FEAR EXTINCTION AND INFRALIMBIC CORTEX IMPAIRMENT AFTER MILD TRAUMATIC BRAIN INJURY

Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with mild TBI (concussions) representing over 80% of cases. Although often considered benign, mild TBI is associated with persistent neuropsychiatric conditions, including posttraumatic stress disorder, anxiety, and depression. A hallmark of these conditions is impaired fear extinction, the process by which learned fear responses are inhibited in safe contexts. This dysfunction contributes to maladaptive fear expression and is linked to altered neurocircuitry, particularly in the infralimbic cortex (IL), a key region in fear extinction. Despite extensive evidence of impaired fear extinction in mild TBI patients and animal models, the specific mechanisms underlying this deficit remain poorly understood. This study aimed to address this gap by combining cued-fear extinction behavior, local field potential recordings, and whole-cell patch-clamp techniques to investigate how mild TBI affects IL network activity and excitability in a mouse model of TBI. Our results demonstrate that mild lateral fluid percussion injury (LFPI) significantly impairs fear extinction memory, as evidenced by an elevated cued-fear response during extinction testing 10 days post-injury. Field potential recordings revealed decreased activation of the IL network in both layers II/III and V, which was consistent with the observed behavioral deficits. Further analysis of synaptic physiology revealed an imbalance in excitatory and inhibitory neurotransmission (E/I imbalance) in the IL, characterized by reduced excitatory input and enhanced inhibitory input to neurons in both layers. Moreover, intrinsic excitability was altered in IL neurons after mild TBI. This study provides novel insights into the mechanisms of how mild TBI disrupts the neurocircuitry underlying fear extinction, specifically by suppressing IL excitability. These results demonstrate the importance of understanding the mechanistic disruptions in IL activity for developing therapeutic strategies to address fear-based disorders in mild TBI patients.

Author dc:creator

• Ubri, Catherine, Estela

Advisor dc:contributor.advisor

• Cohen, Akiva, S

• Neuroscience and Neurobiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/61297

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/61297