Dissecting the roles of deep anterolateral system neurons in pain; a cross-species approach.

Chronic pain is debilitating, affects ~30% of the UK adult population and consequently has significant societal and economic impacts. Projection neurons of the anterolateral system (ALS) are essential for conveying pain signals from spinal cord to brain, and therefore make an attractive therapeutic target. ALS cells in the deep dorsal horn are thought to be essential for pain sensation and activation of these cells is thought to be a sufficient condition to produce acute pain in humans. However, identifying and manipulating ALS neurons is challenging due to extensive functional heterogeneity within the system. I have recently identified 5 distinct clusters of neurons within this system using single-nucleus RNA sequencing and in this project, I will capitalise on these novel fundamental insights. My overall aim is to is to better understand the role of ALS neurons in pain via three complementary work-packages. In the first two I will focus on deep neurons belonging to the ALS4 cluster and ask; How do these neurons contribute to pain and itch behaviour and do transcriptional changes occur in ALS4 neurons in neuropathic pain? I will then employ a cross-species spatial transcriptomics approach using post-mortem tissue to dissect ALS-centred spinal pain mechanisms.