Characterization of the neuron-glia communication in somatosensory cortex during neuropathic pain

• Applicant: Dr. Rangel Leal Silva
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519990994

Chronic pain is a common cause of disability, generates high healthcare costs, and profoundly impacts the quality of life of individuals. It leads to long-lasting changes in neuronal activity (neuroplasticity) commonly initiated by inflammation, lesion, or disease in the somatosensory nervous system. Recent studies suggest the involvement of astrocytes in the neuroplasticity associated with the development of chronic pain. However, it remains unclear how astrocytes participate in this process, and whether astrocytes can differentially regulate the function of neuronal sub-types during chronic pain. Our preliminary data suggested that astrocytes in the primary somatosensory (S1) cortex might play a crucial role in inducing chronic pain. We performed Ca2+ imaging using 2-photon microscopy on transgenic mice expressing Ca2+ sensor mGCaMP3 in astrocytes and found that astrocytes develop aberrant Ca2+ kinetics during neuropathic pain. Ca2+ transients in astrocytes are mainly triggered by neurotransmitters and neuromodulators by activating astrocytic G-protein coupled receptors (GPCRs). After analyzing their expression in astrocytes, we found that the highest expressed GPCRs in astrocytes are Gi-coupled receptors (Gi-GPCRs). On selective activation of Gi-GPCRs in the S1 cortical astrocytes using chemogenetics induced long-term mechanical hyperalgesia in mice. Thus, suggesting that activation of cortical astrocytes can induce enduring changes in neuronal circuits involved in pain sensation in the S1 cortex. To further understand the mechanism behind the astrocyte-induced neuroplasticity in the S1 cortex, we propose to study functional and structural changes in the cortical neurocircuits by combining cutting-edge technologies such as in vivo electrophysiology silicon probes, chronic 2-photon microscopy in awake mice, genetically encoded Ca2+ sensors, chemogenetics, and transcriptomics analysis. In summary, our project focuses on identifying and characterizing the changes in different neuronal subtypes induced by astrocytes in the cortex during chronic pain and identifying possible therapeutic targets.

• DFG Programme: Research Grants
• Co-Investigators: Claudio Acuna Goycolea, Ph.D.; Amit Agarwal, Ph.D.; Professor Alexander Groh, Ph.D.