Aberrant inhibition of fear: mechanisms and novel therapeutic approaches

Deficits in fear inhibiting mechanisms are thought to be critical components in the development and maintenance of pathological anxiety. Supporting research in human anxiety patients, we have recently identified cortico-limbic networks as key systems being affected in a novel genetic animal model of impaired extinction, the 129S1/SvImJ (129S1) mice. We could show that successful rescue of impaired extinction learning in 129S1 was concomitant with normalization of aberrant activation of these regions, Based on these findings, we will now further characterize this animal model using behavioural, neuroanatomical, neurochemical and physiological tools to explore the detailed mechanisms underlying dysfunctional fear extinction, and its reversal. In particular we will address the question: which neuronal populations and neurobiological systems in which brain areas are critical targets to facilitate impaired extinction learning and which mechanisms are required to promote extended maintenance of extinguished fear? Here, we will gain information on connectivity and neurochemistry of neuronal populations involved in successful extinction by using neuroanatomical, neurochemical and electrophysiological approaches. Functional proof of a causal involvement of identified neuronal populations in extinction mechanisms will be studied by selective modulation of activity in candidate areas which show normalization of aberrant activity after successfully induced extinction learning. Taken together, by gaining insight into mechanisms of suppressing persistent fear in an appropriate animal model of impaired fear extinction, and considering the accepted translational value of animal research in this field, the results of this project should provide an important basis for the development of novel innovative therapeutic strategies for anxiety disorders.

Exposure-based therapy (EBT) is an important non-pharmacological treatment option in patients with fear, anxiety- and trauma-related disorders. However, a considerable proportion of shows only partial long-term therapeutic benefit as fear often relapses with the passage of time, with changes in context (out of the therapy context), or under conditions of stress including trauma reminders. Fear extinction is the central mechanisms of EBT and involves the formation of a new inhibitory association, the fear eliciting conditioned stimulus no longer predicts an aversive consequence. This memory is consolidated, exists in parallel to the initial far association and inhibits it upon recall. In patients these fear-inhibiting mechanisms are often dysfunctional. It is now hoped that the fragile extinction memory can be strengthened and made long-lasting and context-independent using appropriate pharmacological adjuncts (Singewald et al 2015). Therefore, the overall aim of the present project was elucidating mechanisms underlying both resistance and rescue of fear extinction in a genetic animal model of deficient fear extinction, the 129S1 (S1) mouse, and, by building on these data, exploring novel extinction augmentation strategies by pharmacological interventions. At first, we characterized the S1 mouse in more detail in terms of sleep/wake characteristics. We observed an impaired sleep architecture and fear memory replay, in particular altered REMS behavior prior to and after a trauma, further strengthening the face validity of the model and, thus, its value in translational research for investigating extinction-facilitating drugs. Next, we demonstrate here that S1 mice display evidence of a blunted dopaminergic neurotransmission in the medial prefrontal cortex (mPFC).Since we were able to show that the activation of the mPFCamygdala pathway,in particular a specific subset of central amygdala neurons, facilitated extinction memory formation, it is suggested that the dopaminergic dysfunctions in the mPFC may contribute to the deficient fear-extinction of S1.Along these lines, we report that the non-sedative and anxiolytic neuropeptideS (NPS), which has been shown to enhance dopamine release in extinction-related brain areas (among other mechanisms), was able to rescue the deficient fear extinction in S1 mice. The extinction-promoting effect of NPS was, however, rather short-lived and fear can return. Therefore, we finally developed a dual pharmacotherapeutic strategy involving a fear-inhibiting/extinction-inducing substance such as NPS and a cognitive enhancer such as d-cycloserine for extinction-augmentation in an extent that temporal, spatial or stress-dependent fear relapse could be prevented in the laboratory. Although the translational value of this concept has to be explored in the future, it may have profound clinical impact for patients with anxiety disorders by means of increasing tolerability of exposure-based therapy and reducing fear relapse in the long-term.