Changes in social behavior and prefrontal cortex transcriptomics in a diabetes type 2 model in aging male rats

Introduction: Metabolic disorders have been shown to accelerate age-related cognitive impairment and contribute to broader neurobehavioral decline across the lifespan. Diabetes type 2 (T2D), the most prevalent metabolic disorder, has been increasingly linked to various social behavioral deficits. In animal models, social behavior is considered a multifaceted domain influenced by various factors, including affective behavior. However, only a limited number of clinical and preclinical studies have examined changes in social behavior in T2D, and their results are conflicting. Moreover, the underlying brain molecular dysfunction in this context, especially during aging, is not thoroughly understood. The medial prefrontal cortex is recognized as a central hub for neural circuits involved in sociability [1], and T2D is associated with altered brain energy metabolism in this region in humans [2]. Therefore, we aimed to assess social behavior in an aging rat model of T2D and to identify transcriptomic changes in the prefrontal cortex that could be linked to emerging social deficits.

Methodology: Middle-aged male Sprague-Dawley rats were randomly assigned to receive either a high-fat diet followed by a low dose of streptozotocin to induce a type 2 diabetes-like metabolic phenotype (T2D model group) or a standard control diet and solvent treatment to represent the control group (CTRL). After model induction, rats continued to receive their respective diets and underwent a comprehensive behavioral testing battery, including the resident-intruder test (RIT) to assess social and aggression-related behaviors during the night phase. Behavioral data were analyzed using the Mann-Whitney U test. Bulk RNA sequencing was performed on dissected medial prefrontal cortex tissue samples from the respective experimental groups, followed by quality control, normalization, and differential expression analysis. KEGG pathway enrichment analysis was then conducted based on differentially expressed genes (DEGs) identified through DESeq2 analysis, which applied multiple testing correction and fold-change threshold.

Results: T2D males exhibited significantly decreased social exploration of unfamiliar conspecifics compared to CTRL males (p < 0.05) in the RIT. However, no significant differences in total offense scores were observed between the groups in the RIT. Transcriptomic profiling revealed that the top five KEGG pathways associated with downregulated DEGs in T2D versus CTRL animals included glycerolipid metabolism, porphyrin metabolism, fat digestion and absorption, ribosome biogenesis in eukaryotes, and Ras signaling pathways.

Conclusions: This aging T2D model was associated with a decline in social exploration and the changes at the transcriptomic level that highlighted alterations in metabolic and cellular regulatory processes in the prefrontal cortex. Collectively, these findings suggest that disruption of prefrontal cortex lipid metabolism and heme biosynthesis may represent early neurobiological changes induced by T2D, potentially contributing to impairments in social behavior in males which should be further investigated in females. However, in future, mechanistic preclinical studies are required to test causality and clarify the underlying pathways linking brain metabolic dysfunction with social behavioral outcomes.

References

Li H, Zhao Z, Jiang S, Wu H. Brain circuits that regulate social behavior. Mol Psychiatry. 2025 Jul;30(7):3240-3256. doi: 10.1038/s41380-025-03037-6.
Puustinen K, Vandersmissen J, Gojevic T, Oeltzschner G, Zöllner HJ, Verboven K, Hansen D, Dewachter I, Hehl M, Cuypers K. Type 2 diabetes is related to neurochemical alterations in the default mode network: An exploratory cross-sectional Magnetic Resonance Spectroscopy study. Neuroimage. 2026 Apr 22:121949. doi: 10.1016/j.neuroimage.2026.121949. This research was supported by the Science Fund of the Republic of Serbia, 10203, titled: “Translational road to elucidate the effects of GLP-1 receptor agonist treatment on adipose tissue–brain axis function in cognitive processes in diabetes type 2 with concomitant obesity – CoD-GOAT.”