Region-specific brain area reductions and increased cholecystokinin positive neurons in diabetic OLETF rats: implication for anxiety-like behavior

Abstract

Metabolic disorders can induce psychiatric comorbidities. Both brain and neuronal composition imbalances reportedly induce an anxiety-like phenotype. We hypothesized that alterations of localized brain areas and cholecystokinin (CCK) and parvalbumin (PV) expression could induce anxiety-like behavior in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Twenty-week-old OLETF and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used. The areas of corticolimbic regions were smaller in OLETF rats. The densities of CCK positive neurons in the lateral and basolateral amygdala, hippocampal cornu ammonis area 2, and prelimbic cortex were higher in OLETF rats. The densities of PV positive neurons were comparable between OLETF and LETO rats. Locomotion in the center zone in the open field test was lower in OLETF rats. These results suggest that imbalances of specific brain region areas and neuronal compositions in emotion-related areas increase the prevalence of anxiety-like behaviors in OLETF rats.

Medial prefrontal area reductions, altered expressions of cholecystokinin, parvalbumin, and activating transcription factor 4 in the corticolimbic system, and altered emotional behavior in a progressive rat model of type 2 diabetes

“…Furthermore, patients with obsessive-compulsive disorder and generalized anxiety disorder showed decreased gray and white matter volume in emotion-related regions, including the medial prefrontal cortex (mPFC), which is associated with anxiety severity [16]. Importantly, we also demonstrated that 20-week-old OLETF rats in the early stage of type 2 diabetes exhibited lower brain weight as well as area reductions in the corticolimbic system, including the mPFC [11]. Therefore, shrinkage of specific regions in the corticolimbic system could be one of the neuroanatomical mechanisms underlying anxiety in type 2 diabetes.…”

“…Therefore, the deficit in CCK-1 receptor alone in OLETF rats cannot sufficiently explain the increased anxiety-like behavior. Interestingly, we found that 20-week-old OLETF rats exhibited increased numbers of CCK-positive neurons in the corticolimbic system, including the mPFC, amygdala, and hippocampus, which might be indicative of the neural mechanisms causing increased anxiety-like behavior [11]. However, whether more CCK-positive neurons are present in the corticolimbic system in OLETF rats in the prediabetic and progressive stages of type 2 diabetes has not been clarified.…”

“…Contrary to CCK-positive neurons, chemogenetic inhibition of PV-positive neurons in the BLA increased anxietylike behavior in the open-field and elevated plus maze tests [31]. CCK-and PV-positive neurons are divided into large or small types according to the size of the somata, especially in the amygdala [11,[33][34][35]. Although functional differences between large and small types of CCKpositive neurons have not been well defined, the neurochemical properties of each type are reportedly different: large CCK-positive neurons co-express calbindin and neurokinin 1 receptor, whereas small CCK-positive neurons co-express calretinin and vasoactive intestinal polypeptide [33,34].…”

“…At 36 h after the oral glucose tolerance test, an open-field test was conducted during the dark phase, as described in our previous study [11]. The rats fasted during and after the test.…”

“…We previously confirmed that OLETF rats showed a progressive course of type 2 diabetes: mild hyperglycemia and normal plasma insulin level at 8 weeks old, indicating the prediabetic stage; hyperglycemia and hyperinsulinemia at 20 weeks old, indicating the early stage of type 2 diabetes; and severe hyperglycemia and a mixture of hyperinsulinemia and hypoinsulinemia at 30 weeks old, indicating the progressive stage of type 2 diabetes from non-insulin-dependent diabetes mellitus to insulin-dependent diabetes mellitus [9,10]. We recently reported that 20-week-old OLETF rats exhibited increased anxiety-like behavior in the open-field test, area reduction, and increased cholecystokinin (CCK)-positive neurons in the corticolimbic system [11]. Previous results obtained in OLETF rats between 10 and 20 weeks old also showed increased anxiety-like behaviors in the elevated plus maze, light-dark box, and open-field tests [12][13][14].…”