ABSTRACT
INTRODUCTION:
Traumatic brain injury (TBI) is a debilitating
neurological disorder caused by an impact to the
head by an outside force. TBI results in persistent
cognitive impairments, including
fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying
fear generalization have not been fully elucidated, and there are no targeted
therapeutics to alleviate this symptom of TBI.
METHODS:
To identify the neural ensembles
mediating fear generalization, we utilized the ArcCreER T2 x enhanced yellow fluorescent
protein (EYFP)
mice, which allow for activity-dependent labeling and quantification of
memory traces.
Mice were administered a sham
surgery or the controlled cortical impact (CCI) model of TBI.
Mice were then administered a contextual
fear discrimination (CFD) paradigm and
memory traces were quantified in numerous
brain regions. In a separate group of
mice, we tested if ( R,S )-
ketamine could decrease
fear generalization and alter the corresponding
memory traces in TBI
mice.
RESULTS:
TBI
mice exhibited increased
fear generalization when compared with sham
mice. This behavioral
phenotype was paralleled by altered
memory traces in the DG, CA3, and
amygdala, but not by alterations in
inflammation or
sleep. In TBI
mice, ( R,S )-
ketamine facilitated
fear discrimination and this behavioral improvement was reflected in DG
memory trace activity.
CONCLUSIONS:
These data show that TBI induces
fear generalization by altering
fear memory traces, and that this deficit can be improved with a single
injection of ( R,S )-
ketamine. This
work enhances our
understanding of the neural basis of TBI-induced
fear generalization and reveals potential
therapeutic avenues for alleviating this symptom.
