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

Abstract

Background A core symptom of post traumatic stress disorder (PTSD) is persistent fear memory, which can be defined as fear memory that is resistant to updating, inhibition, or extinction. PTSD 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 amygdala (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 (pAkt) were assayed in the Amy at 0 and 30 min 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 pAkt 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.

Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice

“…All these findings would suggest that these miRNAs are part of a complex transcriptional and post-transcriptional machinery that controls fundamental processes in neurons and, consequently, their dysregulation would contribute to molecular cascades induced by neuropsychological stress. Moreover, enrichment analysis of miR-15a-5p, miR-497a-5p, miR-511-5p, and let-7d-5p network showed that such miRNA circuits could affect multiple cellular and molecular processes associated with PTSD pathogenesis [ 47 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Based on these considerations, the inverse correlation between arousal score and hippocampal expression of miR-15a-5p and miR-511-5p is not surprising, as it suggests the existence of a linear relationship between the behavioral arousal score of mice and miRNA levels in the brain that, in turn, coherently influences BDNF and FKBP5 transcripts.…”

Duration of exposure to epidural anesthesia at delivery, DNA methylation in umbilical cord blood and their association with offspring asthma in Non-Hispanic Black women

“…NFkB, for example, is a key transcription factor in stress regulation and stress adaptation [ 40 , 41 ]. Traumatic stress, which may be associated with labor, may enhance PI3-Akt signaling in the basolateral amygdala in the brain, leading to the persistence of fear memory and posttraumatic stress disorder like symptoms [ 42 ]. NFkB and Akt pathways have been implicated in both inflammatory and opioid-induced neuropathic pain pathways [ 43–46 ].…”

Immune-metabolic mechanisms of post-traumatic stress disorder and atherosclerosis

“…Patients with PTSD and impaired glutamate systems cannot maintain adequate glutamate delivery when re-experiencing trauma-related stimuli, leading to increased over-attention, stress response, and fear ( Pitman et al, 2012 ). Activated PI3K/Akt is crucial for the formation of fear memory, and the PI3K/Akt pathway may underlie the anti-regression of fear memory caused by traumatic stress ( Yang et al, 2015 ) and be related to the formation of anxiety-like symptoms in PTSD ( Knox et al, 2021 ). Akt plays an important role in neural development, learning, and memory, and upregulation of the PI3K/Akt pathway may prevent and treat cognitive impairment ( Palumbo et al, 2021 ; Tong et al, 2021 ).…”