Sex-specific effects of N-3 PUFA supplementation on brain plasticity in the developing brain

这项研究计划扩展了omega-3多不饱和脂肪酸（n-3 PUFA）补充饮食对大脑功能和行为重塑的研究。大脑发育和功能严重依赖于人体无法轻易合成的必需脂肪酸的摄入。鱼油是长链n-3 PUFA的主要膳食来源。鲑鱼是一种丰富的膳食来源，高级药用鱼油配方也很容易供人类食用。考虑到西方社会加工食品的消费量不断增长，评估n-3 PUFA的作用是一个重要的问题，这导致n-3缺乏和不成比例的n-6/n-3 PUFA比例过高，这已被证明会使大脑活动失调。众所周知，妊娠期间富含n-3 PUFA的饮食促进神经元发育，并对老年动物或脑损伤后的认知功能和神经可塑性/保护具有有益作用。人体研究报告了n-3 PUFA对青少年认知和情绪的有益影响，这在男孩和女孩中表现出不同。青少年时期是大脑成熟的关键时期，突触的重要重塑和神经化学系统的重组是这一时期的特征。因此，令人惊讶的是，在对照研究中尚未确定n-3 PUFA在该发育阶段的影响。我的研究表明，青少年的大脑对环境变化高度敏感，并且大脑可塑性的重要调节因子（脑源性神经营养因子（BDNF）及其受体TrkB）的表达受到雄性和雌性大鼠饮食组成和应激暴露的不同影响。这些变化影响了中皮质边缘系统的关键结构，包括调节认知功能和情绪反应的杏仁核、杏仁核和海马体。因此，拟议的一系列实验旨在表征青少年n-3 PUFA补充对认知和学习诱导的可塑性的影响，并确定中皮质边缘系统中性别特异性的可塑性变化如何影响生化信号传导，以及记忆，社会/情感功能。这项研究还将确定饮食中补充omega-3是否可以减轻青少年所经历的压力效应，并影响与前额叶皮层成熟相关的认知功能（即决策和冲动）。考虑到青春期的性二态激素变化可能会影响生物行为反应，我们的研究包括男性和女性，使研究结果外推到整个人口。这项研究计划将促进了解omega-3 PUFA摄入对独特大脑系统功能可塑性的影响，检查伴随的行为变化，并表征青春期摄入n-3 PUFA的益处是否在成年期持续。

This research program expands the study of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplemented diets on remodelling of brain function and behavior. Brain development and function is critically dependent on the intake of essential fatty acids that cannot be readily synthesized by the human body. Fish oil is the principal dietary source of the longer-chain n-3 PUFA. Salmon is a rich dietary source, and high-grade pharmaceutical fish oil formulations are also easily available for human consumption. Assessment of the role of n-3 PUFA is an important question considering the growing consumption of processed foods in Western societies, which result in n-3 deficiency and disproportionately high n-6/n-3 PUFA ratio which has been shown to dysregulate brain activity. It is well acknowledged that n-3 PUFA rich diet during gestation promotes neuronal development, and has beneficial effects on cognitive function and neuroplasticity/protection in aged animals or consequent to brain injury. Human studies have reported beneficial effects of n-3 PUFA on cognition and mood in adolescents, which appear different in boys and girls. The adolescent period is a critical period for brain maturation and important remodelling of synapses and reorganization of neurochemical systems characterize this period. Therefore, it is surprising that effects of n-3 PUFA during this developmental stage has not been determined in controlled studies. My research has shown that the adolescent brain is highly sensitive to environmental changes, and expression of important regulators of brain plasticity (Brain-Derived Neurotrophic Factor (BDNF) and its receptor TrkB) is differentially affected by dietary composition and stress exposure in male and female rats. These changes affect key structures of the mesocorticolimbic system, including the nucleus accumbens, amygdala and hippocampus, which regulate cognitive function and emotional responses. Thus, the proposed series of experiments aim to characterize effects of adolescent n-3 PUFA supplementation on cognition and learning-induced plasticity, and determine how sex-specific plastic changes in the mesocorticolimbic system affects biochemical signaling, and memory, social/emotional functions. This research will also determine if dietary omega-3 supplementation can mitigate stress effects experienced as adolescents, and influence cognitive function associated with prefrontal cortex maturation (i.e, decision making and impulsivity). Considering sexually dimorphic hormonal changes in the pubertal period likely to influence bio-behavioural responses, our studies include both males and females, enabling extrapolation of findings to the population as a whole. This research program will foster knowledge of the impact of omega-3 PUFA intake on functional plasticity of distinctive brain systems, examine concomitant behavioural changes, and characterize if benefits of n-3 PUFA consumption in adolescence are perduring in adulthood.