Host institution: University of Bristol, UK

ESR7 Cerebellar contributions to fear extinction and chronic pain

Project overview

Chronic pain is a multidimensional experience including potentially debilitating affective responses and changes in emotional responses processing. There is a link between mood disorders (such as anxiety and depression) and individual susceptibility to the development of chronic pain (e.g. Woo, Rev pain, 2010; McWIlliams et al, Pain, 2003). Phenotypes of anxiety in humans and rodents range from high to low and this project seeks to understand the link between this and those individuals more susceptible to developing chronic pain.

It is hypothesised that chronic pain could be a dysfunction of extinction learning i.e. an inability to forget pain causing a persistent fear of pain, anxiety and pain catastrophisation.

We (and others- Jimena et al; Utz et al) have previously shown how cerebellar vermal regions are involved in fear extinction learning. This project aims to further understand how the cerebellum contributes to emotional control via extinction learning using animal models in a neuropathic pain state and human studies.

Experimental plan in rodents

  1. Separate animals into phenotypes based on their ability to extinguish a fear memory using a fear conditioning paradigm.
  2. Modulate cerebellar limbic networks (e.g. cerebellar to periaqueductal grey pathways) using chemogenetic techniques. This will involve surgery to allow viral transfection of neural networks followed, during a period of several weeks, by sensory and affective state behavioural testing.
  3. Terminal experiments in the same animals will investigate how modulation of these networks affects descending pain modulatory system. This will involve long electrophysiological recordings in anaesthetised animals.

Planned secondments: Essen, month 13-14, purpose: to compare cerebellar stimulation experiments in rodents and human; Cerevance, month 25, purpose: training in Biotech industry.