Connexin43 (Cx43) is one of the most abundant gap junction proteins in the central nervous system. Abnormal opening of Cx43 hemichannels after ischemic insults causes apoptotic cell death. In this study, we found persistently increased expression of Cx43 8 h to 7 d after hypoxia/ischemia (HI) injury in neonatal rats. Pre-treatment with Gap26 and Gap27, two Cx43 mimetic peptides, significantly reduced cerebral infarct volume. Gap26 treatment at 24 h after ischemia improved functional recovery on muscle strength, motor coordination, and spatial memory abilities. Further, Gap26 inhibited Cx43 expression and reduced active astrogliosis. Gap26 interacted and co-localized with Cx43 together in brain tissues and cultured astrocytes. After oxygen glucose deprivation, Gap26 treatment reduced the total Cx43 level in cultured astrocytes; but Cx43 level in the plasma membrane was increased. Degradation of Cx43 in the cytoplasm was mainly via the ubiquitin proteasome pathway. Concurrently, phosphorylated Akt, which phosphorylates Cx43 on Serine373 and facilitates the forward transport of Cx43 to the plasma membrane, was increased by Gap26 treatment. Microdialysis showed that increased membranous Cx43 causes glutamate release by opening Cx43 hemichannels. Extracellular glutamate concentration was significantly decreased by Gap26 treatment in vivo. Finally, we found that cleaved caspase-3, an apoptosis marker, was attenuated after HI injury by Gap26 treatment. Effects of Gap27 were analogous to those of Gap26. In summary, our findings demonstrate that modulation of Cx43 expression and astroglial function is a potential therapeutic strategy for ischemic brain injury.

Concussion is a popular clinical topic that has been the subject of unprecedented recent media coverage. As concerns about the potential short- and long-term implications of repetitive head injury in sports such as football continue to mount, the proper clinical management of concussion seems to increase in importance. The days of ignoring the ''ding'' on the sideline are definitely over. A series of updated clinical evaluation and management recommendations from international experts are highlighted in this review. The clinical presentation of an acute concussion, both the typical and more subtle variations, may be evaluated with new validated sideline evaluation tools (eg, Sports Concussion Assessment Tool 2). In addition, the role of computerized neuropsychological and balance testing in the acute and ongoing evaluation are discussed, along with how they contribute to the return-to-play decision. Same-day return to play is outdated, and the relative insensitivity of current neuroimaging modalities to demonstrate structural damage is highlighted. New therapeutic interventions such as amantadine and cognitive rest may improve recovery time. The appropriate management of concussion typically results in a normal functional and neurocognitive outcome. The recommendations in this article may guide clinicians, with varying degrees of prior experience managing concussion, to increase the likelihood of an excellent outcome.

The purpose of the current study was to explore potential differences in pre- and post-concussion performance on a computerized neurocognitive concussion test between African American and White high-school and collegiate student-athletes. A prospective case-control design was used to compare baseline and 2- and 7-day post-concussion computerized neurocognitive performance and symptoms between 48 White and 48 African American athletes matched for age, gender, and concussion history. The Immediate Post-Concussion Assessment Cognitive Test (ImPACT) version 2.0 (NeuroHealth System, LLC, Pittsburgh, PA, USA) computer software program was used to assess neurocognitive function (i.e., verbal and visual memory, motor processing speed, and reaction time) and concussion symptoms. Regardless of race/ethnicity, there were significant decrements in computerized neurocognitive performance and increased symptoms following a concussion for the entire sample. African Americans and Whites did not differ significantly on baseline or post-concussion verbal memory, visual memory, reaction time, and total reported symptoms. However, African American participants were 2.4× more likely to have at least one clinically significant cognitive decline on ImPACT at 7 days post-concussion and scored lower at 7 days post-concussion compared with baseline on processing speed than White participants. The authors concluded that the baseline ImPACT test was culturally equivalent and construct valid for use with these two racial/ethnic groups. However, in contrast, the findings support deleterious performance for the African American athletes compared with the White athletes on the ImPACT post-concussion evaluation that is of critical clinical relevance and warrants further research.

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In this paper, we investigate the potential for the development of a composite score investigating population-level phenotype changes in a mouse model of traumatic brain injury. Traumatic brain injuries (TBI) are a growing concern in the United States because the number of individuals impacted by TBI and associated symptoms is increasing, leading to a growing demand for research both in the clinical and preclinical setting. However, preclinical TBI modeling is complicated by the lack of inter and intra lab consistency in the assessment of behavioral and pathologic outcomes. Indeed, it remains unclear which behavior assessments are most useful in evaluating the effects of preclinical TBI. To investigate the relative contribution of various behavior tests in the assessment of preclinical TBI, three statistical models (simple linear regression, pairwise correlation, and factor analysis) were conducted on behavioral data from the Mannix-Meehan lab at Boston Children’s Hospital in Boston, Massachusetts, U.S.A. from 2012-2018. In this paper, a composite metric was created from the computation analysis of the three statistical methods. The score revealed MWM and EPM as the most potent behavioral tests. The Open Field and Rotarod test had a small impact on the outcome, but only in one of the three statistical models assessed. Thus, to effectively analyze treatment efficiencies, injury severity and long-term impairments, MWM and EPM are the best behavioral test for a mouse model. Furthermore, this method of analysis of entire populations of mice allows for more subtle phenotypic changes resultant from injury models to be revealed, and the generalizability of this model lends to widespread use.

Indiana University-Purdue University Indianapolis (IUPUI) / Traumatic brain injury (TBI) is a critical public health issue in the United States, affecting about 2.8 million people annually. Extensive cell death and neural degeneration directly and diffusively caused by the initial mechanical insult results in a wide range of neurological complications post-trauma. Learning and memory dysfunction is one of the most common complains. Hippocampal neuronal loss, together with other mechanisms, largely contributes to learning and memory impairment as well as other cognitive dysfunctions post-trauma. To date, no FDA-approved drug is available to target cell death or improve learning and memory following TBI. It is of great interest to develop alternative approaches targeting neural repair instead. Neural stem/progenitor cells (NSCs) in the adult hippocampus undergo life-long neurogenesis supporting learning and memory functions, thus hold great promise for post-traumatic neuronal replacement. The previous studies demonstrated that TBI transiently increase NSC proliferation. However, it is debated on whether TBI affects neurogenesis. The mechanism of TBI-enhanced NSC proliferation remains elusive. In the current studies, I have investigated post-traumatic neurogenesis after different injury severities, evaluated integration of post-injury born neurons, illustrated a molecular mechanism mediating TBI-enhanced NSC proliferation, proposed a de novo state of NSCs, and tested effects of a pharmacological approach on spatial learning and memory function recovery. My results demonstrated that post-traumatic neurogenesis is affected by injury severities, partially explained the pre-existing inconsistency among works from different groups. Post-injury born neurons integrate in neural network and receive local and distal inputs. TBI promotes functional recruitment of post-injury born neurons into neural circuits. Mechanistically, mechanistic target of rapamycin (mTOR) pathway is required primarily for TBI-enhanced NSC proliferation; NSCs feature a de novo alert state, in which NSCs are reversibly released from quiescence and primed for proliferation. Furthermore, my data demonstrated a beneficial role of ketamine in improving post-traumatic spatial learning possibly by activating mTOR signal in NSCs and/or promoting neuronal activity of post-injury born neurons. Together, my data support the feasibility of neurogenesis mediated neuronal replacement, provide a target for enhancing post-traumatic NSC proliferation and subsequent neurogenesis, and prove a potential pharmacological approach benefiting post-traumatic functional recovery in learning and memory. / 2021-11-04

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21035号 / 人健博第51号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 田村 恵子, 教授 十一 元三, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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