Uncovering the role of glycinergic neurons in the periaqueductal grey

Abstract

Chronic pain is a debilitating condition affecting nearly 4 million Australians and 20% of the global population. It is a complex biopsychosocial disorder that significantly impacts quality of life and is often associated with depression, anxiety, and sleep disturbances. Understanding the brain circuits involved in pain signalling is crucial for addressing chronic pain. The midbrain periaqueductal grey (PAG), a key integrator of pain and related behaviours, contains over 100 neuronal subpopulations. Glycine, an inhibitory neurotransmitter, plays an important role in spinal pain signalling, and glycinergic neurons (GlyT2-PAG) are located in the ventrolateral PAG. These neurons have been shown to bidirectionally modulate nociception in naïve states, but their role in other PAG-mediated behaviours and chronic pain was unknown. This thesis aimed to characterise GlyT2-PAG neurons in both naïve and chronic pain states. Chapter 2 presented a scoping review revealing strong evidence for glycinergic involvement in supraspinal pain modulation and other behaviours. Chapter 3 mapped the distribution, projections, and function of GlyT2-PAG neurons using circuit tracing, electrophysiology, and chemogenetics, showing they modulate nociception and affective behaviours such as anxiety and aversion. Chapter 4 examined nociception and anxiety-like behaviours in a CFA-induced inflammatory pain model, informing Chapter 5’s chemogenetic experiments. Findings revealed that GlyT2-PAG neurons shift roles between naïve and chronic pain states, with neuronal activity suggesting engagement of distinct projection regions. Overall, this thesis uncovered the complex role of GlyT2-PAG neurons and identified novel midbrain circuitry for modulating nociception and affective behaviours in both sexes across pain states.