Clinical and preclinical studies that have examined the neurobiology of persistent fear memory in posttraumatic stress disorder (PTSD) have focused on the medial prefrontal cortex, hippocampus, and amygdala. Sensory systems, the periaqueductal gray (PAG), and midline thalamic nuclei have been implicated in fear and extinction memory, but whether neural activity in these substrates is sensitive to traumatic stress (at baseline or during emotional learning and memory) remains unexplored. To address this, we used the single prolonged stress (SPS) model of traumatic stress. SPS and control rats were either subjected to fear conditioning (CS-fear) or presented with CSs alone (CS-only) during fear conditioning. All rats were then subjected to extinction training and testing. A subset of rats were euthanized after each behavioral stage and c-Fos and c-Jun used to measure neural activation in all substrates. SPS lowered c-Jun levels in the dorsomedial and lateral PAG at baseline, but the elevated c-Jun expression in the PAG during emotional learning and memory. SPS also altered c-Fos expression during fear and extinction learning/memory in midline thalamic nuclei. These findings suggest changes in neural function in the PAG and midline thalamic nuclei could contribute to persistent fear memory induced by traumatic stress. Interestingly, SPS effects were also observed in animals that never learned fear or extinction (i.e., CS-only). This raises the possibility that traumatic stress could have broader effects on the psychological function that are dependent on the PAG and midline thalamic nuclei.

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.

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NMDA receptors (NMDARs) and AMPA receptors (AMPARs) in amygdala nuclei and the dorsal hippocampus (dHipp) are critical for fear conditioning. Enhancements in synaptic AMPAR expression in amygdala nuclei and the dHipp are critical for fear conditioning, with some studies observing changes in AMPAR expression across many neurons in these brain regions. Whether similar changes occur in other nodes of the fear circuit (e.g., ventral hippocampus [vHipp]) or changes in NMDAR expression in the fear circuit occur with fear conditioning have not been sufficiently examined. To address this we used near-infrared immunohistochemistry (IHC) to measure AMPAR and NMDAR subunit expression in several nodes of the fear circuit. Long-term changes in GluR1 and GluR2 expression in the ventral hippocampus (vHipp) and anterior cingulate cortex (ACC), enhanced NR2A expression in amygdala nuclei, and changes in the ratio of GluR1/NR2A and GluR2/NR2A in the dHipp was observed with fear conditioning. Most of these changes were dependent on protein synthesis during fear conditioning and were not observed immediately after fear conditioning. The results of the study suggest that global changes in AMPARs and NMDARs occur in multiple nodes within the fear circuit and raise the possibility that these changes contribute to fear memory. Further research examining how global changes in AMPAR, NMDAR, and AMPAR/NMDAR ratios within nodes of the fear circuit contribute to fear memory is needed.

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