Cerebral Mechanisms of Vulnerability Following Female Traumatic Brain Injury

女性脑外伤后易受伤害的大脑机制

• 批准号: 10223447
• 负责人: Tiffany Greco
• 金额: $ 35.77万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10223447
• 关键词: Acute; Affect; Affective; Amenorrhea; Anxiety; Attenuated; Behavior; Caring; Cell Death; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Research; Consensus; Corticosterone; Corticotropin-Releasing Hormone; Coupling; Data; Data Analyses; Data Reporting; Development; Drug Metabolic Detoxication; Enrollment; Enzymes; Estradiol; Estrogen Receptor beta; Estrogens; Estrus; Etiology; Excitatory Amino Acids; Exclusion; Female; Free Radicals; Functional disorder; Gender; Glycolysis; Gonadal Steroid Hormones; Hormonal; Hormones; Hospitalization; Impairment; Incidence; Inflammation; Injury; Intervention; Knowledge; Measurement; Measures; Mediating; Menstrual cycle; Mental Depression; Metabolic; Metabolism; Military Personnel; Mitochondria; Monitor; Mood Disorders; Moods; Neuronal Plasticity; Nociception; Norepinephrine; Outcome; Outcome Measure; Oxidative Phosphorylation; Pain; Pain Disorder; Pathway interactions; Pattern; Physiological; Play; Production; Proestrus; Quality of life; Reactive Oxygen Species; Recovery; Regulation; Research; Role; Secondary to; Serotonin; Severities; Sex Differences; Signal Transduction; Stress; Symptoms; Therapeutic Intervention; Time; TimeLine; Traumatic Brain Injury; Woman; Work; base; biopsychosocial; chronic pain; classical conditioning; combat; contact sports; duloxetine; expectation; experience; female sex hormone; glucose metabolism; glucose transport; gray matter; hormone regulation; improved outcome; inhibitor/antagonist; injury recovery; insight; interest; male; men; mortality; negative affect; neuronal circuitry; neurotransmission; novel; pre-clinical; preclinical study; prevent; reproductive hormone; reuptake; sex; symptomatology; targeted treatment; transmission process; treatment strategy

ABSTRACT Females comprise 41% of annual cases of traumatic brain injury (TBI). Further, when the rate of injury is compared, female TBI is either the same or higher than males, indicating a unique vulnerability of females. In addition, rates of both incidence and hospitalization have significantly increased over the past decade in females and growing numbers are likely attributed to increased participation in combat and collision sports and military enrollment. Despite the high number of injuries, little has been done to study factors that may make females more susceptible to injury and the specific constellation of symptoms they experience. This may be due in part to the prevailing opinion that female reproductive hormones are neuroprotective against TBI. Pre-clinical work has strongly demonstrated that females have better outcomes following injury, although when care is taken to properly normalize data, females commonly have the same or worse outcomes than males. Clinically, studies have shown contradictory results and differences may be due to choice of timepoints and outcome measures used that do not consider biopsychosocial aspects and gender-based expectations. While pre-injury levels of reproductive hormones have been of interest, few studies have looked at the role of sex-hormones post-injury in females. Hormonal dysfunction following TBI is a well-established phenomenon and likely has a large role in recovery and outcome. Less established is how changes in regulation of these hormones may influence sex-specific symptomatology including pain and affective disorders. Neuroplasticity, mood and learning are associated with menstrual-cycle stage and disruptions in hormonal patterns negatively affect these domains. Pre-clinical work has shown that both stress and sex-hormones are disrupted acutely and chronically following TBI. Our work shows evidence of perturbed cerebral metabolism and abnormal changes in affective and nociceptive behaviors. The central premise of this proposal is that female sex- hormones (1) modulate cerebral metabolism at the time injury, contributing to initial injury severity and (2) changes in the regulation and production of female sex-hormones are responsible for sex-specific difference in symptomology post-injury. The current proposed aims will identify pre- and post-injury variables and mechanisms that make females more susceptible to 1) TBI and 2) prolonged recovery and differential outcomes compared to males. The research findings from these aims are critical to understanding sex-based differences to develop sex-specific therapeutic interventions.

摘要 女性占每年创伤性脑损伤病例的41%。此外，当受伤率为 相比之下，女性的创伤性脑损伤与男性相同或高于男性，表明女性具有独特的脆弱性。在 此外，在过去十年中， 女性和越来越多的人可能归因于越来越多的参与战斗和碰撞运动 和军队登记尽管受伤的人数很多，但很少有人研究可能导致死亡的因素。 使女性更容易受到伤害和他们所经历的特定症状。这可能 部分原因是普遍认为女性生殖激素对TBI具有神经保护作用。 临床前的工作已经有力地证明，女性在受伤后有更好的结果，尽管 当注意适当地将数据标准化时，女性通常具有与男性相同或更差的结果。 男性。在临床上，研究显示了相互矛盾的结果，差异可能是由于时间点的选择 所使用的成果衡量标准没有考虑到生物心理社会方面和基于性别的期望。 虽然损伤前生殖激素的水平一直受到关注，但很少有研究关注 女性受伤后的性激素水平创伤性脑损伤后的激素功能障碍是一个公认的现象 并且可能在恢复和结果中起很大作用。不太确定的是， 激素可影响性别特异性精神病学，包括疼痛和情感障碍。神经可塑性， 情绪和学习与月经周期阶段和荷尔蒙模式的破坏有负面关系 影响这些领域。临床前的研究表明，压力和性激素都受到严重干扰， TBI后的慢性病我们的工作显示了大脑代谢紊乱和异常变化的证据 在情感和伤害性行为中。这项提议的核心前提是女性- 激素（1）在损伤时调节脑代谢，促进初始损伤 严重程度和（2）女性性激素的调节和产生的变化， 造成损伤后神经病理学的性别特异性差异。目前提出的目标将 确定受伤前和受伤后的变量和机制，使女性更容易受到1）TBI和2） 与男性相比，恢复时间延长且结局不同。这些目标的研究结果是 这对于理解基于性别的差异以制定针对性别的治疗干预措施至关重要。