Rowan University, Department of Chemistry and Biochemistry, Science Hall 301G, 230 Meditation Walk, Glassboro, NJ 08028, USA.
Rowan University, Department of Cell Biology and Neuroscience, Science Center 220, 2 Medical Center Drive, Stratford, NJ, 08084, USA.
Brain Res. 2024 Sep 15;1839:149040. doi: 10.1016/j.brainres.2024.149040. Epub 2024 May 28.
Traumatic brain injury (TBI) is a complex pathophysiological process that results in a variety of neurotransmitter, behavioral, and cognitive deficits. The locus coeruleus-norepinephrine (LC-NE) system is a critical regulator of arousal levels and higher executive processes affected by TBI including attention, working memory, and decision making. LC-NE axon injury and impaired signaling within the prefrontal cortex (PFC) is a potential contributor to the neuropsychiatric symptoms after single, moderate to severe TBI. The majority of TBIs are mild, yet long-term cognitive deficits and increased susceptibility for further injury can accumulate after each repetitive mild TBI. As a potential treatment for restoring cognitive function and daytime sleepiness after injury psychostimulants, including methylphenidate (MPH) that increase levels of NE within the PFC, are being prescribed "off-label". The impact of mild and repetitive mild TBI on the LC-NE system remains limited. Therefore, we determined the extent of LC-NE and arousal dysfunction and response to therapeutic doses of MPH in rats following experimentally induced single and repetitive mild TBI. Microdialysis measures of basal NE efflux from the medial PFC and arousal measures were significantly lower after repetitive mild TBI. Females showed higher baseline PFC-NE efflux than males following single and repetitive mild TBI. In response to MPH challenge, males exhibited a blunted PFC-NE response and persistent arousal levels following repetitive mild TBI. These results provide critical insight into the role of catecholamine system dysfunction associated with cognitive deficits following repeated injury, outcome differences between sex/gender, and lack of success of MPH as an adjunctive therapy to improve cognitive function following injury.
创伤性脑损伤（TBI）是一个复杂的病理生理过程，导致多种神经递质、行为和认知缺陷。蓝斑-去甲肾上腺素（LC-NE）系统是一个关键的调节觉醒水平和更高的执行过程，受 TBI 影响，包括注意力、工作记忆和决策。LC-NE 轴突损伤和前额叶皮层（PFC）内信号受损是单一、中度至重度 TBI 后神经精神症状的潜在原因。大多数 TBI 是轻度的，但长期认知缺陷和对进一步损伤的易感性会在每次重复轻度 TBI 后累积。作为一种恢复损伤后认知功能和日间嗜睡的潜在治疗方法，包括增加 PFC 内去甲肾上腺素水平的哌醋甲酯（MPH），正在被“超说明书”使用。轻度和重复轻度 TBI 对 LC-NE 系统的影响仍然有限。因此，我们确定了在实验诱导的单次和重复轻度 TBI 后，LC-NE 和觉醒功能障碍的程度以及对 MPH 治疗剂量的反应。重复轻度 TBI 后，内侧 PFC 中基础 NE 外排的微透析测量和觉醒测量显著降低。与单次和重复轻度 TBI 后，女性的 PFC-NE 基础流出量高于男性。对 MPH 挑战的反应，雄性在重复轻度 TBI 后表现出 PFC-NE 反应迟钝和持续的觉醒水平。这些结果提供了关于重复损伤后与认知缺陷相关的儿茶酚胺系统功能障碍、性别/性别之间的结果差异以及 MPH 作为改善损伤后认知功能的辅助治疗的缺乏成功的关键见解。
