Chronic pain is a debilitating condition that affects one in four Americans, and for which there is no consistently effective treatment devoid of deleterious consequence. A hallmark of chronic pain is that sensory input from touch and pressure becomes abnormally amplified, and the spinal cord appears to play a key role in this phenomenon. However, the neural circuits that underlie this amplification are poorly understood, and this gap in knowledge hinders the development of new and safe therapies for the treatment of pain. Sarah Ross, Ph.D., and her laboratory at the University of Pittsburgh, use molecular genetic, electrophysiological, and behavioral studies in mice to understand itch and pain and to characterize pain and itch circuits that have hitherto been largely unstudied. Ross’ approach to gaining insight into the nervous system is compelling because pain and itch, which induce innate spinal reflexes, are likely to be mediated by genetically-encoded circuits that may be tractable for study and which ultimately could yield clues to newer, more effective therapies for pain and itch.
What’s needed, according to Ross, is a deep understanding of the basic wiring and logic of the spinal circuits that mediate pain and itch. Early in her career, Ross developed several tools to allow investigators to ask new questions about pain and itch circuitry. These included a “knock-in” mouse in which a gene for a pain receptor (kappa opioid receptor) was added. Most recently, Ross has made another genetically modified tool which helps her selectively label spinal projection neurons, the neurons that convey information about noxious stimuli from the spinal cord to the brain. These and other tools have allowed Ross and investigators around the world to ask questions about pain and itch that were previously impossible to address.
In a recent advance, Ross in collaboration with H. Richard Koerber, Ph.D., Professor of Neurobiology at Pitt, has developed the first-of-its-kind nerve preparation to study living circuits outside a whole animal. Her system is allowing spinal microcircuits to be delineated with new precision. This unique preparation incorporates several technical advances, including control of sensory input, measurement of the sensory system’s neural response (called nociceptive output), and the manipulation of genetically defined spinal interneurons. Using this system, Ross and her colleagues can now delineate the neuronal microcircuits that mediate the sensory system’s response to harmful stimuli at a level of cellular specificity not achieved to date. Already, it has provided an explanation for a long-observed phenomenon called “wind-up,” wherein the nervous system is thought to be maintained in a persistent state of elevated reactivity, so that most sensory input leads to persistent itching or long-standing pain. (See next page).
Ross’ lab has consistently been funded through NIH grants and private foundations, including the Rita Allen Foundation, Whitehall Foundation, Fight for Sight, and the American Hearing Research Foundation. Throughout her career, publications of her landmark discoveries have garnered many citations (over 7000). As an assistant professor at the university of Pittsburgh, she has continued to publish in top-tier journals such as Neuron, Cell and the Journal of Clinical Investigation. She has attracted and cultivated outstanding talent within her lab, as evidenced by the awards received by her students and post-dos. She has delivered over 30 seminars and talks around the world since arriving at the university in 2011.
Ross received her doctorate in physiology from the University of Michigan in 1995, and she was a Jane Coffin Childs postdoctoral fellow at Harvard Medical School. Ross, who has secondary appointments in Anesthesiology and the Clinical and Translational Science Institute, is a member of the Center for Neuroscience at the University of Pittsburgh and the Center for the Neural Basis of Cognition.
A chief goal of the Ross lab is to investigate the neural circuit basis for “wind-up.” Wind-up was first described 50 years ago as a frequency-dependent increase in the response of spinal neurons upon repeated stimulation of input from sensory neurons, such as those under the skin. Importantly, wind-up is a physiological mechanism that amplifies input from harmful stimuli, and whether it plays a role in pathological pain is a key question that remains unclear. Moreover, while the synaptic mechanisms of wind-up have been studied in detail, the neural circuit basis of this phenomenon has yet to be defined.
To begin to address these issues, the Ross lab has identified populations of spinal interneurons that modulate wind-up (red). In particular, they have identified a population of specific spinal excitatory interneurons (purple) that is sufficient to cause wind-up, as well as a population of specific inhibitory interneurons (green) that is sufficient to block wind-up.
These findings imply that wind-up is not simply a synaptic mechanism, but rather a type of spinal amplification that is mediated by a polysynaptic network involving both excitatory and inhibitory interneurons.
Ross proposes to dissect this polysynaptic spinal circuit, and determine whether the same circuits are engaged in the presence of chronic pain, using the spinal nerve ligation (SNL) model of peripheral neuropathy. Their overarching hypothesis is that 1) wind-up is a mechanism of sensory amplification that is mediated by specific excitatory interneurons and inhibited by another population of specific inhibitory interneurons and that 2) alteration of these spinal microcircuits in the context of nerve injury contributes to persistent itching and hypersensitivity to pain.