Aberrant prelimbic activity is associated with elevated fear in SAPAP3 knockout mice

Abstract

Obsessive compulsive disorder (OCD), characterized by intrusive thoughts and repetitive actions, affects 1-3% of the population. One theory of OCD pathophysiology is that patients form maladaptive fear responses to neutral stimuli, leading to heightened fear and anxiety that drive repetitive behaviors. Thus, understanding abnormal fear processing in OCD may provide new treatment avenues. To investigate the mechanisms of aberrant fear processing in OCD, I used SAPAP3 KO mice, an OCD-relevant model. In Chapter 2, I characterize fear conditioning in KOs and WTs and examine nociception and audition, which are relevant to fear learning. KO mice display elevated fear conditioning compared to WTs that cannot be explained by altered nociceptive or auditory signaling. In Chapter 3, I assess conditioning-related neural activity in fear-associated regions using the proxy of cFos expression. cFos in the prelimbic cortex (PL) and basolateral amygdala (BLA) is significantly correlated in KOs, but not WTs. In contrast, PL cFos is correlated with freezing in WT mice only. This suggests that freezing behavior is linked to PL activity in WTs, while broad alterations in fear-related circuitry in KOs may be unrelated to behavioral output, and may impair normal fear learning. Finally, in Chapter 4 I examine PL/BLA circuitry in KOs and WTs using fiber photometry. Interestingly, modulation in this circuit, particularly the PL, is associated with online learning of specific aversive associations in WTs. In KOs, modulation is absent, suggesting that their behavior is driven by both specific and generalized fear. Next, I directly determined that KOs generalize more than WTs during discriminative fear conditioning. Finally, I demonstrate that PL activity underlies online fear processing via optogenetic inhibition during fear conditioning. Together, these data suggest that modulation within the PL/BLA circuit, particularly the PL node, is critical for online fear processing in WTs. Conversely, a lack of PL modulation across conditioning trials could indicate that fear learning is driven by both specific and generalized fear learning in KOs. These data provide the first systematic characterization of PL/BLA functioning during online fear processing in WTs and a viable model for studying aberrant fear processing in the context of OCD