Patel Mital Y, Yang Ruoting, Chakraborty Nabarun, Miller Stacy-Ann, DeMar James C, Batuure Andrew, Wilder Donna, Long Joseph, Hammamieh Rasha, Gautam Aarti
TechWerks, Arlington, United States.
Medical Readiness Systems Biology Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
Front Genet. 2024 Sep 13;15:1373447. doi: 10.3389/fgene.2024.1373447. eCollection 2024.
Blast injury has been implicated as the major cause of traumatic brain injury (TBI) and ocular system injury, in military operations in Iraq and Afghanistan. Soldiers exposed to traumatic stress also have undiagnosed, chronic vision problems. Here we hypothesize that excessive intake of ω-6 fatty acid linoleic acid (LA) and insufficiency of dietary long chain ω-3 polyunsaturated fatty acids (PUFAs, e.g., docosahexaenoic acid; DHA) would dysregulate endocannabinoid-mediated neuronal plasticity and immune response. The study objective was to determine the effect of blast-TBI and traumatic stress on retinal gene expression and assess the role of dietary deficiency of long chain ω-3 PUFAs on the vulnerability to these injury models.
Linoleic acid was used as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% present in the current western diets, and these custom LA diets were also devoid of long chain ω-3 PUFAs. Animals were exposed to a simulated blast overpressure wave followed by a weight drop head-concussion to induce TBI. A Separate group of rats were subjected to traumatic stress by a forced immersion underwater.
Our findings showed that blast-TBI exposure, post 14 days, produced significant neuropathological changes such as axonal degeneration in the brain optic tracts from all the three diet groups, especially in rats fed the DHA-deprived 1 en% LA diet. Transcriptomic analysis showed that presence of DHA in the house chow diet prevented blast-induced disruption of neuronal plasticity by activating molecular networks like SNARE signaling, endocannabinoid pathway, and synaptic long-term depression when compared to DHA-deprived 8 en% LA diet group. Under traumatic stress, retinal synaptic function, neurovascular coupling, and opioid signaling mechanisms were dysregulated in rodents fed DHA-deficient diets (i.e., 8 en% LA and 1 en% LA), where reducing the levels of ω-6 linoleic acid from 8 en% to 1 en% was associated with increased neuronal plasticity and suppressed immune signaling.
The findings of our study suggest that deprivation of long chain ω-3 PUFAs in the diet affects endocannabinoid-mediated neuronal plasticity, vascular function and inflammatory response that could influence the resistance of veterans to TBI and psychological trauma.
在伊拉克和阿富汗的军事行动中，爆炸伤被认为是创伤性脑损伤（TBI）和眼系统损伤的主要原因。暴露于创伤性应激的士兵也存在未被诊断出的慢性视力问题。在此，我们假设过量摄入ω-6脂肪酸亚油酸（LA）以及膳食中长链ω-3多不饱和脂肪酸（PUFAs，如二十二碳六烯酸；DHA）不足会导致内源性大麻素介导的神经元可塑性和免疫反应失调。本研究的目的是确定爆炸伤性脑损伤和创伤性应激对视网膜基因表达的影响，并评估膳食中长链ω-3多不饱和脂肪酸缺乏在这些损伤模型易感性中的作用。
以亚油酸作为自变量，反映西方现代饮食中LA从占能量的1%（能量百分比，en%）增加到8 en%的情况，这些定制的LA饮食中也不含长链ω-3多不饱和脂肪酸。动物先暴露于模拟爆炸超压波，随后进行重物落体致头部撞击以诱导TBI。另一组大鼠通过强迫浸入水下遭受创伤性应激。
我们的研究结果表明，爆炸伤性脑损伤暴露14天后，所有三个饮食组的脑视束均出现了显著的神经病理变化，如轴突退变，尤其是在喂食缺乏DHA的1 en% LA饮食的大鼠中。转录组分析表明，与缺乏DHA的8 en% LA饮食组相比，普通饲料中存在DHA可通过激活SNARE信号传导、内源性大麻素途径和突触长期抑制等分子网络，防止爆炸诱导的神经元可塑性破坏。在创伤性应激下，喂食缺乏DHA饮食（即8 en% LA和1 en% LA）的啮齿动物视网膜突触功能、神经血管耦合和阿片类信号传导机制失调，将ω-6亚油酸水平从8 en%降至1 en%与神经元可塑性增加和免疫信号抑制有关。
我们的研究结果表明，饮食中缺乏长链ω-3多不饱和脂肪酸会影响内源性大麻素介导的神经元可塑性、血管功能和炎症反应，这可能会影响退伍军人对TBI和心理创伤的抵抗力。
