Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca2+-Activin A circuit in chronic cerebral hypoperfusion rats.

Xin Zhang,Xiaohua Shi,Jiaoqi Wang,Zhongxin Xu,Jinting He

doi:10.18632/aging.203462

Xin Zhang, Xiaohua Shi + Show 3 more

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https://doi.org/10.18632/aging.203462

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Journal: Aging	Publication Date: Aug 30, 2021
Citations: 13	License type: cc-by

Affiliation: Union Hospital, Jilin University

Abstract

Chronic cerebral ischemia (CCI) is one of the critical factors in the occurrence and development of vascular cognitive impairment (VCI). Apoptosis of nerve cells and changes in synaptic activity after CCI are the key factors to induce VCI. Synaptic stimulation up-regulates intraneuronal Ca2+ level through N-methyl-D-aspartic acid receptor (NMDAR) via induction of the activity-regulated inhibitor of death (AID) expression to produce active-dependent neuroprotection. Moreover, the regulation of synaptic plasticity could improve cognition and learning ability. Activin A (ActA), an exocrine protein of AID, can promote NMDAR phosphorylation and participate in the regulation of synaptic plasticity. We previously found that exogenous ActA can improve the cognitive function of rats with chronic cerebral ischemia and enhance the oxygenated glucose deprivation of intracellular Ca2+ level. In addition to NMDAR, the Wnt pathway is critical in the positive regulation of LTP through activation or inhibition. It plays an essential role in synaptic transmission and activity-dependent synaptic plasticity. The enriched environment can increase ActA expression during CCI injury. We speculated that the NMDAR-Ca2+-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca2+-ActA, Wnt/β-catenin pathway is involved in this process. For the hypothesis verification, this study intends to establish chronic cerebral hypoperfusion (CCH) rat model, explore the improvement effect of enriched environment on VCI, detect the changes in plasticity of synaptic morphology and investigate the regulatory mechanism NMDAR-Ca2+-ActA-Wnt/β-catenin signaling loop, providing a therapeutic method for the treatment of CCH.

Highlights

Chronic cerebral hypoperfusion (CCH) is a common pathological state of the nervous system and an essential in the occurrence and development of vascular cognitive impairment (VCI) [1]
Hippocampus and other regions are more sensitive to ischemia and hypoxia, the changes in neuronal apoptosis and synaptic activity caused by CCH are more detectable, CCH is the crucial cause of VCI [2]
While EE could significantly improve the performance of the rats' performance of spatial memory ability (Figure 1F and 1G), and the escape latency of CCH rats were gradually shortened, the crossing time of the original platform was increased after 4w and 8w of EE stimulation, and the impairment of learning and memory functions was repaired and nerve function damage was reduced in CCH rats

Summary

Introduction

Chronic cerebral hypoperfusion (CCH) is a common pathological state of the nervous system and an essential in the occurrence and development of vascular cognitive impairment (VCI) [1]. Targeting the regulation of synaptic activity and plasticity is a new direction to improve CCH-induced cognitive impairment. Environmental stimulation can affect the morphology and function of the brain and play an essential role in brain development, Hebb first proposed the concept of the enriched environment (EE) in 1947 [4], which is www.aging-us.com mainly composed of three main parts: sensory stimulation, cognitive activities and physical exercise [5]. Recent studies have found that the EE stimulation can regulate synaptic activity and plasticity, increase long-term potentiation (LTP), and improve the pathologically and physiologically cerebral cognitive dysfunctions [6, 7]. EE can improve spatial learning and memory functions in CCH rats [10]

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