Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan.
Metabolic Regulation Group, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan; Clinical Research Institute, Kanagawa Children's Medical Center, Japan.
Behav Brain Res. 2025 Jan 5;476:115291. doi: 10.1016/j.bbr.2024.115291. Epub 2024 Oct 12.
A combination of genetic predisposition and environmental factors contributes to the development of psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. Previous studies using mouse models suggested that prolonged high sucrose intake during puberty can serve as an environmental risk factor for the onset of psychiatric disorders. However, the impact of both the duration and timing of high sucrose consumption during different developmental stages on pathogenesis remains poorly defined. We therefore investigated the effects of a long-term high sucrose diet on cognitive deficit, a core symptom of psychiatric disorders, using Disrupted-in-Schizophrenia 1 locus-impairment heterozygous mutant (Disc1) mice as a model for genetic predisposition. First, Disc1 mice and their littermate control (WT) were fed either a high sucrose diet or a control starch diet for nine weeks starting at weaning (postnatal day 24), and tested for cognitive performance in the object location test (OLT) and the novel object recognition test (NORT) (assessing spatial and recognition memory, respectively). Only Disc1 mice on a high sucrose diet displayed deficits in OLT (p < 0.0001), demonstrating impaired hippocampus-dependent spatial memory. This behavioral abnormality was accompanied by a decreased proportion of the high parvalbumin-expressing interneurons (High-PV neurons) in the ventral hippocampus, a cell type that regulates neural activity and a variety of learning and memory processes such as spatial and working memory. We further explored the critical developmental period for high sucrose intake to cause cognitive deficits in adulthood by comparing specific feeding periods during puberty (P24-P65) and post-puberty (P65-P90). Compared to those on a standard chow diet, high sucrose intake caused deficits in spatial memory in both WT and Disc1 mice, with more pronounced effects in Disc1 mice. In particular, Disc1 mice on a sucrose diet during adolescence showed more pronounced cognitive deficit than those fed after adolescence. Our results suggest that adolescence is particularly vulnerable to nutritional environmental risk factors, and that high sucrose consumption may cause hippocampus-dependent memory deficits via decreased High-PV interneuron function when combined with Disc1-related genetic predisposition.
遗传易感性和环境因素的结合导致了精神疾病的发展，如精神分裂症、双相情感障碍和重度抑郁症。之前使用小鼠模型的研究表明，青春期长时间摄入高蔗糖可以作为精神疾病发病的环境风险因素。然而，不同发育阶段高蔗糖消耗的持续时间和时间对发病机制的影响仍不清楚。因此，我们使用精神分裂症 1 位点缺失突变体（Disc1）杂合突变小鼠作为遗传易感性模型，研究了长期高蔗糖饮食对精神疾病核心症状认知缺陷的影响。首先，Disc1 小鼠及其同窝对照（WT）从断奶后（出生后第 24 天）开始分别用高蔗糖饮食或对照淀粉饮食喂养 9 周，并在物体位置测试（OLT）和新物体识别测试（NORT）中测试认知表现（分别评估空间和识别记忆）。只有高蔗糖饮食的 Disc1 小鼠在 OLT 中表现出缺陷（p<0.0001），表明其海马依赖性空间记忆受损。这种行为异常伴随着腹侧海马中高表达 parvalbumin 的中间神经元（High-PV 神经元）比例降低，中间神经元调节神经活动和多种学习和记忆过程，如空间和工作记忆。我们通过比较青春期（P24-P65）和青春期后（P65-P90）特定的喂养期，进一步探讨了高蔗糖摄入引起成年认知缺陷的关键发育期。与标准饲料饮食相比，高蔗糖摄入导致 WT 和 Disc1 小鼠的空间记忆缺陷，而 Disc1 小鼠的影响更为明显。特别是，在青春期摄入蔗糖的 Disc1 小鼠比青春期后摄入蔗糖的小鼠表现出更为明显的认知缺陷。我们的研究结果表明，青春期特别容易受到营养环境风险因素的影响，而高蔗糖摄入可能通过降低与 Disc1 相关的遗传易感性相关的 High-PV 中间神经元功能，导致海马依赖性记忆缺陷。
