The Role And Mechanism Study Of Glucocorticoid Receptor Signaling In The Differential Regulation Of Amygdala Neuronal Structure By Chronic Stress

Persistent stress exposure(Chronic stress)is among the most common social and environmental factors which cause psychiatric disorders,such as anxiety disorders.Anxiety disorders have the highest prevalence in China and the world and have become a major public health problem affecting human health,economic and social development.It is of great significance and urgence to understand the pathogenic mechanism of anxiety disorders and other psychiatric disorders comprehensively and deeply,so as to develop more accurate and effective strategies for prevention and treatment of the diseases.Amygdala is one of the core target area of chronic stress impairing the emotional function of brain,especially the basolateral amygdala(BLA),and its structure and function remodeling are closely related to the occurrence of psychiatric disorders,such as anxiety disorders.The previous study of our group found that in the process of chronic stress-induced anxiety,it differentially regulates the synaptic structure of BLA neurons in different neural circuits.Chronic restraint stress(CRS)selectively affected BLA neurons projected to the ventral hippocampus(vHPC),increasing the density of mature spines and enhancing the excitatory glutamatergic transmission.The projection of BLA neurons to the medial prefrontal cortex(mPFC)and nucleus accumbens(NAc)were not significantly affected,but the underlying regulatory mechanisms remain unclear.BLA neurons are highly heterogeneous in terms of their connectivity and functionality.Although these neurons are extensively intermingled neurons,two adjacent neurons are likely to be involved in completely different neural circuits.It should be pointed out that their micro-environments(e.g.,significant increased concentration of corticoid during the stress process)are quite similar,but the individual BLA neurons undergo sharply different adaptation,suggesting that potentially different mechanisms of signal reception or transmission emerge among these neurons.Chronic stress exposure causes excessive activation of hypothalamic-pituitary-adrenal(HPA)axis,yielding continuous release of glucocorticoid levels with resultant activation of glucocorticoid receptor(GR)signaling,which is thought to play an important role in the regulation of neuronal structure and function in amygdala.Previous studies have shown that abnormal GR activation can cause changes in neuronal morphology,synaptic function.We hypothesized that GR signaling may play a corresponding role in the differential regulation of BLA neurons in different circuits by chronic stress.To answer the above questions,we used a chronic restraint stress(CRS)paradigm to explore the role and potential mechanisms of glucocorticoid receptor signaling in the differential regulation of different BLA neurons by chronic stress.The results showed that:(1)CRS significantly enhanced the GR expression of BLA neurons projected to vHPC(BLA→vHPC Projection Neuros,PNs),while had no obvious effect on the GR expression of BLA neurons projected to mPFC and NAc.(2)The glucocorticoid level in mice increased continuously with the increase of stress time,which caused GR Overresponsive in BLA→vHPC PNs.(3)Blocking GR pathway could effectively reverse CRS induced the dendritic proliferation and spine remodeling of BLA→vHPC PNs.(4)Blocking GR pathway could effectively relieve the increasing effect of CRS on anxiety like behaviors in mice.Together,CRS can cause elevated glucocorticoid levels in mice and cause preferential increase of glucocorticoid receptor expression in BLA→vHPC PNs,which may mediate the differential regulation of the synaptic structure of BLA neurons engaged in different neural circuits,and subsequently affect the occurrence of anxiety-like behavior.This study provide further insight into the understanding of the mechanisms by which chronic stress affects the emotional function in brain,laying more comprehensive theoretical and experimental foundations for seeking the precise approaches to prevent and treat the stress-related affective disorders.