Establishment of an gastric dysfunction and depression comorbidity model simulating clinical etiology in mice using a combined stress protocol

doi:10.12122/j.issn.1673-4254.2026.05.09

Abstract

Abstract:

Objective To establish a mouse model with the comorbidity of gastric dysfunction and depression mimicking clinical onset of the condition. Methods Thirty male C57BL/6J mice were randomly divided into control, 14-day model, and 28-day model groups (n=10). The mice in the latter two groups were subjected to continuous combined stresses induced by tail clamping, cold-saline gavage and irregular feeding for 14 or 28 days. Gastric motility, gastric emptying and histopathological changes of the mice were evaluated using strain gauge sensors, in vivo imaging and HE staining, respectively, and behavioral tests were used to assess their depression-like behaviors. Serum corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF), gastrin, motilin, and gastric nitric oxide synthase (NOS) and acetylcholinesterase (AChE) levels were measured by ELISA to explore the peripheral mechanisms. Results Compared with control mice, the mice in 14-day model group exhibited reduced body weight, food intake and gastric motility amplitude with delayed gastric emptying but showed no significant depression-like behaviors; in 28-day model group, these changes were further exacerbated, and significant depression-like behaviors were observed. Compared with 14-day model group, the 28-day model group displayed severer gastric dysfunction and depression-like behaviors. Compared with control group, exposure to complex stresses for 14 days significantly increased serum CRF and decreased BDNF, gastrin and motilin levels, increased gastric NOS and decreased gastric AChE level, which were worsened after a 28-day exposure. HE staining showed no obvious histological changes in the gastric mucosa in the two model groups. Conclusion Combined stresses induced by tail clamping, cold-saline gavage and irregular feeding for 28 days can induced the comorbidity of gastric dysfunction and depression in mice, and abnormal changes in serum neurotransmitters, brain-gut peptides and vagus activity may partly participate in the pathogenesis of the comorbidity.

Key words: gastric dysfunction, depression-like behavior, animal model, combined stress, gastric motility, behavioral assessment

Qingyang HUANG, Wenwen SHEN, Jin HU, Hongkun MA, Yanbing HU, Chengjie ZHANG, Guoming SHEN, Hao WANG. Establishment of an gastric dysfunction and depression comorbidity model simulating clinical etiology in mice using a combined stress protocol[J]. Journal of Southern Medical University, 2026, 46(5): 1059-1065.

Figures/Tables 5

Fig.1 Changes in body weight and food intake of the mice at different time points in each group. A: Weight change (##P<0.01, △△P<0.01, **P<0.01 vs Control; n=10). B: Change in food intake (#P<0.05, △△P<0.01, **P<0.01 vs Control; n=10).

Fig.2 Changes in gastric motility and gastric fluorescent discharge in each group. A: Schematic diagram of gastric motility experiment. B: Gastric motility waveforms for each group. C: Average amplitude of gastric motility in each group (*P<0.05, **P<0.01 vs Control; ##P<0.01 vs Model 14 d; n=10). D: Schematic diagram of small animal in vivo imaging. E:Gastric fluorescence heatmaps. F: Gastric residual rate (**P<0.01 vs Control; ##P<0.01 vs Model 14 d; n=6).

Fig.3 Changes in depressive-like behaviors in each group. A: Open-field test trajectory diagram in each group. B: Total distance. C: Time in the center. D: Center entry number. E: Elevated plus maze trajectory and percentage heat map. F: Open arms entry number. G: Time in open arms. H: Sucrose preference. I: Schematic diagram of the tail suspension test. J: Immobility time. K: Schematic diagram of forced swimming test. L: Immobility time. **P<0.01 vs control; ##P<0.01 vs 14-day model (n=10).

Fig.4 Serum CRF, BDNF, GAS, and MTL and gastric NOS and AchE levels in each group. A: Serum BDNF level. B: Serum CRF level. C: Serum MTL level. D: Serum GAS level. E: Expression of NOS in gastric tissue. F: Expression of AchE in gastric tissue. *P<0.05, **P<0.01 vs Control; #P<0.05, ##P<0.01 vs Model 14 day; n=6.

Fig.5 HE staining of the gastric tissue in each group (Scale bar=250 μm).

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