Investigating the Role of HDAC3 in Memory Reconsolidation

Open Access
- Author:
- Bennetts, Sofia
- Area of Honors:
- Neuroscience
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Janine Kwapis, Thesis Supervisor
Bernhard Luscher, Thesis Honors Advisor - Keywords:
- Memory reconsolidation
fear conditioning
HDAC3
epigenetics
memory updating
hippocampus
fear extinction
OUL
amygdala - Abstract:
- Memory reconsolidation is a process by which existing memories re-enter a labile state and become susceptible to enhancement or impairment. During reconsolidation, epigenetic mechanisms such as histone acetylation and deacetylation are thought to control expression of memory relevant genes to modify synaptic connections. One enzyme of interest, Histone Deacetylase 3 (HDAC3), is highly expressed in the brain and acts as a critical negative regulator of long-term memory formation (Kwapis et al., 2018). The role of HDAC3 in regulating memory reconsolidation molecularly and behaviorally remains unclear, and my work aims to investigate how inhibiting its activity can affect the strength of a memory. I utilized the Objects in Updated Locations (OUL) behavioral paradigm alongside contextual fear conditioning to investigate behavioral outputs of memory reconsolidation after HDAC3 inhibition. Our data show that inhibiting HDAC3 in the brain after the update session leads to enhancement of the updated memory, but impairment of the original memory, suggesting that there may be competition between the original and updated memory. When we conducted a separate experiment with a subthreshold update session where mice had less time to learn the update in the OUL paradigm, we found that the original memory was restored without affecting the updated memory, consistent with our competition hypothesis. These findings prompted us to investigate whether our results could transcend paradigms, and we began to consider memory reconsolidation in contextual fear conditioning. In this experiment, we tested whether we could use memory updating to persistently reduce fear memory. Specifically, we compared whether updating fear memory could produce a more persistent reduction in fear than standard extinction procedures, which are notoriously susceptible to fear relapse. We observed that memory updating produced a more persistent reduction in fear memory (in both spontaneous recovery and reinstatement) compared to mice that received standard extinction training. Overall, our work suggests that memory updating can manipulate existing memories of both incidental spatial information and more salient aversive information and may be a potential strategy to improve memory function and prevent relapse.