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

LaPalombara, Zoe (2020) Aberrant prelimbic activity is associated with elevated fear in SAPAP3 knockout mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
LaPalombara, Zoezfl1@pitt.eduzfl1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorAhmari, SusanneSAHMARI@pitt.edusahmari
Committee ChairSeal, Rebeccarpseal@pitt.edurpseal
Committee MemberGittis, Arynagittis@andrew.cmu.edu
Committee MemberGrace, AnthonyGraceAA@pitt.eduGraceAA
Committee MemberTorregrossa, Marytorregrossam@upmc.edutorregrossam
Committee MemberLikhtik, Ekaterinaelikhtik@genectr.hunter.cuny.edu
Date: 9 August 2020
Date Type: Publication
Defense Date: 15 July 2020
Approval Date: 9 August 2020
Submission Date: 30 June 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 227
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Fear conditioning, obsessive-compulsive disorder, basolateral amygdala, fear generalization, fiber photometry, optogenetics, cFos, darting
Date Deposited: 09 Aug 2020 20:20
Last Modified: 09 Aug 2020 20:20
URI: http://d-scholarship.pitt.edu/id/eprint/39295

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