Year: 2024
Type: dissertation
Abstract: Traumatic brain injury (TBI) disturbs sleep which delays recoveries and leads to long-term neurological morbidities in TBI survivors. Clinical data indicate that TBI alters acute sleep following mild and moderate brain injury. However, little preclinical research has employed injury severity as a parameter to investigate post-traumatic sleep after TBI. Efforts have also been made to include both male and female animals (e.g., rodents) in preclinical sleep research. Nevertheless, when sleep is used as a physiological outcome in research, few studies have disaggregated sleep data based on sex. The overall goal of these studies was to identify biological sex differences in sleep, explore how the exclusion of sex as a biological factor in analyses affects results through simulations, and to investigate how post-injury sleep architecture can be altered as a function of both sex and brain injury severity. We hypothesized that there would be sex differences in sleep under healthy uninjured conditions (baseline sleep), and that post-injury sleep disturbances would occur independent of injury severity, but in a sex-dependent manner. We recorded physiological parameters for 48 hours to determine non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, and wakefulness (WAKE) under baseline conditions and following mild or moderate TBI. Using hierarchical generalized mixed models with nonlinear time effects, we found substantial sex differences in baseline sleep of male and female mice. Female mice slept less overall, specifically during the dark period- with less NREM sleep compared to males- and exhibited more REM sleep and WAKE than male mice. We then used simulation to evaluate the consequences of ignoring true sex differences by simulating a hypothetical TBI treatment that altered the sleep of females but not males. When a sex × treatment interaction was included in the analysis of simulated data, the female-specific treatment response was accurately estimated in equal sample size scenarios but was not detected when sample sizes were male-biased, as is common in mixed-sex studies. In our final experiments we investigated acute post-injury sleep as a function of brain injury severity and biological sex. TBI- regardless of injury severity- increased percent NREM sleep and total minutes of NREM sleep during the post-injury period for both male and female mice. Mice of both sexes subjected to mild or moderate TBI also exhibited shorter WAKE bouts, predominately during the dark (active) period. In conclusion, biological sex differences should be considered in study designs and failure to include both sexes in experimental designs or appropriately account for sex during analyses could lead to flawed inferences and inaccurate translational recommendations in pre-clinical sleep studies. Furthermore, TBI substantially altered sleep after both mild and moderate TBI, in male and female mice. Thus, disturbed sleep architecture should be further explored as a bioindicator of brain injury and future studies should investigate the clinical utility of using disturbed sleep as a diagnostic tool for diffuse brain injury.
Author: Mannino, Grant
Institution: University of Colorado Boulder
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203527751