Scientific Rationale

The research underlyling the current PTSD investigations at Neurovation Labs utilized a robust model of PTSD in rodents called stress-enhanced fear learning (SEFL). In the SEFL model an acute, severe, and unpredictable stressor permanently sensitizes conditional fear learning. Rats are given 15 unsignaled footshocks in a certain context (the “trauma” context) and some time later are given a single footshock in a novel context (the “reminder” context). When rats are tested for changes in freezing levels (i.e., fear levels) in the reminder context in absence of a shock, they show exaggerated levels of freezing behavior. This is analogous to a PTSD trigger, like a car backfiring, setting off a disproportionate fear reaction in a patient suffering from PTSD. Such a reaction is the crux of PTSD symptomatology and is captured in the SEFL rodent model along with the other PTSD symptoms identified in the DSM-V checklist.

SEFL is a unique PTSD model in that it combines multiple techniques. Because of this, it is able to capture multiple aspects of PTSD, including exaggerated or sensitized fear, as seen through freezing, and blunted emotional reactivity, as measured through reactivity to the shock (we focus on the former aspect as a tractable measure of fear). These animal studies also show dysregulated HPA axis activation can enhance fear responding, and their results are consistent with the stress response of PTSD patients. Rats exhibiting SEFL further show anxiety behavior, increased consumption of alcohol, potentiated startle response, and a depression-like phenotype in a forced swim test.

Dr. Perusini together with Dr. Fanselow determined the mechanisms underlying both the induction and expression of SEFL. They found that immediately after a traumatic experience, a rise in corticosterone, or cortisol in humans, is necessary for SEFL to occur, and it in part increases GluA1 levels in the basolateral amygdala (BLA), the fear center of the brain, long after the traumatic experience. Increased GluA1 in turn increases functional glutamatergic AMPA receptors in the BLA, providing an exceptional target for therapeutic intervention. Neurovation Labs is building on these discoveries to develop a treatment that focuses on the physiological cause of PTSD, as well as a companion diagnostic to determine those who would benefit from the treatment. The company also aims to tackle other CNS disorders that implicate the glutamate system.

Perusini, et al. 2015