A Mild Traumatic Brain Injury in Mice Produces Lasting Deficits in Brain Metabolism

Abstract

Metabolic uncoupling has been well-characterized during the first minutes-to-days after a traumatic brain injury (TBI), yet mitochondrial bioenergetics during the weeks-to-months after a brain injury is poorly defined, particularly after a mild TBI. We hypothesized that a closed head injury (CHI) would be associated with deficits in mitochondrial bioenergetics at one month after the injury. A significant decrease in state-III (adenosine triphosphate production) and state-V (complex-I) driven mitochondrial respiration was found at one month post-injury in adult C57Bl/6J mice. Isolation of synaptic mitochondria demonstrated that the deficit in state-III and state-V was primarily neuronal. Injured mice had a temporally consistent deficit in memory recall at one month post-injury. Using proton magnetic resonance spectroscopy (1H MRS) at 7-Tesla, we found significant decreases in phosphocreatine, N-Acetylaspartic acid, and total choline. We also found regional variations in cerebral blood flow, including both hypo- and hyperperfusion, as measured by a pseudocontinuous arterial spin labeling MR sequence. Our results highlight a chronic deficit in mitochondrial bioenergetics associated with a CHI that may lead toward a novel approach for neurorestoration after a mild TBI. MRS provides a potential biomarker for assessing the efficacy of candidate treatments targeted at improving mitochondrial bioenergetics.

Photobiomodulation for Alzheimer’s Disease: Has the Light Dawned?

“…It is a general finding that mitochondrial dysfunction, inadequate supplies of ATP, and oxidative stress are contributory factors in almost all forms of brain disease [60]. This has been reported for neurological conditions such as major depressive disorder [61], traumatic brain injury [62], Parkinson's disease [63], and for AD [64].…”

Validation and standardization of a new radial-arm water maze protocol using a murine model of mild closed head traumatic brain injury

“…In this experiment, we evaluated whether our 7-trial protocol was able to detect memory deficits in a mTBI model. In the past, it has been shown that the same animal model of CHI was memory impaired in a 6-arm RAWM when a 15-trial protocol and 2-day test [27, 36] and a 15-trial protocol and 4-day test [30] protocol were used. To compare differences between SHAM and CHI mice, we used the median of errors made during the 4-day test (Fig.…”

“…A major finding of our study was that the reduction of number of trials significantly separates the acquisition curves of CHI and SHAM mice and the sex had no effect on results. Previously, we demonstrated that CHI mice had memory impairment in a 6-arm RAWM at 2 week post-CHI in a 4-day protocol and 15-trial per day [30] or in 2-day protocol and 15-trial per day [27, 36]. However, due to the knowledge that training schedule and spacing of training sessions can impact learning ability [10–13, 24, 25], we sought to determine if reduction of training increased the learning separation between mice affected by mTBI and controls.…”

“…We have shown that the sex of the mice affects response to the CHI for some variables [30]; thus, the data for the CHI experiments were disaggregated by sex.…”

Optimization and validation of a modified radial-arm water maze protocol using a murine model of mild closed head traumatic brain injury

“…Therefore, we report the results of the second statistical model without sex of the mice included in the model. We have shown that the sex of the mice affects response to the CHI for some variables [30]; thus, the data for the CHI experiments were disaggregated by sex.…”