Differential expression and function of excitatory glutamate receptors across spinal cord anatomy, development, sex, and species

点击翻译按钮获取中文摘要

The dorsal horn of the spinal cord is an essential component of the pain transmission pathway. Neurons in the outer layers of the dorsal horn receive incoming sensory information from the periphery, including pain-producing stimuli, and combine these signals with descending modulation from the brain. After combining and integrating these inputs, output neurons from the dorsal horn send processed pain signals up to brain pain centers. Changes in excitability within this dorsal horn neuronal network can lead to chronic pain, and yet even the basic electrical properties of these critical pain processing neurons remain incompletely understood. For example, the exact types of glutamate receptors that receive excitatory messages from the periphery and brain have not been explored. Moreover, what is known on excitatory neurotransmission in the dorsal horn is largely based on studies using male rodents. To develop better treatments for pain, foundational knowledge is required on what specific types of receptors shape dorsal horn pain processing across sex and species. To address this large translational gap, we will investigate the expression and function of excitatory glutamate receptors in subpopulations of dorsal horn neurons in both male and female rats as well as in humans. Through a unique collaboration with a neurosurgeon researcher at the Ottawa Hospital, Dr. Eve Tsai, our team is able to collect viable human spinal cord tissue from neurologic determination of death organ donors. Thus, we are one of a handful of labs in the world capable of exploring molecular determinants of pain processing in the human spinal cord. By combining complementary experimental approaches that include electrical recordings, protein staining, and single-cell RNA sequencing, we will systematically investigate how glutamate receptor expression and function changes across dorsal horn anatomy, development, sex and species. This information will shed light on how specific neuron types and signaling mechanisms can drive healthy pain sensation, and how molecular susceptibility to hyperexcitability and chronic pain may diverge between males and females as well as during aging. These discoveries will form the first steps towards identifying which pain-producing molecules are best suited as potential targets for new chronic pain treatments. The training of scientists throughout this research program will provide Canada with highly skilled workers equipped for careers in industrial, academic, health, and government professions. Given the novelty of our human tissue approaches, trainees in the lab will have opportunities to work alongside international research partners that are currently forming a major human tissue pain research consortium. These efforts will therefore increase Canada's competitiveness in a knowledge-based global economy.