Traumatic brain injury and aging: targeting the cholinergic system for deficits in sustained attention and executive function

创伤性脑损伤（TBI）每年影响美国280万人，其中老年人超过65岁 面临更大的风险。幸存者表现出长期的认知障碍和精神病理学，如 焦虑，更容易患阿尔茨海默病和相关痴呆症，如额颞叶痴呆症。 退化TBI模型通常不关注复杂的注意力障碍， 常见于大多数TBI，如持续注意力，目标导向行为和认知灵活性的缺陷。 胆碱能系统是认知的一个重要调节器，其中发现了烟碱受体（nACHRs）。 在整个大脑中。α7受体在注意力、工作记忆、奖赏以及 神经保护和抗炎途径。α7 nAChR的正变构调节剂（PAM）是 一种新的和有前途的治疗工具，可以在内源性 乙酰胆碱显示出高受体选择性，并可提供神经保护作用。I型PAM增强 激动剂诱发的峰值电流而不延迟脱敏，并且不重新激活脱敏的受体。 因此，本新/早期研究者R 01申请旨在a）评估认知行为 以及对TBI和衰老敏感的焦虑样维度，b-c）评估的潜在益处 单独或联合给药NS 1738（一种I型PAM）的亚急性（7天）和慢性（4周）给药 结合简短的环境富集（EE），一种临床前康复模型， 年轻成年和老年大鼠TBI后的注意力功能障碍，以及d）解决机制 关于胆碱能神经传递改变导致这种行为缺陷的问题 研究相关脑区的蛋白质组学和神经递质调节标记物。具体地说， 目的是1）评估中度顶叶TBI和持续注意力老化的相互作用（3- 选择系列反应时任务），认知灵活性（注意定势转移测试），焦虑样反应 （高架十字迷宫试验），2）评估NS 1738治疗的组合方法的年龄依赖性作用 和缩短EE（每天4小时），以恢复神经行为功能，以及测试受体选择性， 用甲基甘草次酸阻断α7 nAChR，3）使用质谱法定量蛋白质组学分析， 鉴定与衰老、脑创伤 和治疗范例;和4）测量胆碱能传递的脑标志物（例如，胆碱 乙酰转移酶、乙酰胆碱酯酶、囊泡胆碱能转运蛋白、α7 nAChRs），因为它们与 神经行为研究将使用雄性和正常的骑自行车的雌性大鼠，因为女性占45%。 创伤的发生与月经周期无关。整合高阶动物模型 TBI后的注意力，以及评估药物治疗和康复相关的胆碱能和蛋白质组学 相关皮质区域的调节对于开发与临床相关的治疗方法是关键的。

Traumatic brain injury (TBI) impacts 2.8 million individuals in the US each year, with older adults over 65 years being at greater risk. Survivors exhibit long-lasting cognitive impairments and psychopathologies, such as anxiety, and are more susceptible for Alzheimer's disease and related dementias, such as frontotemporal degeneration. TBI models have typically not focused on complex attentional impairments, which are common in most TBIs, such as deficits of sustained attention, goal-directed behavior, and cognitive flexibility. The cholinergic system is an important modulator of cognition, with nicotinic receptors (nACHRs) found throughout the brain. The α7 receptors play important roles in attention, working memory, reward, as well as in neuroprotective and anti-inflammatory pathways. Positive allosteric modulators (PAMs) of α7 nAChRs are novel and promising therapeutic tools that can potentiate α7 currents in the presence of endogenous acetylcholine, display high receptor selectivity, and may provide neuroprotective effects. Type I PAMs enhance agonist-evoked peak currents without delaying desensitization and do not reactivate desensitized receptors. Therefore, this New/Early Stage Investigator R01 application aims to a) assess cognitive-behavioral and anxiety-like dimensions sensitive to both TBI and aging, b-c) evaluate potential benefits of subacute (7 days) and chronic (4 weeks) administration of NS 1738, a Type I PAM, alone or in combination with abbreviated environmental enrichment (EE), a preclinical rehabilitation model, on attentional dysfunction after TBI in young adult and aged rats, as well as d) address mechanistic questions regarding altered cholinergic neurotransmission responsible for such behavioral deficits by investigating proteomic and neurotransmitter regulation markers in relevant brain regions. Specifically, the aims are designed to 1) evaluate interactions of moderate parietal TBI and aging on sustained attention (3- choice serial reaction time task), cognitive flexibility (attentional set-shifting test), and anxiety-like responses (elevated plus-maze test), 2) assess age-dependent effects of the combined approach of NS 1738 treatment and abbreviated EE (4hrs daily) to restore neurobehavioral function, as well as test receptor selectivity by blocking α7 nAChRs with methyllycaconitine, 3) quantitate proteomic profiling using mass spectrometry to identify key biomarkers (tissue and serum) correlating with neurobiological responses to aging, brain trauma, and treatment paradigms, and 4) measure brain markers of cholinergic transmission (e.g., choline acetyltransferase, acetylcholinesterase, vesicular cholinergic transporter, α7 nAChRs), as they correlate with neurobehavior. Studies will employ both male and normal cycling female rats, as women represent up to 45% of TBIs, with injuries occurring independent of menstrual cycles. Integrating animal models of higher-order attention after TBI, as well as assessing pharmacotherapy- and rehabilitation-related cholinergic and proteomic regulation in relevant cortical regions is pivotal to developing treatment approaches relevant to the clinic.