Caloric restriction promotes sustained neurological recovery after TBI

创伤性脑损伤(TBI)导致广泛的细胞结构损害，继而导致广泛的功能障碍 分子级联反应；包括适应不良的激活和/或内源性损伤反应的失调 机械装置。这些会导致进行性组织丢失和慢性神经功能缺陷--继发性损伤。这个 小胶质细胞对功能障碍的神经毒性激活表型的不适应性强而持久的激活 脑创伤，导致进行性神经变性和认知能力下降。更好地理解 控制继发性损伤与修复途径的过程对于设计有效的治疗方法至关重要 促进神经功能持续恢复的干预措施--康复。 我们的长期目标是设计出有效的疾病修正治疗方法，与 退伍军人事务系统通过审查非药物治疗干预措施 促进修复/神经可塑性途径，如减轻继发性损伤的神经病理，这是 颅脑损伤后慢性期活动活跃。退伍军人是脑创伤患者中的一个独特群体，因为军队脑外伤 以影响发育中的神经病理的特定条件为特色。一个关键的悬而未决的问题是 治疗干预在颅脑损伤后慢性期有效，以减轻促炎和神经毒性 小胶质细胞处于激活状态，从而促进神经功能的修复和恢复-康复。 间歇性禁食(卡路里限制)已被证明可以减弱关键的炎症途径，刺激 干细胞产生新的神经元(神经发生)；以及增强突触的可塑性，认知 功能，并增加大脑在创伤后恢复的能力。口服酮酯已被证明可以 减轻脑损伤的神经病理，导致脑代谢的变化，促进脑创伤后的修复。 口服烟酰胺核苷可改善大鼠认知功能和突触可塑性 神经退行性疾病，以及减轻兴奋性毒性引起的轴突变性。 我们假设非药物干预包括间歇性禁食；以及口服酮酯 烟酰胺核苷可减轻脑损伤后慢性期的脑部和外周炎症。因此， 促进与神经恢复性小胶质细胞表型相关的持续神经康复。 我们将通过解决以下具体目标来检验这些新的假设： 目的1：卡路里限制减轻促炎小胶质细胞的非适应性激活，并导致 颅脑损伤后慢性期持续神经功能康复。 目的2：口服酮酯抑制进行性神经炎并促进神经功能康复 颅脑损伤后的慢性期。 目的3：口服烟酰胺核苷减少持续的小胶质细胞激活并促进神经功能 颅脑损伤后慢性期恢复。

Traumatic brain injury (TBI) results in extensive cellular structural damage followed by widespread dysfunctions in molecular cascades; including maladaptive activation and/or dysregulation of endogenous injury-response mechanisms. These lead to progressive tissue loss and chronic neurological deficits - secondary injury. The maladaptive strong and persistent activation of microglia to a dysfunctional neurotoxic activation phenotype after brain trauma, contributes to progressive neurodegeneration and cognitive decline. A better understanding of the processes that control secondary injury vs. repair pathways is crucial for the design of effective therapeutic interventions that promote sustained recovery of neurological function-rehabilitation. Our long-term goal is to devise effective disease-modifying treatments that are relevant to patients in the Veterans Affairs system by examining non-pharmacologic therapeutic interventions focused as much on the promotion of repair/neuroplasticity pathways, as on attenuation of secondary injury neuropathology, and that are active in the chronic phase after TBI. Veterans are a distinct group of brain trauma patients because military TBI features specific conditions that impact the developing neuropathology. A critical unsolved question is what therapeuticinterventionsareeffective in the chronic phase after TBI to attenuate thepro-inflammatory and neurotoxic microglial activation state; and thus, promote repair and restoration of neurological function - rehabilitation. Intermittent fasting (caloric restriction) has been shown to attenuate key inflammatory pathways, stimulate production of new neurons from stem cells (neurogenesis); as well as enhance synaptic plasticity, cognitive function, and increase the ability of the brain to recover after trauma. Oral ketone esters have been shown to attenuate TBI neuropathology leading to changes in brain metabolism that promote repair after brain trauma. Dietary treatment with oral nicotinamide riboside may improve cognitive function and synaptic plasticity in neurodegenerative diseases, as well as attenuate excitotoxicity-induced axonal degeneration. We hypothesize that non-pharmacologic interventions including intermittent fasting; as well as oral ketone esters and nicotinamide riboside attenuate brain and peripheral inflammation in the chronic phase after TBI. Thus, promoting sustained neurological rehabilitation associated with neurorestorative microglia phenotypes. We will test these novel hypotheses by addressing the following specific aims: Aim 1: Caloric restriction attenuates the maladaptive activation of pro-inflammatory microglia, and results in sustained neurological function rehabilitation in the chronic phase after TBI. Aim 2: Oral ketone esters inhibit progressive neuroinflammation and foster neurological function rehabilitation in the chronic phase after TBI. Aim 3: Oral nicotinamide riboside reduces persistent microglia activation and promotes neurological function recovery in the chronic phase after TBI.