Multimodal Assessment of Behavioral flexibility after Frontal Brain Trauma

摘要 创伤性脑损伤（TBI）每年影响美国200万人，范围从轻度到中度。 脑震荡到严重创伤甚至死亡TBI幸存者忍受长期的认知障碍 额叶损伤以及精神病理后果实验室中的TBI模型已经被 与长期学习和记忆的下降有关，尽管行为类型 迄今为止进行的测试并没有集中在与额叶有关的复杂注意力障碍上， 损伤或功能障碍，这在大多数TBI中很常见。具体来说，高阶认知过程， 因为认知灵活性和行为抑制明显受到TBI的影响，并且对于指导和 将认知活动集中在特定的刺激上，或者使用环境反馈来“忘记”先前有效的集合。 的规则，开关齿轮和过滤不必要的分心，分别。本提案的总体目标是 评估对额叶TBI敏感的临床相关认知行为维度，并开始 为了解决有关改变神经传递的机制问题， 通过长期治疗米那普仑来恢复认知能力， 双重降钙素-去甲肾上腺素再摄取抑制剂。具体而言，目标旨在：1）采用 多模态方法确定中度额叶脑外伤后高阶认知灵活性能力 通过使用两种不同的，但有效的注意定势转移任务，操作和挖掘范式， 在实验性脑外伤后尚未使用，2）评估有前途的新型双重治疗的疗效， 具有抗抑郁和促智特性的降钙素-去甲肾上腺素再摄取抑制剂，米那普仑，和3） 评估TBI诱导的脑单胺合成标志物（酪氨酸羟化酶、多巴胺β-受体）的变化。 羟化酶、色氨酸羟化酶）、储存/释放（囊泡单胺转运蛋白2）和再摄取 （去甲肾上腺素和5-羟色胺转运蛋白）在离散的大脑区域的关键直接或间接 调节认知灵活性和执行功能。拟定的研究将在两种男性中进行 和正常骑自行车的雌性大鼠，这是一种临床相关的方法。具体而言，女性代表多达 45%的创伤性脑损伤病例与发情期无关，因此评估 正常的骑自行车的女性与真实的世界相似。将高阶认知的动物模型整合到 额叶TBI后的标准神经创伤行为电池，探索新的治疗靶点，以及 评估脑外伤后皮质区单胺调节的研究还不够深入， 治疗和康复方法更适合临床。两年的R21 探索性/发展性研究补助金将产生初步数据，作为概念验证， NIH R 01个人资助申请，允许未来的工作也进一步评估潜在的药理学 以及创伤性脑损伤引起的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.