Background: Accumulating evidence has highlighted the importance of microglial and astrocyte responses in the pathological development of postoperative cognitive dysfunction (POCD). However, the mechanisms involved are not well understood. Methods: A perioperative neurocognitive disorders (PND) mouse model was generated by administering etomidate, and cognitive function was assessed using the Morris water maze and novel object recognition tests. Excitatory and inhibitory postsynaptic currents were recorded to analyze neuronal activity. In addition, microglia and astrocytes were isolated by magnetic-activated cell sorting, and genes that were activated in these cells were identified using quantitative polymerase chain reaction. Results: We observed dramatic cognitive impairment at 1 and 3 weeks after etomidate was administered to 18 month-old mice. Microglia and astrocytes isolated from the hippocampus showed significant microglial activation during the early pathological stage (i.e., 1 week after etomidate injection) and an A1-specific astrocyte response during the late pathological stage (i.e., 3 weeks after etomidate injection). Furthermore, when microglia were eliminated before etomidate was injected, the A1-specific astrocyte activation response was significantly reduced, and cognitive function improved. However, when microglia were eliminated after etomidate application, astrocyte activation and cognitive function were not significantly altered. In addition, activating microglia immediately after a sedative dose of etomidate was injected markedly increased A1-specific astrocyte activation and cognitive dysfunction. Conclusions: A1-specific astrocyte activation is triggered by activated microglia during the initial pathological stage of PND and induces long-term synaptic inhibition and cognitive deficiencies. These results improve our understanding of how PND develops and may suggest therapeutic targets.

Triggering receptor expressed in myeloid cells (TREM)2 is a genetic high‐risk factor for sporadic Alzheimer's disease (AD) and is considered a potential target for AD diagnosis and therapy, although its role in the different stages of AD remains controversial. We generated an embryonic deletion of Trem2 (whole body deletion) and induced hippocampa1‐ and cortical‐specific knockdown of microglial Trem2 at different stages of the AD process in amyloid precursor protein/Psen1 mice by adeno‐associated virus (AAV) infection. AAV infection induced microglial Trem2 overexpression in the hippocampus of wild‐type (WT) and thymus cell antigen 1–enhanced green fluorescent protein mice. Mice were subjected to ethological and pathologic tests. Whole body genetic deletion of Trem2 exerted different electrophysiological outcomes between different AD pathologic stages, which results from a complex integration of synaptic loss and amyloid aggregation. Interestingly, knockdown of Trem2 at the early‐middle stage of AD (2–6 mo) prevents synaptic loss through directly inhibiting microglial phagocytosis, whereas knockdown of Trem2 at the middle‐late stage of AD (6–10 mo) accelerates synaptic dysfunction because of more severe amyloid deposition caused by the depression of microglial phagocytosis. Additionally, hippocampal overexpression of Trem2 in WT mice results in significant synaptic impairment. Here, with transgenic technology and electrophysiological assay, we revealed that TREM2 up‐regulation promotes microglial phagocytosis equally against synapse and amyloid plaques and eventually results in different outcomes. During the early‐middle pathologic stage, TREM2 enhancing microglial phagocytosis mainly causes synaptic loss. However, TREM2 up‐regulating microglial phagocytosis gradually supports a positive role when amyloid deposition occupies the leading position at the middle‐late pathologic stage. In this study, we highlighted that TREM2 triggers synaptic loss during AD pathology development.—Sheng, L., Chen, M., Cai, K., Song, Y., Yu, D., Zhang, H., Xu, G. Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice. FASEB J. 33,10425‐10442 (2019). http://www.fasebj.org

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Recent studies have shown that the precursor of nerve growth factor (proNGF) is highly elevated in aging brains and in the brains of patients with Alzheimer's Disease. proNGF accumulates in hippocampus which is an important neurogenic region related to learning and memory. However, it remains unclear whether proNGF has an influence on hippocampal neurogenesis. In this study, we demonstrated that the high-affinity receptor of proNGF, p75 neurotrophic factor (p75NTR), was expressed both on cells undergoing mitosis and postmitotic mature cells in mouse hippocampus. proNGF infusion into adult mouse hippocampus significantly reduced the density of BrdU-incorporating cells and the density of BrdU/Doublecortin double positive cells in the subgranular zone of hippocampus, indicating an inhibitory effect of proNGF on hippocampal neurogenesis. proNGF infusion also induced prominent cell apoptosis and activated residential astrocyte and microglia, which might further impair the hippocampal neurogenesis. These results implied that proNGF played a pivotal role in regulating the hippocampal neurogenesis and might account for the memory deficit and cognitive impairment.

Since the depressive disorder manifests complex and diverse symptoms clinically, its pathological mechanism and therapeutic options are difficult to determine. In recent years, the advent of optogenetics, chemogenetics and viral tracing techniques, along with the well‐established rodent model of depression, has led to a shift in the focus of depression research from single molecules to neural circuits. In virtue of the powerful tools above, psychiatric disorder such as depression could be well related to the disfunction of brain's connection. Moreover, compelling studies also support that the diversity of depressive behaviour could be involved with the discrete changes in a distinct circuit of the brain. Therefore, summarising the differential changes of the neural circuits in mice with depression‐like behaviour may provide a better understanding of the causal relationships between neural circuit and depressive behaviour. Here, we focus on the changes in the neural circuitry underlying various depression‐like phenotypes, including motivation, despair, social avoidance and comorbid sequelae, which may provide an explanation to circuit‐specific discrepancy in depression‐like behaviour.

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