Caloric restriction promotes sustained neurological recovery after TBI

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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.