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Astrocyte-Derived Lactate Modulates the Passive Coping Response to Behavioral Challenge in Male Mice.

ABSTRACT: Every organism inevitably experiences stress. In the face of acute, intense stress, for example, periods of passivity occur when an organism's actions fail to overcome the challenge. The occurrence of inactive behavior may indicate that struggling would most likely be fruitless. Repeated serious stress has been associated with mood disorders such as depression. The modulation of passive coping response patterns has been explored with a focus on the circuit level. However, the cellular and molecular mechanisms are largely uncharacterized. Here, we report that lactate is a key factor in the astrocytic modulation of the passive coping response to behavioral challenge in adult mice. We found increased extracellular lactate in the medial prefrontal cortex (mPFC) when mice experienced the forced swimming test (FST). Furthermore, we discovered that disturbing astrocytic glycogenolysis, which is a key step for lactate production in the mPFC, decreased the duration of immobility in the FST. Knocking down monocarboxylate transporter 4 (MCT4), which is expressed exclusively in astrocytes and transports lactate from astrocytes to the extracellular space, caused similar results in the FST. The behavioral effect of both the pharmacological disturbance of astrocytic glycogenolysis and viral disruption of MCT4 expression was rescued via the administration of L-lactate. Moreover, we found that both pharmacological and viral modulation of astrocyte-derived lactate in mPFC slices increased the excitability of layer V pyramidal neurons, and this enhancement was reversed by exogenous L-lactate administration. These results highlight astrocyte-derived lactate as a biological mechanism underlying the passive coping response to behavioral challenge and may provide new strategies to prevent mood disorders.

SUBMITTER: Yin YN

PROVIDER: S-EPMC7811973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Stress coping styles are very common in fish, and investigations into this area can greatly improve fish welfare and promote the sustainable development of aquaculture. Although most studies have focused on the behavioral and physiological differences of these fishes, the endocrine response of different coping styles fish when undergoing salinity challenge is still unclear. We examined the physiological response in olive flounder with active coping (AC) style and passive coping (PC) style after transferred from seawater (SW) to freshwater for 0, 2, 5, 8, and 14 days. The results showed that: 1) the plasma prolactin level of FW-acclimated AC flounder was substantially higher than that of FW-acclimated PC flounder at 5, 8, and 14 days, and the branchial gene expression of prolactin receptor (PRLR) in AC flounder was slightly higher than PC flounder after transfer. While there was no remarkable difference observed in cortisol (COR) levels between AC and PC flounder. After transfer, glucocorticoid receptor (GR) expression in AC flounder was significantly higher compared with PC flounder at 8 days. 2) Branchial NKA-IR ionocytes numbers were reduced in PC flounder after transfer, while ionocytes number remain stable in AC flounder. 3) The branchial stem cell transcription factor foxi1 gene expression of AC flounder was significantly higher than PC flounder at 2, 5, and 14 days after transfer, while branchial stem cell transcription factor p63 gene expression of FW-acclimated AC flounder was only substantially higher than that of PC flounder at 5 days. 4) As an apoptosis upstream initiator, the branchial gene expression of caspase-9 in PC flounder was considerably higher than in AC flounder after transfer at 8 days. This study revealed that olive flounder with active and passive coping styles have different endocrine coping strategies after facing the low-salinity challenge. AC flounder adopt an active endocrine strategy by increasing ionocyte differentiation and prolactin secretion significantly. In contrast, PC flounder employ a passive strategy of reducing ionocytes differentiation and retaining prolactin content at a low level to reduce branchial ionocytes number.

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Astrocyte-Derived Lactate Modulates the Passive Coping Response to Behavioral Challenge in Male Mice.

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