Witnessed Trauma Exposure Induces Fear in Mice Through a Reduction in Endogenous Neurosteroid Synthesis

The study investigates the role of neurosteroids in the behavioral outcomes of direct and witnessed trauma, both risk factors for post-traumatic stress disorder (PTSD). It was found that both mice directly subjected to threat (foot shocks) and those witnessing the threat had decreased plasma levels of allopregnanolone, a neurosteroid. The expression of 5α-reductase type 2, a key enzyme involved in neurosteroid synthesis, was decreased in the basolateral amygdala (BLA), an area implicated in PTSD. Knockdown of 5α-reductase type 2 exaggerated the behavioral expression of fear in response to witnessed trauma. However, treatment with a synthetic neuroactive steroid GABAA receptor PAM, similar to allopregnanolone, decreased the behavioral response to observational fear. The data suggests that impaired neurosteroidogenesis may be involved in the pathophysiology of threat exposure and that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for treating PTSD.