Department of Nutrition, CRCHUM and Montreal Diabetes Research Center, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
Int J Obes (Lond). 2013 Mar;37(3):382-9. doi: 10.1038/ijo.2012.48. Epub 2012 Apr 17.
The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain obscure. Dopamine- and plasticity-related signalling in mesolimbic reward circuitry is implicated in the pathophysiology and aetiology of depression.
To determine the impact of a palatable high-fat diet (HFD) on depressive-like behaviour and biochemical alterations in brain reward circuitry in order to understand the neural processes that may contribute to the development of depression in the context of diet-induced obesity (DIO).
Adult male C57Bl6 mice were placed on a HFD or ingredient-matched, low-fat diet for 12 weeks. At the end of the diet regimen, we assessed anxiety and depressive-like behaviour, corticosterone levels and biochemical changes in the midbrain and limbic brain regions. Nucleus accumbens (NAc), dorsolateral striatum (DLS) and ventral tegmental area dissections were subjected to SDS-PAGE and immunoblotting using antibodies against D1A receptor, D2 receptor, brain-derived neurotrophic factor (BDNF), phospho-DARPP-32(thr75), phospho-CREB and ΔFosB.
HFD mice showed significant decreases in open arm time and centre time activity in elevated plus maze and open field tasks, respectively, and increased immobility (behavioural despair) in the forced swim test. Corticosterone levels following acute restraint stress were substantially elevated in HFD mice. HFD mice had significantly higher D2R, BDNF and ΔFosB, but reduced D1R, protein expression in the NAc. Notably, the expression of BDNF in both the NAc and DLS and phospho-CREB in the DLS was positively correlated with behavioural despair.
Our results demonstrate that chronic consumption of high-fat food and obesity induce plasticity-related changes in reward circuitry that are associated with a depressive-like phenotype. As increases in striatal BDNF and CREB activity are well implicated in depressive behaviour and reward, we suggest these signalling molecules may mediate the effects of high-fat feeding and DIO to promote negative emotional states and depressive-like symptomology.
将抑郁的发展与肥胖和糖尿病等代谢紊乱联系起来的生物学机制仍不清楚。中脑边缘奖赏回路中的多巴胺和可塑性相关信号在抑郁的病理生理学和病因学中起作用。
确定美味高脂肪饮食（HFD）对抑郁样行为和大脑奖赏回路生化改变的影响，以了解可能导致饮食诱导肥胖（DIO）背景下抑郁发展的神经过程。
成年雄性 C57Bl6 小鼠接受 HFD 或成分匹配的低脂饮食 12 周。在饮食方案结束时，我们评估了焦虑和抑郁样行为、皮质酮水平以及中脑和边缘脑区的生化变化。使用针对 D1A 受体、D2 受体、脑源性神经营养因子 (BDNF)、磷酸化 DARPP-32(thr75)、磷酸化 CREB 和 ΔFosB 的抗体对伏隔核 (NAc)、背外侧纹状体 (DLS) 和腹侧被盖区进行 SDS-PAGE 和免疫印迹分析。
HFD 小鼠在高架十字迷宫和旷场任务中分别表现出开放臂时间和中心时间活动显著减少，强迫游泳试验中不动（行为绝望）增加。急性束缚应激后，HFD 小鼠的皮质酮水平显著升高。HFD 小鼠的 D2R、BDNF 和 ΔFosB 显著升高，但 NAc 中的 D1R 和蛋白表达降低。值得注意的是，NAc 和 DLS 中的 BDNF 表达以及 DLS 中的磷酸化 CREB 与行为绝望呈正相关。
我们的结果表明，长期食用高脂肪食物和肥胖会导致奖赏回路的可塑性变化，与抑郁样表型相关。由于纹状体 BDNF 和 CREB 活性的增加与抑郁行为和奖赏密切相关，我们认为这些信号分子可能介导高脂肪喂养和 DIO 的影响，以促进负面情绪状态和抑郁样症状。
