Santos Carlin Patricia, Coons Michael, Bele Priyanka, Kaplan Lewis J, Culkin Matthew, Georges Anastasia, Jacovides Christina L, Martinez-Quinones Patricia, Meaney David, Kauffman Alexandra, Smith Douglas, Bass Gary A, Pascual Jose L
From the Department of Surgery (P.S.C., M.C., P.B., L.J.K., M.C., A.G., P.M.-Q., A.K., G.A.B., J.L.P.), Division of Traumatology, Surgical Critical Care and Emergency Surgery, and Center for Brain Injury and Repair, Department of Neurosurgery (P.S.C., M.C., P.B., L.J.K., M.C., A.G., C.L.J., P.M.-Q., D.M., A.K., D.S., G.A.B., J.L.P.), Perelman School of Medicine, University of Pennsylvania; and Division of Trauma and Acute Care Surgery, Department of Surgery (C.L.J.), Temple University Hospital, Philadelphia, Pennsylvania.
J Trauma Acute Care Surg. 2025 Jun 19. doi: 10.1097/TA.0000000000004668.
A number of sex-related outcomes following severe traumatic brain injury (TBI) appear to principally favor females. However, sex-related differences in post-TBI learning and memory remain underexplored. We hypothesized that females realize greater cognitive recovery than males following severe TBI.
CD1 male (n = 12) and female (n = 12) mice were randomized to controlled cortical impact (severe TBI: impactor tip diameter, 3 mm; impact velocity, 6 m/s; depth, 1 mm; dwell time, 100 milliseconds) or sham craniotomy and followed for 14 days. Body weight loss recovery was measured daily as a surrogate of neuroclinical recovery. Mice underwent Morris water maze testing to evaluate learning (locating submerged escape platform) with cued and spatial trials and to recall (remembering platform location after it was removed) with probe trials.
Compared with uninjured male mice, male mice with TBI failed to recover lost weight for the first 7 postinjury days (i.e., day 5: MTBI: -3.7% ± 1.5% vs. MSh: +4.1% ± 1.4% body weight; p < 0.01), while female mice with TBI recovered the same lost weight and at the same rate as sham female mice (FTBI: -1.6% ± 1.0% vs. FSh: -1.8% ± 0.9%, -0.02% ± 0.01%; p > 0.9). Learning (cued and spatial) after TBI was significantly worse in males but not in females. In probe trials, impaired memory after injury was only observed in females.
Severe TBI worsens cued and spatial learning and impairs weight loss recovery in male but not female mice. Female, but not male, mice sustain memory impairment after identical severe TBI. While the mechanism(s) that underpin these observations remain unclear, sex-related neurocognitive outcome differences question the universal applicability of trial-based evidence for clinical care.
重度创伤性脑损伤（TBI）后的一些性别相关结果似乎主要有利于女性。然而，TBI后学习和记忆方面的性别差异仍未得到充分研究。我们假设，重度TBI后女性比男性实现更大程度的认知恢复。
将12只雄性（n = 12）和12只雌性（n = 12）CD1小鼠随机分为控制性皮质撞击组（重度TBI：撞击器尖端直径3毫米；撞击速度6米/秒；深度1毫米；停留时间100毫秒）或假开颅手术组，并随访14天。每天测量体重减轻恢复情况，作为神经临床恢复的替代指标。小鼠接受莫里斯水迷宫测试，以通过线索和空间试验评估学习（定位水下逃生平台），并通过探针试验评估回忆（平台移除后记住平台位置）。
与未受伤的雄性小鼠相比，TBI雄性小鼠在伤后前7天未能恢复体重减轻（即第5天：MTBI：体重减轻-3.7%±1.5%，而MSh：体重增加+4.1%±1.4%；p < 0.01），而TBI雌性小鼠恢复了相同的体重减轻，且恢复速度与假手术雌性小鼠相同（FTBI：-1.6%±1.0%，而FSh：-1.8%±0.9%，-0.02%±0.01%；p > 0.9）。TBI后雄性小鼠的学习（线索和空间）明显比雌性小鼠差。在探针试验中，仅在雌性小鼠中观察到损伤后记忆受损。
重度TBI会使雄性而非雌性小鼠的线索和空间学习能力恶化，并损害体重减轻恢复。相同的重度TBI后，雌性而非雄性小鼠会出现记忆障碍。虽然支撑这些观察结果的机制尚不清楚，但性别相关的神经认知结果差异质疑了基于试验的证据在临床护理中的普遍适用性。
