Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats

Abstract

Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

Keywords: anxiety; fear conditioning; mild traumatic brain injury; monoamine; posttraumatic stress disorder; social stress.

FIGURE 1

Plasma corticosterone concentration 30 mins after social defeat or control treatment. ^∗ indicates significant difference between groups (p < 0.05).

FIGURE 2

Behavioral measures from EPM testing 6 days following stress and/or mTBI, including (A) total number of entries into open arms, (B) total time spent in open arms and (C) total distance moved during testing. ^∗ Overlying a bar indicates significant difference between individual groups (p < 0.05).

FIGURE 3

Freezing behavior from contextual fear conditioning testing beginning 7 days following stress and/or mTBI, including (A) response to footshock during fear conditioning acquisition day and (B) response to context during the three test days in 1 min time bins, each 8 min test separated by 24 h (as indicated by the gray dashed vertical lines). ^∗ Indicates significant difference from the control + sham group, while the symbol # indicates significant difference between the social defeat with mTBI vs. all other groups (p < 0.05).

FIGURE 4

Serotonin (5-HT) measurements 7 days following stress and/or mTBI, including (A) 5-HTP concentration in the ventral hippocampus, (B) 5-HIAA concentration in the dorsal hippocampus, (C) 5-HT activity in the central amygdala, and (D) 5-HT synthesis in the medial prefrontal cortex. ^∗ Indicates significant difference from all other groups, while ^∗ overlying a bar indicates significant difference between individual groups (p < 0.05).

FIGURE 5

Catecholamine meatsurements 7 days following stress and/or mTBI, including (A) dopamine (DA) concentrations in the dorsal hippocampus, (B) dopamine concentrations in the ventral hippocampus, (C) epinephrine (Epi) concentrations in the medial amygdala, (D) epinephrine concentrations in the dorsal raphe nucleus, and (E) norepinephrine concentrations in the central amygdala. ^∗ indicates significant difference from all other groups, while ^∗ overlying a bar indicates significant difference between individual groups (p < 0.05).