Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
University of Bath, Claverton Down, Bath, United Kingdom.
J Neurotrauma. 2023 Jan;40(1-2):112-124. doi: 10.1089/neu.2022.0289. Epub 2022 Sep 28.
Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 μL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors ( < 0.05), which generally normalized in MLN-treated rats ( < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.
创伤性脑损伤（TBI）每年在全球影响超过 1000 万名患者，导致长期认知和社会心理障碍。额叶 TBI 通常会损害执行功能，但实验室模型通常主要侧重于空间学习和陈述性记忆。我们采用多模态方法对 TBI 大鼠的额叶功能进行了临床相关的认知行为评估，并评估了 5-羟色胺去甲肾上腺素再摄取抑制剂米那普仑（MLN）的治疗益处。两项注意定势转移任务（AST）通过大鼠通过学习、遗忘和重新学习具有转移显著线索的顺序规则集来定位基于食物的奖励的能力，评估了认知灵活性。成年雄性大鼠在 3-4 周内达到稳定的术前操作 AST（oAST）表现，然后用异氟烷麻醉，接受单侧额叶皮质控制冲击伤（2.4 毫米深度，4 米/秒速度）或假手术，并随机分配到治疗组。米那普仑（30mg/kg/天）或载体（VEH；10%乙醇在生理盐水中）通过植入的渗透微型泵（手术后持续输注，60μL/h）腹腔内给药。TBI/假手术后大鼠有 10 天恢复期，然后进行光/位置 oAST 10 天，随后在最后一次测试日（损伤后 26-27 天）进行气味/媒体挖掘 AST（dAST）。两项 AST 测试均显示 TBI+VEH 大鼠存在明显缺陷，表现为总试验和错误增加（<0.05），而 MLN 治疗大鼠的这些缺陷通常正常化（<0.05）。这是首次同时进行双重 AST 评估，表明 oAST 和 dAST 足够灵敏和稳健，可以检测大鼠额叶 TBI 后注意力和认知灵活性执行功能的细微缺陷。慢性 MLN 给药显示出有希望减轻 TBI 后执行功能缺陷，因此值得进一步研究。
