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Repetitive mild traumatic brain injury alters diurnal locomotor activity and response to the light change in mice.

ABSTRACT: Mild traumatic brain injury (mTBI) is a common cause of brain damage with a high incidence of multiple mTBIs found among athletes and soldiers. The purpose of this study is to examine the diurnal behavioral changes after multiple mTBIs. Adult mice were anesthetized; mTBI was conducted by dropping a 30-g weight to the right temporal skull once (mTBI1) or three times (mTBI3) over 3-week. Open-field motor behavior was recorded for 3 days after the last mTBI. In the first 4-hour exploratory phase, mTBI1 or mTBI3 equally reduced locomotor activity. A significant reduction of locomotor activity was found in the dark cycle between 4-72 hour in mTBI1 or mTBI3 mice; higher motor activity was seen after mTBI3 compared to mTBI1. In the light cycle, mTBI3 mice demonstrated an earlier immobilization followed by hyperactivity. The response to light change significantly correlated with the number of impacts. The IBA1 and BAX protein levels were equally increased in the lesioned cortex after mTBI1 and mTBI3. mTBI3 selectively upregulated the expression of circadian clock gene Per1 in hypothalamus and hippocampus as well as iNOS expression in the lesioned side cortex. Our data suggest multiple mTBIs alter diurnal locomotor activity and response to the change of light, which may involve Per1 expression in the lesioned brain.

SUBMITTER: Wang YS

PROVIDER: S-EPMC6773703 | biostudies-other | 2019 Oct

REPOSITORIES: biostudies-other

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Repetitive mild traumatic brain injury alters diurnal locomotor activity and response to the light change in mice.

Wang Yu-Syuan YS Hsieh Wei W Chung Jia-Ru JR Lan Tsuo-Hung TH Wang Yun Y

Scientific reports 20191001 1

Mild traumatic brain injury (mTBI) is a common cause of brain damage with a high incidence of multiple mTBIs found among athletes and soldiers. The purpose of this study is to examine the diurnal behavioral changes after multiple mTBIs. Adult mice were anesthetized; mTBI was conducted by dropping a 30-g weight to the right temporal skull once (mTBI1) or three times (mTBI3) over 3-week. Open-field motor behavior was recorded for 3 days after the last mTBI. In the first 4-hour exploratory phase, m ...[more]

PMID: 31575951

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Project description:Mild traumatic brain injury (mTBI) or concussion is a common injury worldwide leading to substantial medical costs and a high burden on society. In adolescents, falls and sports related trauma are often the causes of mTBI. Importantly, critical brain growth and development occurs during this sensitive period making the prospect of a brain injury a worrying phenomenon. Upwards of 70% of patients report circadian disruption following these injuries and this has been shown to impede recovery. Therefore, we sought to determine if core circadian clock gene expression was disrupted in rat model of repetitive mTBI (RmTBI). Male and female adolescent rats (n = 129) received sham or RmTBI. The animals were then euthanized at different times throughout the day and night. Tissue from the hypothalamus, cerebellum, hippocampus, liver, and small intestine were evaluated for the expression of per1, per2, cry1, clock, bmal1 and rev-erb-α. We found most clock genes varied across the day/night indicating circadian expression patterns. In the hypothalamus we found RmTBI altered the expression of cry1 and bmal1 in addition to sex differences in per2, cry1, clock, bmal1 and rev-erb- α. In the cerebellum, per1, per2, cry1, clock, bmal1 and rev-erb-α rhythms were all knocked out by RmTBI in addition to sex differences in cry1, clock and bmal1 expression. We also detected a significant decrease in overall expression of all clock genes in males in the middle of the night. In the hippocampus we found that RmTBI changed the rhythm of rev-erb-α expression in addition to sex differences in bmal1 expression. In the liver we detected strong rhythms in all genes examined, however only per2 expression was knocked out by RmTBI, in addition we also detected sex differences in per2 and cry1. We also detected an overall decrease in female clock gene expression in the early night. In the small intestine, RmTBI altered cry1 expression and there were sex differences in rev-erb-α. These results indicate that RmTBI alters core circadian clock gene expression in the central and peripheral nervous system in a time, tissue and sex dependent manner. This may be disrupting important phase relationships between the brain and peripheral nervous system and contributing to post-injury symptomology and also highlights the importance for time and sex dependent assessment of injury outcomes.

Project description:BackgroundRepetitive mild traumatic brain injury (mTBI) can result in chronic visual dysfunction. G-protein receptor 110 (GPR110, ADGRF1) is the target receptor of N-docosahexaenoylethanolamine (synaptamide) mediating the anti-neuroinflammatory function of synaptamide. In this study, we evaluated the effect of an endogenous and a synthetic ligand of GPR110, synaptamide and (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-hydroxy-2-methylpropyl) docosa-4,7,10,13,16,19-hexaenamide (dimethylsynaptamide, A8), on the mTBI-induced long-term optic tract histopathology and visual dysfunction using Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA), a clinically relevant model of mTBI.MethodsThe brain injury in wild-type (WT) and GPR110 knockout (KO) mice was induced by CHIMERA applied daily for 3 days, and GPR110 ligands were intraperitoneally injected immediately following each impact. The expression of GPR110 and proinflammatory mediator tumor necrosis factor (TNF) in the brain was measured by using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in an acute phase. Chronic inflammatory responses in the optic tract and visual dysfunction were assessed by immunostaining for Iba-1 and GFAP and visual evoked potential (VEP), respectively. The effect of GPR110 ligands in vitro was evaluated by the cyclic adenosine monophosphate (cAMP) production in primary microglia isolated from adult WT or KO mouse brains.ResultsCHIMERA injury acutely upregulated the GPR110 and TNF gene level in mouse brain. Repetitive CHIMERA (rCHIMERA) increased the GFAP and Iba-1 immunostaining of glia cells and silver staining of degenerating axons in the optic tract with significant reduction of N1 amplitude of visual evoked potential at up to 3.5 months after injury. Both GPR110 ligands dose- and GPR110-dependently increased cAMP in cultured primary microglia with A8, a ligand with improved stability, being more effective than synaptamide. Intraperitoneal injection of A8 at 1 mg/kg or synaptamide at 5 mg/kg significantly reduced the acute expression of TNF mRNA in the brain and ameliorated chronic optic tract microgliosis, astrogliosis, and axonal degeneration as well as visual deficit caused by injury in WT but not in GPR110 KO mice.ConclusionOur data demonstrate that ligand-induced activation of the GPR110/cAMP system upregulated after injury ameliorates the long-term optic tract histopathology and visual impairment caused by rCHIMERA. Based on the anti-inflammatory nature of GPR110 activation, we suggest that GPR110 ligands may have therapeutic potential for chronic visual dysfunction associated with mTBI.

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Repetitive mild traumatic brain injury alters diurnal locomotor activity and response to the light change in mice.

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Repetitive mild traumatic brain injury alters diurnal locomotor activity and response to the light change in mice.

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