Locus coeruleus-CA1 projections are involved in chronic depressive stress-induced hippocampal vulnerability to transient global ischaemia

Qian Zhang,Bo Tian,Feng He,Chun Yang Li,Tong Xia Li,Jie Ming,Guang Jian Qi,Dian Xing Hu,Pei Zhang,Hong Wei Cai,Xiao Qian Chen

doi:10.1038/s41467-019-10795-9

Abstract

Depression and transient ischaemic attack represent the common psychological and neurological diseases, respectively, and are tightly associated. However, studies of depression-affected ischaemic attack have been limited to epidemiological evidences, and the neural circuits underlying depression-modulated ischaemic injury remain unknown. Here, we find that chronic social defeat stress (CSDS) and chronic footshock stress (CFS) exacerbate CA1 neuron loss and spatial learning/memory impairment after a short transient global ischaemia (TGI) attack in mice. Whole-brain mapping of direct outputs of locus coeruleus (LC)-tyrosine hydroxylase (TH, Th:) positive neurons reveals that LC-CA1 projections are decreased in CSDS or CFS mice. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determine that Th:LC-CA1 circuit is necessary and sufficient for depression-induced aggravated outcomes of TGI. Collectively, we suggest that Th:LC-CA1 pathway plays a crucial role in depression-induced TGI vulnerability and offers a potential intervention for preventing depression-related transient ischaemic attack.

Highlights

Depression and transient ischaemic attack represent the common psychological and neurological diseases, respectively, and are tightly associated
Mice with the same transient global ischaemia (TGI) time-points exhibited significant differences in the Morris water maze (MWM) test, which is highly sensitive to hippocampal damage and reflects performance related to spatial learning and memory[34]
This study aimed to investigate the effect of depression on ischaemia-caused neurological disorders and to ascertain the underlying neural circuit mechanism

Summary

Introduction

Depression and transient ischaemic attack represent the common psychological and neurological diseases, respectively, and are tightly associated. We find that chronic social defeat stress (CSDS) and chronic footshock stress (CFS) exacerbate CA1 neuron loss and spatial learning/memory impairment after a short transient global ischaemia (TGI) attack in mice. Given that TGI is a major cause of chronic neurological disabilities, including spatial memory impairment and delayed neuronal death of CA1 region neurons within the hippocampus[29], it is possible that the connections between depression and TGI may be targeted and manipulated through the Th:LC-CA1 neural circuit. We determine that depression in mice, including chronic social defeat stress (CSDS) and chronic footshock stress (CFS), induce an aggravated response to TGI that is found to be mediated by the Th:LC-CA1 pathway. Our findings reveal a previously undefined role for Th:LC-CA1 projections in how depression increases TGI vulnerability

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