Concussive Brain Injury Enhances Fear Learning and Excitatory Processes in the Amygdala

Abstract

Background Mild traumatic brain injury (mTBI; cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders including post-traumatic stress disorder (PTSD). However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether TBI itself is a cause of augmented fear and anxiety. Methods Rats were trained with one of five fear conditioning procedures (N = 105) two days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring NMDA receptor subunits and GAD-67 protein levels in the hippocampus and basolateral amygdala complex (BLA). Results Injured rats exhibited an overall increase in fear conditioning regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to over generalize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant up-regulation of excitatory NMDA receptors in the BLA. There was a trend toward decreased GABA related inhibition (GAD-67) in the BLA and hippocampus. Conclusions These results suggest that mTBI predisposes the brain toward heightened fear learning during stressful post-injury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the co-morbidity of PTSD and TBI.

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

“…Several studies have reported increased anxiety-like behavior in rodent TBI models, [29][30][31][32] including increased conditioned 33 and unconditioned 34 fear responses to both learned and novel stimuli. TBI in rodents also increases levels of activated glial cells and proinflammatory cytokines, [34][35][36][37][38] and administration of these cytokines increases anxiety-like behaviors.…”

“…97,99,100 Other neuroimaging reports of patients with non-trauma-related OCD and phobia, as well as those with PTSD, have revealed that aversive anticipation (a hallmark of anxiety) involves increased activation of both the amygdala and insula. 92 Evidence for the specific involvement of these brain areas in human post-traumatic anxiety is complemented by animal models, including findings of increased PTSD-related traits and increased Stathmin 1 (a protein known to increase fear responses) expression in the amygdala after blast injury, 101 increased fear conditioning and up-regulation of excitatory N-methyl-D-aspartate receptors (crucial receptors for normal fear learning and memory) in the amygdala after concussive injury, 33 and our current results showing increased anxiety-like behavior and reactive gliosis in insula and amygdala at long-term time points after LFPI. However, though these results support findings from our previous study 34 indicating increased gliosis in these areas, the insula and amygdala are not the only regions involved in anxiety and do not exclude the possibility that other regions may be contributing to the results reported here.…”

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

“…The N-methyl-D-aspartate (NMDA) glutamate receptors in the amygdala appear to regulate fear and anxiety. In a rat model of mild TBI, the levels of NMDA receptors in the amygdala increased while the levels of gamma-aminobutyric acid (GABA) decreased (Reger et al, 2012). Excitatory events created by an elevation of NMDA receptors levels and a decrease in GABA activity may increase the risk for developing fear and anxiety.…”

Targeting Microglia to Prevent Post-Traumatic Epilepsy

“…Glial activation is normally neuroprotective (26,32); however, the chronic inflammatory responses and exaggerated proinflammatory cytokine levels observed following injury initiate neurotoxic processes resulting in secondary tissue damage (20,(33)(34)(35), neuronal death (29,(36)(37)(38), secondary injury cascades (39)(40)(41)(42)(43) and neuronal hyperexcitability (28, 34, 38, 44). There is substantial support for chronic inflammation following TBI.…”

“…The ongoing inflammatory response to tissue injury may contribute to damage and dysfunction in brain regions associated with anxiety, as TBI has been found to induce both acute and chronic neurodegeneration that could be caused by delayed cellular death pathways initiated by complex signaling cascades in activated glial cells (49,50). Several new lines of evidence support this hypothesis: (a) innate immune responses triggered by TBI (20,34,35), (b) resultant prolonged post-traumatic release of proinflammatory cytokines by activated glial cells (29,33,51,52), (c) chronic peripheral elevations of proinflammatory cytokines in patients with PTSD and panic disorder (19,21,23,24), (d) increased levels of activated microglia and astrocytes, IL-1β, TNF-α and IL-6 following controlled cortical impact and weight drop injury in rats (53)(54)(55)(56), (e) increased anxiety-like behavior (57)(58)(59)(60), and (f) elevated plasma corticosterone concentrations (61) when these cytokines are administered centrally or systemically in rats. Overall, these findings provide evidence for a potential role of the neuroimmune system in the pathophysiology of posttraumatic anxiety.…”