Multimodal Assessment of Behavioral flexibility after Frontal Brain Trauma

摘要 在美国，创伤性脑损伤(TBI)每年影响200万人，范围从轻微到轻微 脑震荡导致严重创伤或死亡。脑外伤幸存者忍受与之相关的长期认知障碍 额叶受损，以及心理病理性后果。实验室中的TBI模型已经被 几十年来与长期学习和记忆的下降有关，尽管行为类型 到目前为止，进行的测试还没有集中在与额叶相关的复杂注意力障碍上 损伤或功能障碍，这在大多数颅脑损伤中很常见。具体地说，更高级的认知过程，如 由于认知灵活性和行为抑制明显受脑创伤的影响，并且对指导和 将认知活动集中在特定刺激上，或使用环境反馈来“忘记”先前有效的集合 对于规则，分别是换档和过滤不想要的分心。这项建议的主要目的是 评估对额叶脑损伤敏感的临床相关认知行为维度，并开始 解决与导致这种情况的神经传递改变有关的机械问题 通过慢性治疗米那普兰恢复认知能力的行为缺陷，一种新型的， 双重5-羟色胺-去甲肾上腺素再摄取抑制剂。具体地说，AIMS旨在1)雇用一名 多通道方法确定额叶中度脑损伤后的高阶认知灵活性能力 通过使用两种不同的、但得到充分验证的注意定势转移任务，操作型和挖掘型范式， 2)评估一种有前景的、新的双重疗法的疗效。 具有抗抑郁和促性作用的5-羟色胺-去甲肾上腺素再摄取抑制剂，米那普兰，和3) 评价脑损伤后脑内单胺合成标志物(酪氨酸羟化酶、多巴胺β)的变化 羟基酶、色氨酸羟基酶)、储存/释放(囊泡单胺转运体2)和再摄取 (去甲肾上腺素和5-羟色胺转运体)在大脑的离散区域，对直接或间接 调节认知灵活性和执行功能。拟议的研究将在两个男性中进行 以及正常骑行的雌性大鼠，这是一种具有临床意义的方法。具体地说，女性代表多达 45%的颅脑损伤病例的损伤发生与发情期无关，因此评估 正常骑自行车的女性与现实世界相似。将高级认知的动物模型整合到 额部脑外伤后的标准神经创伤行为组合，探索新的治疗靶点，以及 评估脑外伤后未得到很好研究的皮质区域的单胺调节对发育至关重要 与临床更相关的治疗和康复方法。本课程为期两年的R21 探索性/开发性研究拨款将生成初步数据，作为以下项目的概念验证 NIH R01个人拨款申请，允许未来的工作也进一步评估潜在的药理学 以及对脑外伤所致认知功能障碍的康复治疗。

ABSTRACT Traumatic brain injury (TBI) affects 2 million individuals in the United States each year, ranging from mild concussions to severe trauma or death. TBI survivors endure long-lasting cognitive impairments associated with frontal lobe damage, as well as psychpathological consequences. TBI models in the laboratory have been associated for decades with declines in long-term learning and memory, although the types of behavioral tests performed to date have not focused on the complex attention impairments related to frontal lobe injury or dysfunction, which are common in most TBIs. Specifically, higher-order cognitive processes such as cognitive flexibility and behavioral inhibition are markedly affected by TBI and are essential to directing and focusing cognitive activity on specific stimuli or using environmental feedback to “unlearn” a previously valid set of rules, switch gears and filter unwanted distractions, respectively. The overarching aim of this proposal is to assess clinically-relevant cognitive-behavioral dimensions sensitive to frontal lobe TBI, and to begin to address mechanistic questions regarding altered neurotransmission responsible for such behavioral deficits by restoring cognitive performance with chronic treatment of milnacipran, a novel, dual serotonin-norepinephrine reuptake inhibitor. Specifically, the aims are designed to 1) employ a multimodal approach to determine higher-order cognitive flexibility capabilities after moderate TBI to the frontal lobe by using two different, yet well-validated attentional set-shifting tasks, the operant and digging paradigms, which have not been utilized after experimental brain trauma, 2) assess the efficacy of a promising, novel dual serotonin-norepinephrine reuptake inhibitor with antidepressant and nootropic properties, milnacipran, and 3) evaluate TBI-induced changes in brain markers of monoamine synthesis (tyrosine hydroxylase, dopamine β- hydroxylase, tryptophan hydroxylase), storage/release (vesicular monoamine transporter 2), and reuptake (norepinephrine- and serotonin- transporters) in discrete brain regions critical for directly or indirectly modulating cognitive flexibility and executive function. The proposed studies will be carried out in both male and normal cycling female rats, an approach that is clinically relevant. Specifically, females represent up to 45% of the TBI cases with injuries occuring independent of estrous stage and therefore evaluating normal cycling females parallels the real world. Integrating animal models of higher-order cognition in the standard neurotrauma battery of behavior after frontal TBI, exploring novel therapeutic targets, as well as assessing monoamine regulation in cortical regions not well studied after TBI is paramount to developing therapeutic and rehabilitative approaches more relevant to the clinic. This two-year R21 exploratory/developmental research grant will generate preliminary data that will serve as proof-of-concept for a NIH R01 individual grant application, allowing future work to also further evaluate potential pharmacological and rehabilitative therapies for TBI-induced cognitive dysfunction.