Neuronal ensemble dynamics in the amygdala-striatal circuitry during fear extinction and fear return – DYNAFEAR

Fear is an evolutionarily conserved behavioural response that is essential for protecting us against dangerous situations. When a danger occurs within a particular place, an associative fear memory is formed in the brain enabling individuals to adapt their behaviour. Yet, fear can severely affect quality of life when uncontrolled. Experiencing a traumatic event can trigger dysregulations of the fear response in safe contexts, and lead to anxiety disorders such as post-traumatic stress disorder (PTSD). This pathological fear manifests with intense, persistent, and unwanted memories of the event. A primary treatment for PTSD involves exposure therapy (Rothbaum & Davis, 2003), which is founded on the principles of extinction in rodents (Milad & Quirk, 2012), where the fear-provoking stimulus is repeatedly presented in the absence of the aversive outcome. This procedure results in a gradual loss of fear and therefore the context represents a safe place (Rothbaum & Davis, 2003; Milad and Quirk, 2012). Yet, even after completion of exposure therapy, pathological fear can return with the simple passage of time, a phenomenon called spontaneous recovery (Quirk 2002; Rescorla 2004; Myers & Davis, 2007).
Neuroanatomical and neuroimaging studies strongly implicate the basal amygdala (BA) in the development of PTSD. Previous findings identified a subset of BA neurons that are activated during fear conditioning and reactivated during memory retrieval. We call them fear neurons. The BA comprises various neuronal cell types encoding positive or negative (e.g. fear neurons) valence, which project preferentially to the nucleus accumbens (NAc) and the central amygdala, respectively. The NAc is classically linked to rewarding experiences but is also thought to participate in aversive memory. Furthermore, the BA-NAc pathway is recruited during fear conditioning and extinction. In this context, optogenetic stimulation of the BA-NAc pathway was shown to reduce spontaneous fear recovery few months after extinction. The contribution of the fear neurons (i.e. activated by the fearful event) projecting to NAc to spontaneous fear recovery effect is unknown. To address this, the proposal employs a powerful transgenic mouse line enabling the tagging, monitoring and manipulation of the fear neurons in behaving mice.

This proposal aims to provide a better understanding of the neuronal circuits and underlying mechanisms of fear extinction and fear recovery embedded in the BA-NAc pathway, and originating from the BA fear neurons. By combining neuronal recordings, optogenetic interventions and anatomical tools we will 1) dissect the BA-NAc pathway that is active during fear conditioning, 2) examine the physiological signatures in the BA-NAc circuit during extinction and fear recovery and 3) design novel and targeted strategies that prevent long-lasting fear recovery by targeting the BA-NAc circuit.The completion of this proposal will provide novel insights into the mechanisms underlying heterogeneity across individuals in the amount of spontaneous recovery and guide the identification of novel and more specific effective therapeutic approaches to alleviate maladaptive fear.