Symptoms following Traumatic Brain Injury in a Drosophila melanogaster CTE Model are Ameliorated by Ketone Body Enantiomers
Authors: Katelyn Mooney 1,2; Geoffrey Tanner 1,2; Jeremy Balsbaugh 1; Kate Gavilanes 1; Dariana Mota 1; Joseph Mooney 1; Mirsha Pierre 1; Alana Grant 1; Hanna Val Pelt 1; Yves Thelusma 1
Affiliations: 1) University of Connecticut; 2) The Connecticut Institute for Brain and Cognitive Sciences
Keywords: h. other (Traumatic Brain Injury, Chronic Traumatic Encephalopathy); a. neural degeneration
Traumatic Brain Injury (TBI) events—which are increasing in both concern and incidence in contact sports—are defined as brain injuries sustained from a blow or force to the head that disrupts normal brain function. Following TBI, individuals may experience headaches, confusion and disorientation, and difficulty speaking. Multiple TBI events may lead to Chronic Traumatic Encephalopathy (CTE), a progressive neurodegenerative condition characterized by impaired judgment and learning and memory, and personality changes including anxiety, depression, and hyper-aggressive behavior. Progressively more young athletes in contact sports are experiencing repeated TBI, making research into TBI and CTE critical. The ketogenic diet (KD) is a low-carbohydrate, adequate-protein, and high-fat diet that has been used effectively in the clinic to treat neurological disorders such as intractable pediatric epilepsy. We have shown that directly supplementing standard high-carbohydrate Drosophila melanogaster diets with ketone bodies (KBs; specifically, beta-hydroxybutyrate, BHB) increases lifespan and decreases male-on-male aggression following TBI events. Our results have suggested that different enantiomeric forms of exogenous BHB may vary in their effectiveness at reducing aggression and increasing lifespan. Compared with a control diet (CD) alone, dietary supplementation with either pure R-BHB (the main endogenous form), or a BHB racemic mixture, both significantly decrease number of post-TBI aggressive events in male-male pairs; racemic and pure-S-BHB lengthen latency to the first aggressive event. The mechanism by which BHB supplementation ameliorates elevated aggression and increases lifespan following TBI is poorly understood. BHB’s primary metabolic function is mitochondrial ATP production under conditions of low circulating glucose levels leading to elevated brain-wide ATP/ADP ratios. However, BHB can also act as a GPCR ligand, a gene-expression regulator (via histone deacetylase inhibition), and a sirtuin protein activator (via increased cytoplasmic [NAD+]). Sir2 activation promotes cell survival through a variety of mechanisms, including activation of autophagy proteins (e.g. autophagy-related protein 8a; Atg8a) which can mediate clearance of damaged cellular components. We hypothesize that BHB works to decrease neuronal cell death following TBI by improving neuronal metabolic stability and by activating and upregulating levels of Sir2 and Atg8a. Future experiments will include confirming reduced neuronal cell death, studying the ability of BHB to rescue learning following TBI, and determining NAD+/NADH ratios in whole brains from TBI-subjected flies receiving exogenous BHB.