Region- and time-dependent gene regulation in the amygdala and anterior cingulate cortex of a PTSD-like mouse model

Abstract

Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD. Electronic supplementary material The online version of this article (10.1186/s13041-019-0449-0) contains supplementary material, which is available to authorized users.

Blast-Related Mild TBI Alters Anxiety-Like Behavior and Transcriptional Signatures in the Rat Amygdala

“…Previous work shows that decreased GABAergic functioning in the amygdala can directly lead to altered performance on the OFT, EPM, and fear conditioning (Babaev et al, 2018). Further, Adcy8 codes for a protein kinase that has been repeatedly implicated in anxiety-like behavior, synaptic plasticity, and mood disorders (Schaefer et al, 2000;de Mooij-van Malsen et al, 2009;Bernabucci and Zhuo, 2016;Tanaka et al, 2019). A recent study found changes in anxiety-like behavior linked to a rodent PTSD-like model accompanied by aberrant Adcy8 expression in the amygdala (Tanaka et al, 2019).…”

“…Further, Adcy8 codes for a protein kinase that has been repeatedly implicated in anxiety-like behavior, synaptic plasticity, and mood disorders (Schaefer et al, 2000;de Mooij-van Malsen et al, 2009;Bernabucci and Zhuo, 2016;Tanaka et al, 2019). A recent study found changes in anxiety-like behavior linked to a rodent PTSD-like model accompanied by aberrant Adcy8 expression in the amygdala (Tanaka et al, 2019). Similar to our results, the stress-induced change in Adcy8 expression was dependent on a time delay following the stressor, highlighting the importance of the treatment by timepoint interaction in regulating brain function and behavior after a stressor.…”

Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring

“…Differentially methylated genes in the vHPC included Fkbp5 , Ksr1 , and Pnpla2 . Interestingly, Fkbp5 and Ksr1 transcription was disrupted in one behavioral mouse model of PTSD, 57 where mice were exposed to an electric footshock and then presented situational reminders. Fkbp5 encodes a glucocorticoid receptor chaperone whose functioning has been associated with a maladaptive prolonged stress response in individuals with PTSD and other anxiety disorders 58 .…”

Basolateral Amygdala but Not Medial Prefrontal Cortex Contributes to Chronic Fluoxetine Treatments for PTSD Symptoms in Mice

“…Previous studies of PTSD involving animal models often examined fear conditioning or fear extinction [ 4 ]; however, the present study used the situational reminder procedure with the traumatic memory associated with the context. This kind of study was aimed at mimicking the reexperiencing of a traumatic memory of PTSD symptoms in humans [ 5 , 6 ].…”