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

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.