The Role of HDAC3 in Stress-Enhanced Fear Learning
Open Access
- Author:
- Lussier, Marc
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Janine Kwapis, Thesis Supervisor
Bernhard Luscher, Thesis Honors Advisor - Keywords:
- fear memory
SEFL
PTSD
amygdala
trauma
mice
epigenetic mechanisms
HDAC3
sex differences - Abstract:
- Certain disorders like post-traumatic stress disorder (PTSD) occur when long-term memory becomes pathogenic. Previous studies have identified epigenetic mechanisms that contribute to memory formation, including histone acetylation. One class of histone deacetylases (HDAC), HDAC3, has been shown to act as a negative regulator of fear memory formation in the amygdala, a part of the brain that is essential for encoding emotional memories. Here, we investigated the role of HDAC3 in trauma learning and subsequent context fear memory. We hypothesized that HDAC3 inhibition would transform a weak stressful event into a stronger, more traumatic event. We injected the amygdala of mice with an attenuated viral vector that blocks HDAC3 activity or an empty control viral vector and subjected the mice to a modified stress-enhanced fear learning (SEFL) procedure. The SEFL protocol, a rodent model of PTSD, involves initially exposing mice to a strong traumatic event via 10, 2-second, 0.7 mA electric shocks in a specific context. These shocks are delivered at randomized time points during a 56-minute period. Later, in a different context, freezing behaviors are assessed to measure fear memory formation after fear conditioning. In a modified procedure, a weaker initial traumatic event is used that is insufficient to elicit maximal fear learning during subsequent fear conditioning. In female mice, inhibiting HDAC3 failed to amplify the effect of trauma on subsequent fear conditioning; all female mice showed the same high level of fear memory when tested by subsequent context fear conditioning, irrespective of the strength of the initial traumatic event However, in male mice injected with an empty vector a weak traumatic event resulted in a submaximal fear response to fear conditioning, which was enhanced if the mice were injected with the HDAC3 inhibitor. This enhanced fear response of the males was similar in strength to the invariant fear response of female mice. The results indicate that there is a basal sex difference in sensitivity of mice to trauma, and HDAC3 inhibition transforms a weak traumatic event into one that causes a persistent exaggeration of subsequent fear learning and memory in male mice. In female mice, this weak traumatic event induced strong learning during subsequent fear conditioning, independent of HDAC3 manipulation. Analyses of transcribed genes and “fear proteins” present during fear conditioning following trauma should provide a potential avenue for future research in the field of PTSD.