Behavioural and metabolic phenotyping of the Flinders Sensitive Line rat in inflammation-associated depression

Background

Major Depressive Disorder frequently co-occurs with obesity, insulin resistance, and chronic low-grade inflammation, suggesting overlapping biological mechanisms involving neuroimmune dysregulation and impaired inflammatory resolution. Clinical studies indicate that inflammation is associated with treatment resistance, relapse, and poorer outcomes in depression. Despite growing recognition of this inflammatory subtype, preclinical models simultaneously capturing depressive vulnerability and metabolic challenge remain limited. The Flinders Sensitive Line rat (FSL) is a well-established genetic model displaying depression-like behavior, while the Flinders Resistant Line rat (FRL) serves as its control counterpart. The present study aimed to establish Phase 1 of the ReMOOD platform by characterizing behavioral and metabolic responses to dietary challenge prior to mechanistic investigation of inflammatory resolution pathways. This approach directly addresses the need for biologically relevant preclinical models that integrate mood-related behavior, metabolic dysfunction, and immune-resolution biology within the same experimental framework.

Methods

Male FSL and FRL rats were assigned to either a control diet or high-fat diet, generating four experimental groups (n=8–20/group). Behavioral phenotyping included spontaneous locomotor activity, Elevated Plus Maze, and Forced Swim Test. Metabolic characterization included longitudinal body-weight monitoring, caloric intake assessment, Oral Glucose Tolerance Test, and terminal organ-weight analysis. These outcomes were selected to support later integration with peripheral and central inflammatory-resolution biomarkers. Statistical analyses were performed using two-way ANOVA followed by Tukey post hoc testing.

Results

Behavioral analyses confirmed a robust depression-like phenotype in FSL rats. In the forced swim test, FSL animals displayed significantly increased immobility compared with FRL rats (strain effect, p<0.001), accompanied by significantly reduced latency to immobility (p<0.001) and decreased swimming behavior (p<0.001). High-fat diet significantly influenced immobility behavior (diet effect, p=0.016), with a significant strain × diet interaction (p=0.008), indicating differential behavioral sensitivity to metabolic challenge.

In the elevated plus maze, anxiety-related behavior differed significantly between strains, with significant strain effects for time spent in open arms (p=0.020) and significant strain × diet interaction effects (p=0.032). Locomotor assessment further revealed significant strain-dependent differences in mobility (p<0.001), together with significant interaction effects (p=0.006).

Metabolic analyses demonstrated pronounced strain-dependent differences. FRL rats exhibited significantly higher endpoint body weight compared with FSL rats (strain effect, p<0.001). Caloric intake was significantly influenced by both strain and diet (both p<0.001). Glucose tolerance analysis revealed significant strain effects for total area under the curve (p=0.003) and incremental area under the curve (p=0.003), while 120-minute glucose concentrations demonstrated significant diet effects (p=0.019). Furthermore, FRL rats displayed significantly greater heart weight (p<0.001) and epididymal fat mass (p=0.002).

Conclusions

These preliminary findings confirm robust strain-dependent behavioral and metabolic phenotypes in the FSL/FRL model and establish a translational platform for investigating impaired inflammatory resolution in depression. Ongoing mechanistic analyses will characterize specialized pro-resolving lipid mediators, cytokine signatures, ChemR23-associated signaling, glial activation markers, and brain-specific transcriptional changes to identify resolution-based therapeutic targets in metabolic mood disorders.

References

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