Introduction: Repeated traumatic events result in long-lasting neuropsychiatric ailments, including neuroendocrine imbalances. Neuropeptide Y (NPY) in the arcuate nucleus (Arc) is an important orexigenic peptide. However, the molecular underpinnings of its dysregulation owing to traumatic brain injury remain unknown. Methods: Rats were subjected to repeated mild traumatic brain injury (rMTBI) using the closed-head weight drop model. Feeding behaviour and the regulatory epigenetic parameters of NPY expression were measured at 48 hrs and 30 days post rMTBI. Further, sodium butyrate, a pan-HDAC inhibitor, was administered to examine whether histone deacetylation is involved in NPY expression post rMTBI. Results: The rMTBI attenuated food intake, which was coincident with a decrease in NPY mRNA and protein levels in the Arc post rMTBI. Further, rMTBI also reduced the mRNA levels of the cAMP response element-binding protein (CREB) and CREB-binding protein (CBP) and altered the mRNA levels of the various isoforms of the histone deacetylases (HDACs). Concurrently, the acetylated H3-K9 levels and the binding of CBP at the NPY promoter in the Arc of the rMTBI-exposed rats were reduced. However, the treatment with sodium butyrate corrected the rMTBI-induced deficits in the H3-K9 acetylation levels and CBP occupancy at the NPY promoter, restoring both the NPY expression and the food intake. Conclusions: These findings suggest that histone deacetylation at the NPY promoter persistently controls NPY function in the Arc after rMTBI. This study also demonstrates the efficacy of HDAC inhibitors in mitigating trauma-induced neuroendocrine maladaptations in the hypothalamus.


中文翻译：

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组蛋白去乙酰化在创伤性脑损伤引起的弓状核神经肽 Y 缺陷中的作用：对摄食行为的可能影响

简介：反复的创伤事件会导致长期的神经精神疾病，包括神经内分泌失衡。弓状核 (Arc) 中的神经肽 Y (NPY) 是一种重要的促食欲肽。然而，由于创伤性脑损伤导致其失调的分子基础仍然未知。方法：使用闭头减重模型对大鼠进行反复轻度创伤性脑损伤（rMTBI）。在 rMTBI 后 48 小时和 30 天测量摄食行为和 NPY 表达的调节表观遗传参数。此外，给予丁酸钠，一种泛HDAC抑制剂，以检查组蛋白去乙酰化是否参与rMTBI后的NPY表达。结果：rMTBI 减少了食物摄入，这与 rMTBI 后 Arc 中 NPY mRNA 和蛋白质水平的降低一致。更远，rMTBI 还降低了 cAMP 反应元件结合蛋白 (CREB) 和 CREB ​​结合蛋白 (CBP) 的 mRNA 水平，并改变了组蛋白脱乙酰酶 (HDAC) 的各种同种型的 mRNA 水平。同时，暴露于 rMTBI 的大鼠的 Arc 中乙酰化 H3-K9 水平和 CBP 与 NPY 启动子的结合降低。然而，丁酸钠处理纠正了 rMTBI 诱导的 H3-K9 乙酰化水平和 NPY 启动子处 CBP 占据的缺陷，恢复了 NPY 表达和食物摄入。结论：这些发现表明 NPY 启动子的组蛋白去乙酰化持续控制 rMTBI 后 Arc 中的 NPY 功能。这项研究还证明了 HDAC 抑制剂在减轻创伤引起的下丘脑神经内分泌适应不良方面的功效。