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

在美国，创伤性脑损伤(TBI)每年影响280万人，65岁以上的老年人 处于更大的风险中。幸存者表现出长期的认知障碍和精神病态，例如 焦虑，更容易患阿尔茨海默病和相关的痴呆，如额颞叶 退化。脑损伤模型通常没有关注复杂的注意力障碍，这些障碍是 在大多数脑外伤中很常见，例如缺乏持续的注意力、目标导向的行为和认知灵活性。 胆碱能系统是认知的重要调节器，发现了烟碱受体(NAChRs) 贯穿整个大脑。α7受体在注意力、工作记忆、奖赏以及 神经保护和抗炎途径。α7nAChRs的正变构调节剂(PAM)是 在内源性药物存在的情况下可以增强α7电流的新型和有前景的治疗工具 乙酰胆碱，表现出高的受体选择性，并可能提供神经保护作用。I型PAMS增强版 激动剂诱发的峰值电流不会延迟脱敏，也不会重新激活脱敏的受体。 因此，这个新的/早期的Investigator R01应用程序旨在a)评估认知行为 和焦虑样维度对脑外伤和衰老都敏感，b-c)评估 亚急性(7天)和慢性(4周)给药NS 1738，一种I型PAM，单独或在 结合简化环境浓缩(EE)，一种临床前康复模式，关于 青壮年和老年大鼠脑损伤后注意功能障碍及机制探讨 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和神经递质调节标记物。具体来说， 其目的是：1)评估中度顶叶脑损伤与持续注意力老化的交互作用(3- 选择系列反应时任务)、认知灵活性(注意定势转移测试)和焦虑样反应 (高架正迷宫试验)，2)评估NS1738联合治疗的年龄相关性效应 和缩写EE(每天4小时)，以恢复神经行为功能，以及通过以下方式测试受体选择性 用甲基乌头碱阻断α7nAChRs，3)用质谱仪定量蛋白质组图谱 确定与衰老、脑损伤、 和治疗范例，以及4)测量胆碱能传递的大脑标志物(例如，胆碱 乙酰胆碱酯酶、囊泡胆碱能转运体、α7nAChRs)，以及它们与 神经行为。研究将同时使用雄性和正常骑自行车的雌性老鼠，因为雌性老鼠占45% 颅脑损伤，损伤发生与月经周期无关。整合高阶动物模型 脑外伤后的关注，以及评估药物治疗和康复相关的胆碱能和蛋白质组 相关皮质区域的调节对于开发与临床相关的治疗方法至关重要。

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.