the hippocampus. We conclude that a reduction in BDNF levels alters expression of genes associated with affective disorders, which may contribute to the development of depressive‐like symptoms.

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Section: Discussionsupporting

confidence: 87%

BDNF^+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

Martis

Wiborg

Holmes

et al. 2019

Genes Brain and Behavior

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“…Neuregulin-1 has also been implicated in the response to antidepressant treatment in genetic analyses in humans and in animal models [38,39]. Our results supporting the hypothesis that altered levels of neuregulin/ErbB members in allostatic overload conditions play a role in the development of depressive behaviors are corroborated by findings in chronic mild stress rats, where neuregulin/ErbB signaling shows a dysregulation reversed by antidepressant treatment [40].…”

Section: Discussionsupporting

confidence: 83%

Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression

Carboni

Marchetti

Lauria

et al. 2018

Neuropsychopharmacol

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An enhanced understanding of the pathophysiology of depression would facilitate the discovery of new efficacious medications. To this end, we examined hippocampal transcriptional changes in rat models of disease and in humans to identify common disease signatures by using a new algorithm for signature-based clustering of expression profiles. The tool identified a transcriptomic signature comprising 70 probesets able to discriminate depression models from controls in both Flinders Sensitive Line and Learned Helplessness animals. To identify disease-relevant pathways, we constructed an expanded protein network based on signature gene products and performed functional annotation analysis. We applied the same workflow to transcriptomic profiles of depressed patients. Remarkably, a 171-probesets transcriptional signature which discriminated depressed from healthy subjects was identified. Rat and human signatures shared the SCARA5 gene, while the respective networks derived from protein-based significant interactions with signature genes contained 25 overlapping genes. The comparison between the most enriched pathways in the rat and human signature networks identified a highly significant overlap (p-value: 3.85 × 10) of 67 terms including ErbB, neurotrophin, FGF, IGF, and VEGF signaling, immune responses and insulin and leptin signaling. In conclusion, this study allowed the identification of a hippocampal transcriptional signature of resilient or susceptible responses in rat MDD models which overlapped with gene expression alterations observed in depressed patients. These findings are consistent with a loss of hippocampal neural plasticity mediated by altered levels of growth factors and increased inflammatory responses causing metabolic impairments as crucial factors in the pathophysiology of MDD.

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“… 14 – 18 Previous research showed that aberrant changes in these NRG1-related pathways are tightly linked to the pathogenesis of depression. 19 …”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Neuregulin-1/ErbB signaling in the hippocampus of rats after administration of doxorubicin

Liao¹,

Guo²,

Xiang³

et al. 2018

DDDT

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ObjectiveLong-term use of doxorubicin (Dox) can cause neurobiological side effects associated with depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural function, much is still unknown concerning the biological link between the NRG1/ErbB pathway and the Dox-induced neurotoxicity. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the hippocampus of rats following Dox treatment.Materials and methodsThe drug was administered every 2 days at a dose of 2.5 mg/kg, and the animals in different groups were treated with intraperitoneal injection for three or seven times, respectively.ResultsOur data showed that the rats treated with Dox for seven times (DoxL group) exhibited depression-like behaviors, whereas the short-term treatment (DoxS group) had no effect on the behavioral changes. Dox treatment also induced the neural apoptosis with more severe neurotoxicity. Intriguingly, the expression of NRG1 and the ratio of pErbB4/ErbB4 and pErbB2/ErbB2 were significantly decreased in the DoxL group, but enhanced activation of ErbB receptors was observed in the DoxS group. In parallel, administration of Dox for seven times suppressed the downstream Akt and ERK phosphorylation, while the Akt phosphorylation was enhanced with the administration of Dox for three times.ConclusionOur data first showed the Dox-induced alterations of the NRG1/ErbB system in the hippocampus, indicating the potential involvement of the NRG1/ErbB pathway in the Dox-induced nervous system dysfunction.

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Dysregulation of Neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress

Cited by 38 publications

References 38 publications

BDNF^+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

BDNF^+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression

Dysregulation of Neuregulin-1/ErbB signaling in the hippocampus of rats after administration of doxorubicin

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Dysregulation of Neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress

Cited by 38 publications

References 38 publications

BDNF+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

BDNF+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression

Dysregulation of Neuregulin-1/ErbB signaling in the hippocampus of rats after administration of doxorubicin

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BDNF^+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders

BDNF^+/− rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders