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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.01140

Dietary supplementation with the ketogenic diet metabolite beta-hydroxybutyrate ameliorates post-TBI aggression in young-adult male Drosophila.

 Derek C. Lee1, 2,  Krishna Vali1, 2, Shane R. Baldwin1, Jeffrey N. Divino1,  Justin L. Feliciano1, Jesus R. Fequiere1, Mirella A. Fernandez1, James C. Frageau1, 2, Frank K. Longo1, Salaheddine S. Madhoun1,  Pasquale P. Mingione V1,  Timothy R. O'Toole1, 2, Maria G. Ruiz1 and  Geoffrey R. Tanner1, 2*
  • 1University of Connecticut, United States
  • 2Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, United States

Traumatic brain injury (TBI), caused by repeated concussive head trauma can induce chronic traumatic encephalopathy (CTE), a neurodegenerative disease featuring behavioral symptoms ranging from cognitive deficits to elevated aggression. In a Drosophila model, we used a high-impact trauma device [Katzenberger et al., 2013, 2015] to induce TBI-like symptoms and to study post-TBI behavioral outcomes. Following TBI, aggression in banged male flies was significantly elevated as compared with that in unbanged flies. These increases in aggressive behavior were not the result of basal motility changes, as measured by a negative geotaxis assay. In addition, the increase in post-TBI aggression appeared to be specific to concussive trauma: neither cold exposure nor electric shock—two alternate types of trauma—significantly elevated aggressive behavior in male-male pairs. Various forms of dietary therapy, especially the ketogenic diet (KD), have recently been explored for a wide variety of neuropathies. We thus hypothesized that putatively-neuroprotective dietary interventions might be able to suppress post-traumatic elevations in aggressive behavior in animals subjected to head- trauma-inducing strikes, or “bangs”. We supplemented a normal high-carbohydrate Drosophila diet with the KD metabolite beta-hydroxybutyrate (-HB)—a ketone body (KB). Banged flies raised on a KB-supplemented diet exhibited a marked reduction in aggression, whereas aggression in unbanged flies was equivalent whether dieted with KB supplements or not. Pharmacological blockade of the ATP-sensitive potassium (KATP) channel abrogated KB effects reducing post-TBI aggression while pharmacological activation mimicked them, suggesting a mechanism by which KBs act in this model. KBs did not significantly extend lifespan in banged flies, but markedly extended lifespan in unbanged flies. We have thus developed a functional model for the study of post-TBI elevations of aggression. Further, we conclude that dietary interventions may be a fruitful avenue for further exploration of treatments for TBI- and CTE-related cognitive-behavioral symptoms.

Keywords: Ketogenic diet (KD), Traumatic brain injuries (TBI), Aggression, Drosophila, Chronic traumatic encephalopathies (CTE), KATP channel, Neuroprotection

Received: 26 Aug 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Lee, Vali, Baldwin, Divino, Feliciano, Fequiere, Fernandez, Frageau, Longo, Madhoun, Mingione V, O'Toole, Ruiz and Tanner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Geoffrey R. Tanner, University of Connecticut, Mansfield, 06269, Connecticut, United States,