Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
System Emotional Science, Faculty of Medicine, University of Toyama, Sugitani, Toyama, Japan.
PLoS One. 2021 Sep 10;16(9):e0256655. doi: 10.1371/journal.pone.0256655. eCollection 2021.
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.
代谢紊乱与精神疾病的风险增加有关。我们之前报道过，20 周龄的 Otsuka Long-Evans Tokushima 肥胖（OLETF）大鼠，一种 2 型糖尿病进展模型，表现出焦虑样行为增加，皮质边缘系统的区域面积减少，胆囊收缩素阳性神经元增加。然而，这些在 OLETF 大鼠中的改变发生在糖尿病的哪个阶段尚不清楚。我们旨在研究 OLETF 大鼠 2 型糖尿病不同阶段的焦虑样行为及其可能的机制。8 周龄和 30 周龄的 OLETF 大鼠分别作为 2 型糖尿病前期和进展期的糖尿病动物模型，年龄匹配的 Long-Evans Tokushima Otsuka 大鼠作为非糖尿病对照。在旷场试验中，OLETF 大鼠在 8 周和 30 周时在中央区域的运动较少，离开中央区域的潜伏期较长。无论年龄大小，OLETF 大鼠的内侧前额叶皮层面积较小。OLETF 大鼠的胆囊收缩素阳性神经元密度仅在 8 周时在外侧和基底杏仁核较高，而在两个年龄时在前扣带回和边缘下皮层以及海马 CA3 区较高。OLETF 大鼠的 parvalbumin 阳性神经元密度在 8 周时在 CA2 区和两个年龄时在额前皮质和边缘下皮层较低。在 OLETF 大鼠中未检测到凋亡细胞死亡，但在两个年龄时，前扣带回和基底杏仁核中激活转录因子 4 和胆囊收缩素与 parvalbumin 共表达的神经元比例较高。这些结果表明，在 OLETF 大鼠的糖尿病前期阶段，皮质边缘系统的情绪行为改变和相关的神经变化已经存在。
