Abstract
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 high-fat, low-carbohydrate 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 (β-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.
Highlights
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative brain disorder caused by repeated traumatic brain injury (TBI), and is prevalent among contact-sport athletes (Maroon et al, 2015)
To model Traumatic brain injury (TBI) in flies, we developed a modified high-impact trauma” (HIT) device— a fly “banger” —(see Figure 1A) similar to that used in recent publications (Katzenberger et al, 2013, 2015) to deliver headtrauma-inducing bangs (“big adverse neurotrauma-generating events”) to young-adult males of the wild-type Canton-S Drosophila melanogaster strain
We found that neither the number of, nor the latency to, aggressive events in CantonS males exposed to extreme cold or electric shock differed significantly from those measures of aggression recorded for control-dieted males subjected to no head trauma at all (For electric shock, a few outlier male-male pairs did exhibit a rather long latency to first aggressive event this result would be indicative of reduced, not elevated post-traumatic aggression: the animals were slower, not quicker, to engage in bouts of aggressive behavior.) These results led us to conclude that the increase in aggressive behavior observed in banged control-dieted flies was specific to head trauma induced by the HIT device
Summary
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative brain disorder caused by repeated traumatic brain injury (TBI), and is prevalent among contact-sport athletes (Maroon et al, 2015). A wide variety of cognitive-behavioral disturbances manifest in cases of CTE, such as mood disorders and depression, cognitive impairment (including memory loss), and elevated aggression (McKee et al, 2012) These behaviors may be related to the high levels of neuronal death evident in cases of CTE, part of the underlying cause for which may be glutamate excitotoxicity (Blaylock and Maroon, 2011) subsequent to elevated glutamatergic neuronal signaling following brain injury (Koenig et al, 2019). This dietary treatment has been used intermittently for nearly 100 years (Wilder, 1921), and much more in recent decades (Thiele, 2003, 2013; Bailey et al, 2005) as an effective—albeit very challenging—therapy for drug-resistant epilepsy in children (Thiele, 2013) and, increasingly, in adults (see, for example, McDonald and Cervenka, 2017)
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