Sex-related differences in cognition after severe murine traumatic brain injury: A Morris water maze study evaluating learning and memory

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: CCI; Morris water maze; TBI; female; learning; mice.