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

这项研究计划扩大了添加omega-3多不饱和脂肪酸(n-3 PUFA)的饮食对大脑功能和行为重塑的研究。大脑的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取。鱼油是长链n-3多不饱和脂肪酸的主要饮食来源。鲑鱼是一种丰富的饮食来源，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消费的增长，n-3多不饱和脂肪酸的作用的评估是一个重要的问题，这导致了n-3缺乏和不成比例的n-6/n-3多不饱和脂肪酸比率，这已被证明是大脑活动的失调。孕期丰富的n-3多不饱和脂肪酸饮食可促进神经元发育，对老年动物或脑损伤后的认知功能和神经可塑性/保护有良好的作用。人体研究报告了n-3多不饱和脂肪酸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。青春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，n-3多不饱和脂肪酸在这一发育阶段的影响尚未在对照研究中确定。我的研究表明，青春期的大脑对环境变化高度敏感，大脑可塑性的重要调节因子(脑源性神经营养因子及其受体TrkB)的表达在雄性和雌性大鼠中受到饮食组成和应激暴露的不同影响。这些变化影响到中皮质边缘系统的关键结构，包括伏隔核、杏仁核和海马体，这些结构调节认知功能和情绪反应。因此，拟议的一系列实验旨在表征补充青少年n-3多不饱和脂肪酸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定的可塑性变化如何影响生化信号、记忆、社会/情感功能。这项研究还将确定饮食中补充omega-3是否可以缓解青少年经历的压力效应，并影响与前额叶皮质成熟相关的认知功能(即决策和冲动)。考虑到青春期性二态荷尔蒙的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，从而能够将研究结果外推到整个人群。这项研究计划将培养有关omega-3多不饱和脂肪酸摄入对独特大脑系统功能可塑性的影响的知识，检查伴随的行为变化，并表征n-3多不饱和脂肪酸在青春期摄入的益处是否在成年后持续。

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.