Salt-inducible kinase 1-CREB-regulated transcription coactivator 1 signalling in the paraventricular nucleus of the hypothalamus plays a role in depression by regulating the hypothalamic–pituitary–adrenal axis

Abstract

Elucidating the molecular mechanism underlying the hyperactivity of the hypothalamic-pituitaryadrenal axis during chronic stress is critical for understanding depression and treating depression. The secretion of corticotropin-releasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus is controlled by salt-inducible kinases (SIKs) and CREB-regulated transcription coactivators (CRTCs). We hypothesized that the SIK-CRTC system in the PVN might contribute to the pathogenesis of depression. Thus, the present study employed chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, virus-mediated gene transfer, enzyme linked immunosorbent assay, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immuno uorescence to investigate this connection. Our results revealed that both CSDS and CUMS induced signi cant changes in SIK1-CRTC1 signaling in PVN neurons. Both genetic knockdown of SIK1 and genetic overexpression of CRTC1 in the PVN simulated chronic stress, producing a depression-like phenotype in naïve mice, and the CRTC1-CREB-CRH pathway mediates the pro-depressant actions induced by SIK1 knockdown in the PVN.In contrast, both genetic overexpression of SIK1 and genetic knockdown of CRTC1 in the PVN protected against CSDS and CUMS, leading to antidepressant-like effects in mice. Moreover, stereotactic infusion of TAT-SIK1 into the PVN also produced bene cial effects against chronic stress. Furthermore, the SIK1-CRTC1 system in the PVN played a role in the antidepressant actions of uoxetine, paroxetine, venlafaxine, and duloxetine. Collectively, SIK1 and CRTC1 in PVN neurons are closely involved in depression neurobiology, and they could be viable targets for novel antidepressants.

Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR‐27b‐3p targeting the SIK1‐CREB1 axis

“…SIK1 is a serine/threonine protein kinase that can phosphorylate and deactivate CRTC1, 40 resulting in a decrease in CREB1 transcriptional activity 41 . We found that Sik1 is down‐regulated by miR‐27b‐3p, and then the transcriptional activity of CREB1 would be improved, in line with observations linking SIK1 to CREB transcriptional activity 56 …”

“…to CREB transcriptional activity. 56 F I G U R E 7 The effects on pro-cardiomyocyte-proliferation and pro-angiogenesis through miR-27b-3p derived from cardiopulmonary progenitor cells (CPPs) through CPPs exosomes (CPPs-Exo). To reveal the downstream genes regulated by CREB1 in our study, we employed Wayne (Venn) analysis to obtain the intersections between up-regulated DEGs in CM and EC cells treated with CPPs-Exo, and four other gene lists, which were CREB1 potential target genes in hESC, cancer cells, the CHEA database and the JASPAR database.…”

“… 41 We found that Sik1 is down‐regulated by miR‐27b‐3p, and then the transcriptional activity of CREB1 would be improved, in line with observations linking SIK1 to CREB transcriptional activity. 56 …”

Social defeat stress induces genome-wide 5mC and 5hmC alterations in the mouse brain

“…Moreover, 12 genes, 9 of which overlap with the published MDD genes, are implicated in Alzheimer's disease (AD). Also in the MDD overlap list is Sik1, a critical regulator of the corticotrophin-releasing hormone, a major hormone in the HPA-axis ( Wang et al . 2022 ).…”

Microglial Responses to Stress-Induced Depression: Causes and Consequences

“…However, poor efficacy of classical anti-depressants in many patients suggests a more complex pathology. Chronic stress is a major risk factor for MDD and has been associated with increased hypothalamic-pituitary-adrenal (HPA) axis activity and inflammatory activation of immune cells [7]. Increased levels of proinflammatory cytokines in the serum of depressed patients have inspired neuroscientists to investigate the possible role of neuroinflammation in depressive behavior [8].…”