Neural circuit dynamics underlying persistent active place avoidance. – NEURAVOID

Post-traumatic stress disorder (PTSD) is the fourth most prevalent psychiatric diagnosis encompassing three clusters of symptoms: re-experiencing the traumatic event, avoidance symptoms and hyper arousal. PTSD is characterized by a high-rate of treatment resistance and inter-individual variability, with heightened prevalence and severity amongst women. The most effective treatment for PTSD consists in cognitive behavioral therapy such as exposure therapy. However, excessive and persistent avoidance of trauma related cues (people, conversations, places, situations) contributes to the maintenance of PTSD by preventing patients from reappraising their perception of the threat. Alleviating avoidance symptoms is therefore a prerequisite to improve the outcome of exposure therapy. In strike contrast with the study of Pavlovian defensive reactions (such as freezing behavior), active avoidance and its neural correlate remain poorly understood. Recent work in rodents suggests that active avoidance involves deep brain regions such as the amygdala, ventral striatum and midbrain motor centers. In contrast, the dentate gyrus in the hippocampus -a brain region implicated in learning and memory, spatial navigation and emotionality- plays an important role in preventing the persistence of active place avoidance. This is especially important as neuroimaging studies in patients suffering from PTSD point to the hippocampus as a critical site of vulnerability to stress. The NEURAVOID project aims at investigating how the hippocampus and its downstream partner the lateral septum prevent persistent place avoidance by inhibiting the activity of the ventral striatum. We will use optical tools in freely moving male and female mice to characterize this neural circuit with high spatial and temporal resolution. These approaches will be implemented in an active place avoidance paradigm to (i) determine whether the activity of lateral septal neurons projecting to the ventral striatum predict persistent place avoidance; (ii) characterize the lateral septum microcircuit linking the hippocampus and ventral striatum which controls persistent active place avoidance; (iii) devise a closed loop system in this circuitry to prevent persistent place avoidance in real time. In the short term, we hope that these findings will guide functional brain imaging studies in order to optimize treatment response across male and female patients suffering from PTSD. In the long term, we hope that this body of work will help refining deep brain stimulation protocols as well as brain-machine interfaces to curb excessive avoidance behavior in PTSD.