Activation of astrocyte Gq pathway in hippocampal CA1 region attenuates anesthesia/surgery induced cognitive dysfunction in aged mice

Abstract

The elderly are particularly vulnerable to brain dysfunction after fracture surgery, but the mechanism underlying the cognitive decline due to anesthesia/surgery is not well understood. In this study, we observed hippocampus-dependent cognitive impairment in aged mice undergoing anesthesia and tibial fracture surgery, a common model of postoperative cognitive dysfunction in aged mice. We used Golgi staining and neuroelectrophysiological techniques to detect structurally and functionally impaired synaptic plasticity in hippocampal CA1 region of Postoperative cognitive dysfunction aged mice, respectively. Based on the ‘third party synapse’ hypothesis of astrocytes, we used glial fibrillary acidic protein to label astrocytes and found an increase in abnormal activation of astrocytes in the CA1 region of hippocampus. We hypothesize that abnormal astrocyte function is the driving force for impaired synaptic plasticity. So we used chemogenetic methods to intervene astrocytes. Injection of adeno-associated virus into the CA1 region of the hippocampus bilateral to aged mice resulted in the specific expression of the Gq receptor, a receptor specially designed to be activated only by certain drugs, within astrocytes. The results of novel object recognition and conditioned fear experiments showed that CNO activation of astrocyte Gq pathway could improve the learning and memory ability and the synaptic plasticity of Postoperative cognitive dysfunction aged mice was also improved. The results of this study suggest that activation of the Gq pathway in astrocytes alleviates Postoperative cognitive dysfunction induced by anesthesia and surgery in aged mice.

Traumatic brain injury promotes neurogenesis at the cost of astrogliogenesis in the adult hippocampus of male mice

“…In addition, RNA velocity predicted “back flow” transitions amongst cells in the astrocytic lineage, irrespective of experimental groups. Interestingly, several studies have showed astrocyte dedifferentiation towards immature cells with NSC potential as a response to gliosis, inflammation and injury conditions, and surgery and anesthesia 74 – 76 . These studies demonstrate a tendency of injury and disease to induce (mature) astrocytes to proliferate and dedifferentiate, acquiring certain properties of progenitor cells, while remaining in the glial cell lineage 73 , 77 .…”

Astrocytes Control Recent and Remote Memory Strength by Affecting the Recruitment of the CA1→ACC Projection to Engrams

“…Each astrocyte in the CA1 engulfs approximately 14 pyramidal cell somata 46 , envelopes multiple synapses, and can modify activity [47][48][49][50] . In recent years, it has been shown that specific manipulation of astrocytes can modify recent and remote memory: when CA1 astrocytes are manipulated by activating the Gq pathway, recent normal memory is improved [20][21][22][23] , impaired memory is enhanced 24 , and if the Gq pathway is attenuated, memory is blocked 25 . Gi pathway activation in astrocytes has the opposite effect -it blocks schema establishment 26 , and whereas its activation during FC acquisition has no effect on recent recall, it dramatically decreases remote recall 27 .…”

“…In general, it can be said that activation of the Gq pathway in astrocytes improves normal memory [20][21][22][23] and enhances it when it is impaired 24 , whereas Gq pathway attenuation blocks memory 25 . On the other hand, activating the Gi pathway in CA1 astrocytes has a harmful effect on memory [26][27][28] and blocks beneficial effects on impaired memory 29 .…”

Electroacupuncture pretreatment protects against anesthesia/surgery-induced cognitive decline by activating CREB via the ERK/MAPK pathway in the hippocampal CA1 region in aged rats

“…The mechanisms underlying POCD are unclear, but numerous studies show that central inflammation [5], oxidative stress [6], apoptosis [7] and synaptic plasticity changes [8] in the hippocampus contribute to POCD following anesthesia/surgery. Dysregulated synaptic plasticity is associated with cognitive dysfunction [9][10][11]. Gao reported that POCD in aged mice having undergone laparotomy under anesthesia was related to a decrease in the synaptic plasticity protein PSD-95, as well as synaptic morphological changes in the hippocampus [9].…”