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伤，随后是脑内广泛的功能障碍。 分子级联反应;包括内源性损伤反应的适应不良激活和/或失调 机制等这些导致进行性组织损失和慢性神经功能缺损-继发性损伤。的 适应不良的强烈和持续的激活小胶质细胞功能失调的神经毒性激活表型后， 脑外伤，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。 促进神经功能康复的持续恢复的干预措施。 我们的长期目标是设计有效的疾病改善治疗方法， 退伍军人事务系统通过检查非药物治疗干预措施， 促进修复/神经可塑性通路，如减轻继发性损伤神经病理学， 在TBI后的慢性期活跃。退伍军人是一个独特的脑外伤患者群体，因为军事TBI 具有影响神经病理学发展的特定条件。一个尚未解决的关键问题是 治疗干预在TBI后的慢性期有效，可减轻促炎性和神经毒性 小胶质细胞激活状态;从而促进神经功能的修复和恢复-康复。 间歇性禁食（热量限制）已被证明可以减弱关键的炎症通路，刺激 从干细胞产生新的神经元（神经发生）;以及增强突触可塑性，认知 功能，并增加大脑在创伤后恢复的能力。已证明口服酮酯 减轻TBI神经病理学，导致脑代谢的变化，促进脑创伤后的修复。 口服烟酰胺核苷饮食治疗可改善认知功能和突触可塑性， 神经变性疾病以及减弱兴奋性毒性诱导的轴突变性。 我们假设，非药物干预，包括间歇性禁食，以及口服酮酯， 和烟酰胺核苷减轻TBI后慢性期的脑和外周炎症。因此，在本发明中， 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测试这些新的假设： 目的1：热量限制减弱促炎性小胶质细胞的适应不良激活，并导致 TBI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症并促进神经功能康复， TBI后的慢性期 目的3：口服烟酰胺核苷可减少持续性小胶质细胞激活并促进神经功能 TBI后慢性期的恢复。

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.