Bertolli, A. | bioRxiv Science

bioRxiv2026

Male mice are particularly vulnerable to cognitive impairment following mTBI

Traumatic brain injuries (TBIs) result from impact to or rapid displacement of the brain and can lead to various neurological deficits involving working memory, decision-making, and anxiety. While large-scale effects of brain damage are well-described for more severe TBIs, less is known about the extent and duration of cognitive deficits at the mild level. Interval timing can provide a helpful window into cognition in mice and humans. Interval-timing behavior is impaired in a wide range of neuropsychiatric disease states, such as Parkinsons disease. Furthermore, novel object recognition (NOR) and the Barnes maze (BM) tests are valuable assays for evaluating spatial learning, working memory, and anxiety-like behavior in mice. Here, we employed a weight-drop model of mild TBI (mTBI) to investigate changes in internal cognitive states resulting from mTBI treatment. mTBI mice were not significantly impaired in either interval timing or NOR, but they demonstrated impaired spatial memory in the Barnes Maze. Interestingly, within-sex comparisons revealed impairments in male mTBI mice in the interval-timing task and the NOR, suggesting that male and female mice may be differently affected by mTBIs.

neuroscience↗

bioRxiv2024

Renovating the Barnes maze for mouse models of Dementia with STARR FIELD: A 4-day protocol that probes learning rate, retention and cognitive flexibility.

Land-based spatial mazes are a low-stress method to evaluate learning in rodent models of dementia. By using innate exploratory and hiding behavior, the Barnes maze requires fewer trials, allowing examination of early learning rate and retention, as well as executive and motivational features that can be characteristic of non-amnestic dementias. However, unwanted odor cues may disrupt interpretation of acquisition rate during typical learning trials. We designed and tested our Barnes FIELD protocol (Find the Invisible Exit to Locate the Domicile) to improve reproducibility, allow evaluation of learning trials, and limit experimenter influence. The protocol uses 3D-printed escape shuttles and docking tunnels, allowing mice to exit the maze to the home cage. We show evidence that our shuttles mitigate the possibility of undesired cues. We demonstrate the feasibility of our protocol across several models of cognitive impairment and aging, and develop an additional stage, the STARR (Spatial Training And Rapid Reversal) maze, to better challenge behavioral flexibility. By examining commonly used outcome measures we identify important considerations for interpretation. These insights are used to evaluate several models of cognitive change, including deficits in an Alzheimers disease mouse model, and behavioral flexibility in a model of brainstem dysfunction. This work provides comprehensive instructions to build, perform, and analyze a robust spatial maze that expands the range of behavioral and motivational outcomes that can be identified and screened. Our findings will aid interpretation of traditional protocols, enhance rigor and reproducibility, and provide an updated method to screen for cognitive changes in mice.

neuroscience↗