CALBINDIN-POSITIVE PYRAMIDAL NEURONS IN HIPPOCAMPAL CA1 MEDIATE EARLY-LIFE STRESS-INDUCED COGNITIVE IMPAIRMENT IN MICE

Abstract Background Early-life stress (ELS) can cause persistent and irreversible damage to the development, plasticity, and cognitive function of the hippocampus, leading to depression and other mental illnesses. However, the mechanism of negative effects induced by ELS remained unclear. Aims & Objectives Calbindin (CB) is one of the molecular markers of the superficial pyramidal neurons (PNs) of the hippocampal CA1 area. Previous research found that calbindin-positive (CB+) PNs and calbindin-negative (CB-) PNs in hippocampal dorsal CA1 (dCA1) region may play distinct roles in the regulation of cognition. Thus, the aim of this study was to explore the mechanism of different types of PNs in mediating ELS- induced cognitive deficits, and to provide new insights for the prevention and treatment of the stress- related mental disorders such as depression. Method We adopted the early-life stress model of the "limited bedding and nesting materials", and explored its impact on cognitive functions as well as neural activity and morphological plasticity of CB+ PNs and CB- PNs in dCA1 using behavioral, morphological and molecular biology techniques. Then, we selectively inhibited or activated CB+ PNs or CB- PNs in dCA1 with combination of transgenic mice and chemogenetic techniques to investigate the roles of different types of PNs in mediating cognitive impairment induced by ELS. Results ELS significantly impaired the cognitive performance in spatial object recognition (SOR) task, as well as the c-Fos expression of PNs in dCA1 after SOR task, with the activation of CB+ PNs outweighing CB- PNs. The dendritic complexity of CB+ PNs was damaged by ELS, but remained unaffected for CB- PNs. Specific inhibition of CB+ PNs in dCA1 mimicked the negative effect of ELS on cognitive functions, while inhibition of CB- PNs did not. Specific activation of CB+ PNs in dCA1 successfully reversed the cognitive impairment caused by ELS, whereas activation of CB- PNs failed to do so. Discussion & Conclusion Our findings indicate that calbindin-positive pyramidal neurons in dorsal hippocampal CA1 mediate the mechanism of cognitive impairment induced by early-life stress. Thus, calbindin-positive neurons in hippocampal CA1 may present new target for the prevention and treatment for cognitive dysfunction in stress-related mental illnesses such as depression.