Repetitive Blast Exposure Increases Appetitive Motivation and Behavioral Inflexibility in Male Mice

Abstract

Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.

Keywords: behavioral flexibility; blast; executive function; motivation; traumatic brain injury; veteran.

Figure 1

Repetitive blast exposure increases behavioral indices of anxiety/compulsivity and hyperreactivity. (A) Timeline schematic. (B) Weight change as % baseline weight. (C) Number of marbles buried. (D) Distance traveled in the elevated zero maze. (E) Time spent in the open arm of the elevated zero maze. (F) Entries into the open arms of the elevated zero maze. (G) Raw acoustic startle amplitude. (H) Acoustic startle habituation rate. (I) Pre-pulse inhibition (PPI). Student’s t-test (C–H), two-way RM ANOVA Bonferroni-Šídák post hoc (B,E). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001, ns, not significant. Values represent mean ± SEM.

Figure 2

Repetitive blast exposure increases appetitive operant behavior. (A) Timeline schematic. (B) Number of active lever presses. (C) Number of inactive lever presses. (D) Discrimination Index (active − inactive/active + inactive). (E) Number of pellets left uneaten. (F) Trial duration in seconds. (G) Number of head entries during lever out. (H) Number of active lever presses during ITI. (I) Number of inactive lever presses during ITI. (J) Number of head entries during ITI. Two-way RM ANOVA Bonferroni-Šídák post hoc (B–J). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001, ns, not significant. Values represent mean ± SEM. ITI, inter-trial-interval.

Figure 3

Repetitive blast exposure increases motivation and willingness to work for reward. (A) Progressive ratio break point (last ratio completed). (B) Number of reinforcers earned. (C) Active lever press inter-response time. (D) Number of inactive lever presses. (E) Number of pellets left uneaten. (F) Number of head entries during lever out. Two-way RM ANOVA Bonferroni-Šídák post hoc (A–F). *p ≤ 0.05, **p ≤ 0.01, ns, not significant. Values represent mean ± SEM.

Figure 4

Repetitive blast exposure results in behavioral inflexibility and perseverative-like responding. (A) Lever press alternation (LPA) schematic—lever contingencies switch every five reinforcers obtained. (B) Number of reinforcers earned. (C,D) Discrimination Index (active−inactive/active+inactive) on original (C) and switch (D) trials. (E,F) Number of inactive lever presses on original (E) and switch (F) trials. Two-way RM ANOVA Bonferroni-Šídák post hoc (A–F). *p ≤ 0.05, **p ≤ 0.01, ns, not significant. Values represent mean ± SEM.