Increased Fear Generalization and Amygdala AMPA Receptor Proteins in Chronic Traumatic Brain Injury

• Published in: Journal of neurotrauma Vol. 39; no. 21-22; p. 1561
• Main Authors: Hoffman, Ann N, Watson, Sonya, Chavda, Nishtha, Lam, Jamie, Hovda, David A, Giza, Christopher C, Fanselow, Michael S
• Format: Journal Article
• Language: English
• Published: United States 01-11-2022
• Subjects: Amygdala - metabolism; Animals; Brain Injuries, Traumatic - metabolism; Brain Injury, Chronic; Fear - psychology; Male; Rats; Receptors, AMPA - metabolism; defensive behavior; AMPA receptor; amygdala; associative learning; fear conditioning; post-traumatic stress
• ISSN: 1557-9042
• DOI: 10.1089/neu.2022.0119

Cognitive impairments and emotional lability are common long-term consequences of traumatic brain injury (TBI). How TBI affects interactions between sensory, cognitive, and emotional systems may reveal mechanisms that underlie chronic mental health comorbidities. Previously, we reported changes in auditory-emotional network activity and enhanced fear learning early after TBI. In the current study, we asked whether TBI has long-term effects on fear learning and responses to novel stimuli. Four weeks following lateral fluid percussion injury (FPI) or sham surgery, adult male rats were fear conditioned to either white noise-shock or tone-shock pairing, or shock-only control and subsequently were tested for freezing to context and to the trained or novel auditory cues in a new context. FPI groups showed greater freezing to their trained auditory cue, indicating long-term TBI enhanced fear. Interestingly, FPI-Noise Shock animals displayed robust fear to the novel, untrained tone compared with Sham-Noise Shock across both experiments. Shock Only groups did not differ in freezing to either auditory stimulus. These findings suggest that TBI precipitates maladaptive associative fear generalization rather than non-associative sensitization. Basolateral amygdala (BLA) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr) subunits GluA1 and GluA2 levels were analyzed and the FPI-Noise Shock group had increased GluA1 (but not GluA2) levels that correlated with the level of tone fear generalization. This study illustrates a unique chronic TBI phenotype with both a cognitive impairment and increased fear and possibly altered synaptic transmission in the amygdala long after TBI, where stimulus generalization may underlie maladaptive fear and hyperarousal.