Liver-derived complement component 3 promotes the susceptibility to stress-induced depression by impairing blood-brain barrier integrity, 2026, Deng+

SNT Gatchaman

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Liver-derived complement component 3 promotes the susceptibility to stress-induced depression by impairing blood-brain barrier integrity
Deng, Tan; Chen, Hong-Sheng; Wang, Hua-Jie; Shi, Yu; Long, Li-Hong; Jin, You; Yao, Honghong; Si, Tianmei; Yu, Xin; Li, Lingjiang; Chen, Jian-Guo; Wang, Fang

Chronic stress can trigger major depressive disorder through peripheral immune factors. Enhanced circulating levels of complement component 3 (C3), a key innate immunity molecule that is predominantly produced by the liver, have been observed in depressed patients. However, the role of liver-derived C3 in the regulation of behavior under chronic stress remains ambiguous.

Here, we found that liver-derived C3 critically contributes to stress susceptibility and blood-brain barrier (BBB) impairment in the nucleus accumbens (NAc) by inhibiting endothelial cell claudin-5, a pivotal tight junction protein for BBB integrity.

In three mouse models of depression, hepatic C3 expression was notably increased in mice, with no comparable changes in other peripheral organs. Genetic ablation of C3 ameliorated chronic social defeat stress (CSDS)-induced increases in NAc BBB permeability and depressive-like behavior, and this amelioration was reversed upon re-expression of hepatic C3.

Consistently, knockdown of hepatic C3 similarly improved these deleterious effects induced by CSDS. Furthermore, overexpression of hepatic C3 was sufficient to induce depressive-like behavior following subthreshold social stress. Hepatic C3 manipulation bidirectionally regulated expression of claudin-5 in NAc endothelial cells.

Mechanistically, the liver-derived C3 suppressed claudin-5 expression in brain endothelial cells and increased stress susceptibility in mice through the C3a receptor-CCAAT/enhancer-binding protein-α signaling pathway in the NAc. Moreover, corticosterone upregulated hepatic C3 release by activation of nuclear factor-κB (NF-κB).

Taken together, these results demonstrate that liver-derived C3 promotes susceptibility to depression by increasing BBB permeability under chronic stress, and propose targeting hepatic C3 as a promising therapeutic strategy for depression.

Web | DOI | PDF | Nature Molecular Psychiatry | Paywall
 
They use a bully mouse. Reference 25 is —

A standardized protocol for repeated social defeat stress in mice
Golden, Sam A; Covington, Herbert E; Berton, Olivier; Russo, Scott J

A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity.

Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice.

The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3–4 weeks for completion.

Web | DOI | PDF | Nature Protocols | Paywall


From this paper's methods —

Chronic social defeat stress (CSDS) and other stress procedures
CSDS was performed as previously described [25]. Male CD-1 mice were screened for aggressive behavior during inter-male social interactions for three consecutive days according to the previous criteria, and were placed in the side of a perforated Plexiglas divider of the social defeat cage (36 × 25 × 17 cm) 24 h before the start of defeat (day 0). Male C57BL/6J mice or C3 -/- mice were subjected to physical aggression by the unfamiliar CD-1 mice for 10 min, and then removed and housed on the opposite side of the divider, where it remained for the next 24 h to undergo continuous psychological stress from the resident CD-1 mouse. The experimental mice were subjected to social defeat stress from different CD-1 mouse for 10 consecutive days. For the control group, two unstressed mice were placed in either side of the cage divider and rotated daily in the same manner without being exposed to CD-1 mice. Experimental mice were single housed after the last round of social defeat and subjected to social interaction test after 24 h. The detailed protocols for subthreshold social defeat stress, chronic unpredictable stress and chronic exposure of corticosterone are provided in the Supplementary Information.
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