PROJECT SUMMARY
Chronic pain is a hallmark of many disease conditions, including nerve and spinal cord injury. Current
mainstays of pain management include analgesics and anesthetics, treatments that are used despite their
uncertain efficacy and known side effects. Safer and more productive approaches for pain management are
urgently needed, but knowledge gaps in basic research have hampered the development and translation of
novel treatments. To accelerate this process an improved understanding of the cellular and molecular basis of
pain signaling is required. The spinal cord is a crucial signaling hub involved in communicating pain-related
signals between peripheral organs and the brain. As the first site of sensory integration within the central
nervous system (CNS), it plays essential roles in central sensitization. Much attention has focused on the
neuronal cell types and circuits that contribute to this process. However, considerably less is known about the
contributions of non-neuronal cells, such as astrocytes. While morphological changes in spinal astrocytes in
relation to onset and progression of chronic pain have been well characterized, little is known about their
dynamic activity patterns and how they relate to neuronal spiking or sex-specific immune responses.
Historically, technical challenges have prevented such measurements in preclinical animal models under
naturalistic conditions. The recent development of two-photon and miniaturized one-photon imaging
approaches has enabled real-time measurement of cellular calcium activity in behaving mammals. This has
provided first insights into how sensory information from mechanoreceptors and nociceptors in the skin acutely
activates dorsal horn neurons and astrocytes. Using these cutting-edge imaging approaches in combination
with computational, genetic, and behavioral techniques, the objective of this proposal is to define how astrocyte
calcium activity changes in relation to neuropathic pain onset and progression, how its targeted manipulation
influences neuronal and non-neuronal responses, and how it alters molecular signaling and animal behavior.
The rationale for the proposed research is that by uncovering cellular and molecular mechanisms that
contribute to pain onset or progression, new analgesic interventions can be devised. Three specific aims will
be pursued: 1) Determine how astrocyte calcium excitation relates to neuropathic pain under naturalistic
conditions; 2) Determine how inhibition of astrocyte calcium excitation modulates normal and aberrant sensory
processing, and 3) Determine molecular pathways involved in astrocyte calcium excitation-mediated
modulation of normal and aberrant sensory processing. In summary, this work will uncover how changes in
astrocyte activity contribute to neuropathic pain on molecular, cellular, and behavioral levels. It will extend
current models of how non-neuronal cells contribute to persistent pain specifically and CNS function broadly.