Multimodal Assessment of Behavioral flexibility after Frontal Brain Trauma

额叶脑外伤后行为灵活性的多模式评估

基本信息

批准号：
9360006
负责人：
Corina Oana Bondi
金额：
$ 19.46万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360006
关键词：
Address Affect Animal Model Anterior Antidepressive Agents Applications Grants Attention Behavior Behavior assessment Behavioral Behavioral inhibition Brain Brain Injuries Brain region Cell Death Cessation of life Chronic Clinic Cognition Cognitive Complex Corpus striatum structure Data Development Dimensions Dopamine Dopamine-beta-monooxygenase Dorsal Estrus Exploratory/Developmental Grant Feedback Female Functional disorder Future Grant Health Care Costs Hippocampus (Brain)Impaired cognition Impairment Impulsivity Individual Injury Ipsilateral Laboratories Learning Lesion Location Measures Medial Mediating Memory Mental Depression Mild Concussions Modeling Motor Nervous System Trauma Nootropic Agents Norepinephrine Performance Pharmacology Play Population Prefrontal Cortex Presynaptic Terminals Productivity Property Rattus Regulation Rehabilitation Research Rehabilitation therapy Research Research Project Grants Role Serotonin Signal Transduction Societies Stimulus Survivors Testing Therapeutic Translations Trauma Traumatic Brain Injury Tryptophan 5-monooxygenase Tyrosine 3-Monooxygenase United States United States National Institutes of Health Work behavior test behavioral impairment bench to bedside cingulate cortex clinically relevant cognitive enhancement cognitive performance cognitive process controlled cortical impact design disability distraction executive function flexibility frontal lobe inhibitor/antagonist male midalcipran monoamine multimodality neurotransmission new therapeutic target noradrenergic novel response reuptake serotonin transporter transmission process vesicular monoamine transporter 2

项目摘要

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.

抽象的每年在美国，创伤性脑损伤（TBI）每年影响200万人严重创伤或死亡的脑震荡。 TBI存活忍受了持久的认知障碍额叶损害以及心理后果。实验室中的TBI模型已经尽管行为的类型迄今为止执行的测试并未集中在与额叶有关的复杂注意力障碍上损伤或功能障碍，在大多数TBI中都是常见的。具体而言，高阶认知过程此类由于认知灵活性和行为抑制受到TBI的显着影响，并且对于指导和将认知活动集中在特定的刺激上或使用环境反馈来“学习”以前有效的集合规则，切换齿轮和过滤不良的干扰。该提议的总体目的是评估临床上与临床相关的认知行为维度对额叶TBI敏感，并开始解决有关此类神经递质改变的机械问题行为通过恢复认知表现来定义，以慢性治疗Milnacipran（一种小说）双5-羟色胺 - 肾上腺素再摄取抑制剂。具体而言，目的设计为1）员工a 多模式的方法来确定中等TBI后高阶认知灵活性能力通过使用两个不同但有效的注意设置转移任务，操作和挖掘范式，LOBE，实验性脑创伤后尚未使用的，2）评估诺言的效率，新型双重 5-羟色胺 - 肾上腺素再摄取抑制剂，具有抗抑郁药和促智能，Milnacipran和3）评估TBI诱导的单胺合成脑标记变化（酪氨酸羟化酶，多巴胺β-）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）在离散的大脑区域中至关重要的直接或间接至关重要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和正常的骑自行车雌性大鼠，这种方法在临床上相关。具体而言，女性代表 45％的TBI案件发生损伤案件，独立于发情阶段，因此评估正常的骑自行车女性与现实世界平行。整合高阶认知动物模型额叶TBI之后的标准神经曲（Neurotrauma）行为电池，探索新型的热目标在TBI之后，评估皮质区域中的单胺调节，对发展至关重要治疗和康复方法与诊所更相关。这两年的R21 探索性/发展研究赠款将生成初步数据，将作为概念证明 NIH R01个人赠款申请，允许将来的工作进一步评估潜在的药物以及针对TBI引起的认知功能障碍的康复疗法。