Agrawal Rahul, Tyagi Ethika, Vergnes Laurent, Reue Karen, Gomez-Pinilla Fernando
Department of Integrative Biology & Physiology, UCLA, Los Angeles, CA 90095, USA.
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Biochim Biophys Acta. 2014 Apr;1842(4):535-46. doi: 10.1016/j.bbadis.2013.12.004. Epub 2013 Dec 15.
Metabolic dysfunction occurring after traumatic brain injury (TBI) is an important risk factor for the development of psychiatric illness. In the present study, we utilized an omega-3 diet during early life as a metabolic preconditioning to alter the course of TBI during adulthood. TBI animals under omega-3 deficiency were more prone to alterations in energy homeostasis (adenosine monophosphate-activated protein kinase; AMPK phosphorylation and cytochrome C oxidase II; COII levels) and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGC-1α and mitochondrial transcription factor A; TFAM). A similar response was found for brain-derived neurotrophic factor (BDNF) and its signaling through tropomyosin receptor kinase B (TrkB). The results from in vitro studies showed that 7,8-dihydroxyflavone (7,8-DHF), a TrkB receptor agonist, upregulates the levels of biogenesis activator PGC-1α, and CREB phosphorylation in neuroblastoma cells suggesting that BDNF-TrkB signaling is pivotal for engaging signals related to synaptic plasticity and energy metabolism. The treatment with 7,8-DHF elevated the mitochondrial respiratory capacity, which emphasizes the role of BDNF-TrkB signaling as mitochondrial bioenergetics stimulator. Omega-3 deficiency worsened the effects of TBI on anxiety-like behavior and potentiated a reduction of anxiolytic neuropeptide Y1 receptor (NPY1R). These results highlight the action of metabolic preconditioning for building long-term neuronal resilience against TBI incurred during adulthood. Overall, the results emphasize the interactive action of metabolic and plasticity signals for supporting neurological health.
创伤性脑损伤（TBI）后发生的代谢功能障碍是精神疾病发展的重要危险因素。在本研究中，我们在生命早期采用ω-3饮食作为代谢预处理，以改变成年期TBI的病程。ω-3缺乏的TBI动物更容易出现能量稳态改变（腺苷单磷酸激活蛋白激酶；AMPK磷酸化和细胞色素C氧化酶II；COII水平）和线粒体生物发生（过氧化物酶体增殖物激活受体γ共激活因子1-α；PGC-1α和线粒体转录因子A；TFAM）。脑源性神经营养因子（BDNF）及其通过原肌球蛋白受体激酶B（TrkB）的信号传导也有类似反应。体外研究结果表明，TrkB受体激动剂7,8-二羟基黄酮（7,8-DHF）上调神经母细胞瘤细胞中生物发生激活剂PGC-1α的水平和CREB磷酸化，这表明BDNF-TrkB信号传导对于参与与突触可塑性和能量代谢相关的信号至关重要。用7,8-DHF处理可提高线粒体呼吸能力，这强调了BDNF-TrkB信号传导作为线粒体生物能量学刺激剂的作用。ω-3缺乏会使TBI对焦虑样行为的影响恶化，并增强抗焦虑神经肽Y1受体（NPY1R）的减少。这些结果突出了代谢预处理对建立长期神经元抗成年期TBI能力的作用。总体而言，结果强调了代谢和可塑性信号对支持神经健康的相互作用。
