Mol Psychiatry—Jiang Bo's research group at Nantong University reveals a new molecular mechanism by which chronic stress induces depressive-like symptoms through HPA axonal excitation

Written by Jiang Bo

Responsible editor—Wang Sizhen, Fang Yiyi

Editor—Sizhen Wang

As we all know, depression is caused by the interaction of physiological, psychological, genetic and other factors, of which chronic stress is an important trigger
.
Multi-year studies have shown that hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis is involved in the neurobiological process of depression [1-3].

Chronic stress causes the HPA axis to release excess glucocorticoids, which continuously and intensively agitate glucocorticoid receptors in neurons in brain regions such as the hippocampus, causing neuronal atrophy, dendritic spine loss, nerve damage, and decreased synthesis of brain-derived neurotrophic factor (BDNF) [4-8].

However, the molecular mechanism by which chronic stress causes hypothalamic paraventricular nuclear neurons to synthesize and release excess adrenocorticotropin-releasing hormone (CRH) and cause HPA axis hyperactivity remains unclear
.

The biosynthesis of CRH is known to be regulated by cyclic adenosine monophosphate reactive element binding protein (CREB)[9], and CREB function is regulated by CREB transcriptionally regulated coactivators ( CRTC1/2/3) is regulated [10-12], while CRTC1/2/3 activity is controlled by salt-induced kinase (SIK1/2/3) (SIK Regulates the transport of CRTC into the nucleus, affecting the formation of CRTC-CREB complexes) [13-17].

Several studies have reported that the transcriptional synthesis of CRH and HPA axis hyperactivity require the joint action of CRTC and CREB in the hypothalamic nucleus, and they are positively correlated [18-20]
。 This can raise a question: whether chronic stress can affect the expression of SIK in the hypothalamus, thereby regulating the formation of intranuclear CRTC-CREB complexes, thereby greatly promoting the active function of CREB and excessive synthesis and secretion CRH, which causes HPA axis hyperactivity and eventually induces depression?

On November 25, 2022, Jiang Bo's research group from the School of Pharmacy of Nantong University published a paper in Molecular Psychiatry ) was published entitled "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", which found the hypothalamic paraventricular nucleus SIK1 It promotes HPA axis hyperactivity by positively regulating the CRTC1-CREB-CRH pathway, and thus mediates the process of chronic stress-induced depression.
Overexpression increases paraventricular nuclear SIK1 function and produces significant antidepressant effects; Paraventricular nuclear SIK1 is involved in the pharmacological effects
of clinical antidepressants fluoxetine, paroxetine, venlafaxine and duloxetine.
In addition, the paper has been invited as a journal cover article
.

The researchers first found (Figure 1) that two classical models of depression, chronic social frustration stress (CSDS) and chronic unpredictable mild stress (CUMS), were induced The depressive-like behavior of C57BL/6I mice significantly reduced the protein and mRNA expression levels of SIK1 in the paraventricular nucleus of the hypothalamus (by more than 60%), without affecting the paraventricular nucleus Protein and mRNA expression levels
of SIK1 and SIK3.
Subsequently, both CSDS and CUMS were found to significantly increase the level of intranuclear CRTC1 protein in paraventricular nuclear neurons, while significantly reducing their cytoplasmic pCRTC1 ( Ser-151) levels without affecting the nucleus CRTC2, CRTC3, and cytoplasmic pCRTC2 (Ser-171 ) with the level of
pCRTC3 (Ser-163).
qRT-PCR and Co-IP experiments have found that both CSDS and CUMS have a significant increase in CRTC1-mRNA in the paraventricular nucleus levels (about 50% increase) and intranuclear CRTC1-CREB binding levels
.
This preliminarily indicates that the SIK1-CRTC1 pathway in the PVN region is involved in the process
of chronic stress-induced depression.

Figure 1 Chronic stress significantly alters the level of the SIK1-CRTC1 signaling pathway in the paraventricular nucleus of mice in the hypothalamic nucleus.