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.

Differential effects of glucocorticoid and mineralocorticoid antagonism on anxiety behavior in mild traumatic brain injury

“…This was tested in a relevant rodent model of psychosocial stress with mild TBI, which reliably increases plasma corticosterone at the time of injury and elicits heightened anxiety-like behavior to a greater extent than either stress or mild TBI alone [7]. We show for the first time that GR antagonism is effective in reducing generalized anxiety caused by mild TBI incurred during stressful events.…”

“…Furthermore, antagonism of either GRs or MRs has been shown to increase the amount of time spent in the open arms of an elevated plus maze in pre-stressed rats [8]. Notably, anxiety-like behavior in rats following a mild TBI concurrent with stress is more pronounced than after injury alone [7]. The ability of GR or MR antagonism to protect against neuronal injury caused by TBI, combined with the anxiolytic effects of GR and MR blockade following stress, suggests that early targeting of one or both types of receptors may potentially abate anxiety resulting from stress-associated mild TBI.…”

“…In such a state of arousal, glucocorticoids such as cortisol (corticosterone in rats) are elevated [7]. These steroids can bind to both glucocorticoid (GR) and mineralocorticoid (MR) receptors, found widely throughout the limbic system [8].…”

“…Drug concentrations were chosen based on efficacy in reducing anxiety-like behaviors in pre-stressed rats [11]. Forty minutes following vehicle or GR or MR antagonism, stress/injury or stress/sham rats underwent a single episode of social defeat by a larger, aggressive male rat (>100g larger than subject), which reliably elevates plasma corticosterone [7] to create the desired conditions for mild TBI incurred under a stressed state. Control rats were placed in an empty cage similar to acclimation days (see Davies et al 2015 [7] for protocol details).…”

“…Rats were acclimated to a solitary cage and the testing room (in preparation for social defeat) for 40 min/day for three days prior to the treatment day [7]. On the treatment day, rats received a single subcutaneous (sc.)…”