Norepinephrine and corticosterone in the medial prefrontal cortex and hippocampus predict PTSD-like symptoms in mice

This study measured changes in brain extracellular norepinephrine (NE) and free corticosterone (CORT) levels in a mouse model of post‐traumatic stress disorder and related them to hyperarousal and fear memory retention. To this end, microdialysis in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of male C57BL/6NCrl mice was performed during an acoustic startle response (ASR) and following an electric foot shock (FS), as well as during an ASR and recall of contextual fear (CF) 1 day later. Changes in ASR‐stimulated NE levels in the mPFC corresponded to ASR 34 days after FS. Changes in basal and ASR‐stimulated extracellular NE levels in the HPC, in contrast, were related to expression of early (day 2) and late (day 34) CF after FS. The increase in extracellular NE levels correlated in a U‐shape manner with arousal levels and CF, thus suggesting a non‐direct relationship. Stress of different modalities/strength (ASR, FS and CF) caused a similar relative increase in free CORT levels both in the mPFC and the HPC. One day after FS, ASR‐induced increases in the CORT content in the mPFC tended to correlate with the FS‐potentiated ASR in a U‐shape manner. Taken together, these data show that the intracerebral increase in free CORT was likely related to an immediate response to stress, whereas NE neurotransmission in the forebrain predicted arousal and CF 1 month after trauma. We used extracellular norepinephrine levels in the medial prefrontal cortex (mPFC) and hippocampus (HPC) to stratify C57BL/6NCrl mice into Low and High norepinephrine cohorts. When taking basal HPC norepinephrine levels during early post‐foot shock period (Basal 2 NE) for stratification, mice with higher Basal 2 NE showed lower contextual fear (CF34) when re‐exposed to shock context. When using norepinephrine levels corresponding to the arousal state during the early post‐foot shock period (ASR2 NE) for stratification, mice with higher ASR2 NE in the mPFC showed a lower degree of delayed fear‐potentiated arousal (ASR34).