Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: implications for treatment-resistance

Although regulation of energy metabolism has been linked with multiple disorders, its role in depression and responsiveness to antidepressants is less-known. We found that an epigenetic and energetic agent, acetyl-L-carnitine (LAC, oral administration), rapidly rescued the depressive- and central and systemic metabolic-like phenotype of LAC-deficient Flinders Sensitive Line (FSL) rats. After acute stress during LAC treatment, a subset of FSL continued to respond to LAC (rFSL), whereas the other subset did not respond (nrFSL). RNAseq for the ventral dentate-gyrus (vDG), a mood-regulatory region, identified metabolic factors as key markers predisposing to depression (insulin receptors Insr, glucose transporters Glut-4 and Glut-12, the regulator of appetite Cartpt) and to LAC responsiveness (leptin receptors Lepr, metabotropic glutamate receptors-2 mGlu2, neuropeptide-Y NPY, and mineralocorticoid receptors MR). Furthermore, we found that stress-induced treatment-resistance in nrFSL shows a new gene profile, including the metabolic regulator factors Elovl7 and Cyb5r2 and the synaptic regulator NPAS4. Finally, while improving central energy regulation and exerting rapid antidepressant-like effects, LAC corrected a systemic hyperinsulinemia and hyperglycemia.tance in rFSL and failed to do that in nrFSL. These findings establish CNS energy regulation as factor to be considered for the development of better therapeutics. Agents, like LAC, which regulate metabolic factors and reduce glutamate overflow, could rapidly ameliorate depression and could also be considered for treatment of insulin-resistance in depressed subjects. The approach here serves as a model for identifying markers and underlying mechanisms of predisposition to diseases and treatment responsiveness that may be useful in translation to human behavior and psychopathology.尽管能量代谢调控与多种疾病存在关联，但其在抑郁症及对抗抑郁药物响应性中的作用仍鲜为人知。本研究发现，一种兼具表观遗传调控与能量调节活性的物质——乙酰-L-肉碱（acetyl-L-carnitine, LAC，经口给药），可快速挽救乙酰-L-肉碱缺乏型弗林德斯敏感系（Flinders Sensitive Line, FSL）大鼠的抑郁样表型以及中枢与全身性代谢紊乱样表型。在LAC给药期间施加急性应激后，部分FSL大鼠仍可对LAC产生响应（响应型FSL，rFSL），而其余大鼠则无响应（无响应型FSL，nrFSL）。对情绪调控核心脑区腹侧齿状回（ventral dentate-gyrus, vDG）进行RNAseq分析后发现，代谢相关因子是抑郁易感的关键标志物，包括胰岛素受体Insr、葡萄糖转运蛋白Glut-4与Glut-12、食欲调控因子Cartpt；同时也是影响LAC响应性的关键标志物，包括瘦素受体Lepr、代谢型谷氨酸受体2 mGlu2、神经肽Y NPY以及盐皮质激素受体MR。此外，本研究发现无响应型FSL大鼠中应激诱导的治疗抵抗呈现全新的基因表达谱，其中包含代谢调控因子Elovl7、Cyb5r2以及突触调控因子NPAS4。最后，尽管LAC可改善中枢能量调控并发挥快速抗抑郁样作用，但其可纠正响应型FSL大鼠的全身性高胰岛素血症与高血糖症状，而在无响应型FSL大鼠中则无法达成该效果。上述研究结果确立了中枢神经系统（CNS）能量调控作为开发更优治疗手段的关键考量因素。诸如LAC这类可调控代谢因子、减少谷氨酸溢出的物质，不仅可快速改善抑郁症状，还可被考虑用于治疗抑郁症患者的胰岛素抵抗问题。本研究采用的研究策略可作为一种模型，用于识别疾病易感标志物与治疗响应性的潜在机制，该模型或可在转化至人类行为与精神病理学研究中发挥应用价值。