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NMDA and dopaminergic contributions to context fear memory reconsolidation

Kochli, Daniel Edward
http://orcid.org/0000-0003-4882-8053
http://rave.ohiolink.edu/etdc/view?acc_num=miami150065280374774

Abstract Details

2017, Doctor of Philosophy, Miami University, Psychology.
Learning about and discriminating between potential threats is an adaptive process. However, improper regulation of fear can result in the development of debilitating disorders such as post-traumatic stress disorder (PTSD). It is well accepted that memories stabilize over time through a consolidation process, in which new proteins are synthesized to stabilize potentiated synapses long-term. However, research demonstrates that reactivation of a previously consolidated memory can temporarily destabilize the memory, which then must be re-stabilized through another protein synthesis-dependent phase called reconsolidation. Reconsolidation may serve as a means of updating existing memories with new information. Indeed, growing evidence suggests that a violation of what is expected at the time of retrieval (i.e. prediction error) is necessary to initiate memory destabilization and subsequent memory reconsolidation. The goal of the present work is to better understand the neurobiological underpinnings of prediction error in memory destabilization and reconsolidation. I examine the role of N-methyl-D-aspartate receptor- (NMDAr) and dopamine-mediated signaling on destabilization and subsequent reconsolidation of aversively-motivated context fear discrimination memory. Evidence regarding the role of NMDArs in reconsolidation is mixed—some evidence suggests antagonism of NMDArs is sufficient to disrupt reconsolidation, while other literature suggests NMDArs are upstream of proteasome-mediated memory destabilization. Dopamine critically underlies prediction error signaling in appetitive models, while less is known in aversive models. I test the hypothesis that preventing memory destabilization (via NMDA- or dopamine-specific mechanisms) will prevent the disruption of the protein-synthesis dependent reconsolidation by a protein synthesis inhibitor. I also compare the efficacy of three systemically administered amnestic agents with considerable translational potential. I show that pre-reactivation administration of the NMDAr antagonist MK-801 attenuates freezing behavior during the reactivation session. Additionally, I show that pre-reactivation systemic NMDAr antagonism, combined with post-reactivation intra-BLA protein synthesis inhibition, disrupts the reconsolidation of a context fear discrimination memory—but this pattern of results only emerges following extinction. These data suggest that NMDArs play a role in memory reconsolidation, but antagonism alone may be insufficient to disrupt reconsolidation. I posit that the deficit emerging following extinction is attributable to a behavioral ceiling induced by strong behavioral training. By better understanding the nature of prediction error and its relationship to memory destabilization, I hope to inform subsequent translational efforts to apply reconsolidation-based therapies to clinical populations such as those that suffer from PTSD.
Jennifer Quinn, PhD (Committee Chair)
Stephen Berry, PhD (Committee Member)
Matthew McMurray, PhD (Committee Member)
Marieke Gilmartin, PhD (Committee Member)
Paul James, PhD (Committee Member)
115 p.
Behavioral Psychology; Behavioral Sciences; Neurosciences; Psychology
reconsolidation; NMDA; dopamine; protein synthesis; prediction error; rat; memory; fear

Recommended Citations

Citations

  • Kochli, D. E. (2017). NMDA and dopaminergic contributions to context fear memory reconsolidation [Doctoral dissertation, Miami University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=miami150065280374774

    APA Style (7th edition)

  • Kochli, Daniel. NMDA and dopaminergic contributions to context fear memory reconsolidation. 2017. Miami University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=miami150065280374774.

    MLA Style (8th edition)

  • Kochli, Daniel. "NMDA and dopaminergic contributions to context fear memory reconsolidation." Doctoral dissertation, Miami University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=miami150065280374774

    Chicago Manual of Style (17th edition)

miami150065280374774
362
© 2017, all rights reserved.
This open access ETD is published by Miami University and OhioLINK.