Chronic Neurobehavioral Impairments and Decreased Hippocampal Expression of Genes Important for Brain Glucose Utilization in a Mouse Model of Mild TBI

Abstract

Glucose is an essential cellular fuel for maintaining normal brain functions. Traumatic brain injury (TBI) decreases brain glucose utilization in both human and experimental animals during the acute or subacute phase of TBI. It remains unclear as to how the damages affect brain glucose utilization and its association with persistent neurobehavioral impairments in the chronic phase of mild TBI (mTBI). Accordingly, we compared expression of selected genes important to brain glucose utilization in different brain regions of mice during the chronic phase in mTBI vs. sham operated mice. These genes included hexokinase-1 (HK1), phosphofructokinase (PFK), pyruvate kinase (PK), pyruvate dehydrogenase (PDH), capillary glucose transporter (Glut-1), neuron glucose transporter (Glut-3), astrocyte lactate transpor1 (MCT-1), neuron lactate transporter (MCT-2), lactate receptor (GPR81), and Hexokinase isoform-2 (HK2). Young adult male C57BL/6J mice were brain injured with repetitive closed-head concussions. Morris water maze (MWM), elevated plus maze (EPM), and neurological severity score test (NSS) were performed for evaluation of mice neurobehavioral impairments at 2, 4, and 6 months post mTBI. Two days after completion of the last behavioral test, the frontal cortex, hippocampus, brainstem, hypothalamus, and cerebellum were collected for gene expression measurements. The expression of the mRNAs encoding PK, and PDH, two critical enzymes in glucose metabolism, was decreased at all-time points only in the hippocampus, but was unchanged in the brainstem, hypothalamus, and cortex in mTBI mice. mTBI mice also exhibited the following behavioral alterations: (1) decreased spatial learning and memory 2, 4, and 6 months after the injury, (2) increased proportion of time spent on open vs. closed arms determined by EPM, and (3) accelerated reduction in motor activity observed at 4 months, two months earlier than observed in the sham group, during the EPM testing. There were no significant differences in NSS between Huynh et al. Chronic Effects of mTBI injury and sham groups at any of the three time points. Thus, mTBI in male mice led to persistent decreased hippocampal expression of mRNAs that encode critical glucose utilization related enzymes in association with long-term impairments in selected neurobehavioral outcomes.

Chronic motor performance following different traumatic brain injury severity—A systematic review

“…Overall, a focal injury was required to lead to persistent decreases in neuroscore, with minimal changes seen with diffuse injury. It should be noted the neurological severity scoring system varied widely among the 15 included studies, with the standard neurological severity score ( 79 – 85 ), modified neurological severity score ( 86 – 88 ), and revised neurological severity score ( 89 ) all represented. Even articles that used the same names for their scoring systems incorporated different tasks within their behavioral battery ( Supplementary Table 4 ).…”

Targeting Nrf2-Mediated Oxidative Stress Response in Traumatic Brain Injury: Therapeutic Perspectives of Phytochemicals

“…TBI, also known as acquired intracranial injury, occurs in the brain. It is caused by an external force, including a blow, bump, or jolt to the head, and the sudden and serious hit of the head by an object or the deep pierce of an object into the skull through the brain tissue [ 14 ]. According to the data from the Center for Disease Control and Prevention (CDC) of Unite States (U.S.), the most common causes mainly include violence, transportation, accidents, construction, and sports.…”

“…Then, NO reacts with free radical superoxide to generate “reactive nitrogen species” peroxynitrite (PN) in the forms of 3-nitrotyrosine (3-NE) and 4-HNE, which are found in the ipsilateral cortex and hippocampus of TBI animal models [ 24 ]. For example, N(omega)-nitro-L-arginine methyl ester (L-NAME), a NO-synthase inhibitor, was reported to attenuate neurological impairment in TBI and reduce the formation of NE and the number of NE-positive neurons [ 14 ]. Therefore, targeting the inhibition of oxidative stress in the brain is a promising strategy for the treatment of TBI.…”

Metabolic disorders on cognitive dysfunction after traumatic brain injury

“…OPEN ACCESS associated with decreased expression of glucose transporters and glycolysis-related kinases [30]. Although there are differences in the temporal and spatial distribution of glucose transport function in different types of brain injury (single or repetitive), it is certain that reduced glucose metabolism in the brain is considered to be a manifestation of patients with TBI-induced cognitive impairment [31,32].…”