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. 2021 Mar 17;24(3):229-238.
doi: 10.1093/ijnp/pyaa083.

PI3K-Akt Signaling in the Basolateral Amygdala Facilitates Traumatic Stress Enhancements in Fear Memory

Dayan Knox  1 , Rebecca Della Valle  1 , Negin Mohammadmirzaei  1 , Brianna Shultz  1 , Matt Biddle  1 , Abigail Farkash  1 , Marisa Chamness  1 , Emily Moulton  1
Affiliations

PI3K-Akt Signaling in the Basolateral Amygdala Facilitates Traumatic Stress Enhancements in Fear Memory

Dayan Knox et al. Int J Neuropsychopharmacol. .

Abstract

Background: A core symptom of posttraumatic stress disorder is persistent fear memory, which can be defined as fear memory that is resistant to updating, inhibition, or extinction. posttraumatic stress disorder emerges after traumatic stress exposure, but neurobiological mechanisms via which traumatic stress leads to persistent fear memory are not well defined. Akt signaling within the amygdala (Amy) is enhanced with traumatic stress, and phosphatidylinositol kinase 3 (PI3K) activation of Akt within the basolateral Amy (BLA) has been implicated as critical to fear memory formation. These findings raise the possibility that traumatic stress enhances PI3K→Akt signaling in the BLA, which leads to persistent fear memory.

Methods: To test this hypothesis, rats were exposed to traumatic stress using the single prolonged stress model, and changes in Akt phosphorylation were assayed in the Amy at 0 and 30 minutes after fear conditioning (FC). In a separate experiment, we inhibited PI3K→Akt signaling in the BLA prior to FC and observed the effect this had on acquisition, expression, and extinction of FC in stressed and control rats.

Results: Enhanced Akt phosphorylation in the Amy at both time points was observed in stressed rats, but not in control rats. PI3K→Akt inhibition in the BLA had no effect on freezing in control rats but decreased freezing during extinction training and testing in stressed rats.

Conclusion: These findings suggest that PI3K→Akt signaling in the BLA could be a mechanism via which traumatic stress leads to fear memory that is resistant to extinction.

Keywords: Basolateral amygdala; PTSD; extinction; fear memory; single prolonged stress.

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Figures

Figure 1.
Figure 1.
(A) Experimental design used for western-blot experiments. Underneath arrows indicate time points when rats were killed. (B) All animals in fear conditioning (FC) groups showed equivalent levels of conditioned freezing during FC. FC-0’/SPS = 9, FC-0’/control = 9, FC-30’/SPS = 9, FC-30’/control = 9. *Main effect of time. Error bars represent SEM.
Figure 2.
Figure 2.
Changes in phosphorylated Akt (pAkt) and Akt in the amygdala (Amy) and medial prefrontal cortex (mPFC). (A) Representative Amy westerns. (B) Single prolonged stress (SPS) had no effect on Akt levels, but (C) enhanced pAkt/actin ratios in the Amy. (D) There was no effect of SPS on pAkt/Akt ratios. (E) Representative mPFC westerns. (F) In control animals, pAkt/actin ratios were enhanced 30’ after fear conditioning (FC), but in SPS rats these ratios were decreased 30’ after FC. (G) SPS had no effect on Akt/actin ratios. (H) In control animals, pAkt/Akt ratios were enhanced 30’ after FC, but in SPS rats these ratios were decreased 30’ after FC. Baseline levels (SPS = 18, control = 18) of Akt and pAkt in the Amy and mPFC were not affected by SPS. One SPS animal’s datum point was dropped from the Amy analysis, because it was more than 2 SDs away from the group mean. Error bars represent SEM, black * indicates main effect of stress, red * indicates stress × time interaction.
Figure 3.
Figure 3.
Changes in pAkt and Akt in the dorsal hippocampus (dHipp) and ventral hippocampus (vHipp). (A) Representative dHipp westerns. (B–D) Single prolonged stress (SPS) had no effect on Akt or phosphorylated Akt (pAkt) levels. (E) Representative vHipp westerns. (F and G) There were no effects observed for pAkt/actin or Akt/actin levels. (E) SPS rats had enhanced pAkt/Akt ratios at baseline (SPS = 18, control = 18), but this effect only approached significance (+ represents P = .06). SPS had no effect on pAkt/Akt ratios during fear conditioning.
Figure 4.
Figure 4.
Effect of inhibiting PI3K→Akt signaling in the basolateral amygdala (BLA) during FC on fear memory. (A) experimental design. (B) Representative placement of infusion tip in the BLA along with schematic of all BLA placements. Red/brown circles are single prolonged stress (SPS) rats and blue/purple circles are control rats. (C) Infusing wortmannin into the BLA prior to fear conditioning reduced conditioned freezing during extinction training (approached significance with P = .06, indicated with a + sign) and testing (P < .05, indicated with an asterisks). These effects were not observed in control rats. SPS/vehicle = 10, SPS/drug = 7, control/vehicle = 11, control/drug = 8. (D) Infusing wortmannin outside of the BLA had no effect on conditioned fear in SPS rats (n = 6). The SPS/vehicle group from C is plotted in this graph for comparison. One SPS/vehicle animal was excluded from all behavioral analyses because its mean for extinction testing was greater than 2 SDs away from the group mean. Error bars represent SEM.
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