Abstract
Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats.
Highlights
Metabolic disorders such as obesity and type 2 diabetes can induce several psychiatric disorders
The mean food intakes during the experimental period were significantly higher in Otsuka Long-Evans Tokushima fatty (OLETF) rats than those in Long-Evans Tokushima Otsuka (LETO) rats at both ages (Fig 2D), and there was a significant main effect of strain (F[1, 4] = 185.39, p < 0.01); the mean food intakes of LETO and OLETF rats increased with age, and there was a significant main effect of age (F[1, 4] = 220.17, p < 0.01), but there was no significant interaction between strain and age
The glucose area under the curves (AUCs) of OLETF rats were significantly higher at 8 and 30 weeks old and dramatically increased with age; those of LETO rats increased with age (Fig 2E), and there was a significant interaction between strain and age (F[1, 18] = 87.18, p < 0.01), significant simple main effects of strain (8 weeks old: F[1, 18] = 10.72, p < 0.01; 30 weeks old: F[1, 18] = 304.01, p < 0.01), and a significant simple main effect of age (LETO rats: F[1,18] = 6.83, p < 0.05; OLETF rats: F[1, 18] = 250.18, p < 0.01)
Summary
Metabolic disorders such as obesity and type 2 diabetes can induce several psychiatric disorders. Patients with diabetes often have a high prevalence of cognitive impairment, depression, and anxiety [1,2]. These psychiatric disorders are associated with obesity and metabolic syndrome [3,4,5]. Obesity and metabolic syndrome likely precede the onset of type 2 diabetes; psychiatric disorders could already be present in the early stages of type 2 diabetes. Little has been reported on the comorbidity of anxiety in different stages of type 2 diabetes and the neural mechanisms. Individuals with anxiety at prediabetic stages are more likely to develop type 2 diabetes [7]. To effectively treat and prevent anxiety in patients with type 2 diabetes, it is important to understand its neural mechanisms
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