A key unresolved question in neuroscience is how different cell types and their activity patterns contribute to sensory processing in the central nervous system. Anatomical and physiological measurements indicate that computations underlying somatosensation are initiated in the dorsal horn of the spinal cord. Genetic, electrophysiological, and circuit-tracing methods have identified a number of neuronal populations involved in this process, as well as their potential contributions. Likewise, histologic, pharmacologic, and genetic studies have revealed important roles for glial cells in the pathogenesis and resolution of aberrant sensations. However, despite these advances, little is known about the dynamic neuronal and glial activity patterns, or the interactions between them, that underlie the moment-to-moment processing of innocuous and noxious stimuli. The recent development of novel two-photon and miniaturized one-photon imaging approaches has enabled stable measurement of cellular calcium excitation in the spinal dorsal horn of behaving animals. These technologies have provided the first insights into how sensory information from mechanoreceptors and nociceptors in the skin activates dorsal horn neurons and astrocytes. Using cutting-edge imaging, optogenetic, and pharmacological approaches, the objective of this proposal is to define how the activity patterns of different types of dorsal horn neurons shape astrocyte calcium excitation, and how astrocyte excitation influences neuronal spiking under physiological and pathophysiological conditions. The rationale for the proposed research is that by uncovering the bi-directional relationship between neuron and astrocyte activity in the spinal dorsal horn, new strategies for pain relief may be developed.
Three specific aims will be pursued: 1) Determine how sensory evoked activity patterns in molecularly defined neurons relate to astrocyte calcium excitation in the spinal dorsal horn of behaving animals; 2) Determine how aberrant neuronal activity patterns in preclinical models of pain relate to astrocyte calcium excitation in the spinal dorsal horn of behaving animals; and 3) Determine how targeted manipulation of astrocyte calcium excitation controls aberrant neuronal activity patterns in the spinal dorsal horn of behaving animals. In summary, this work will reveal how molecularly defined neurons encode different sensory stimuli and how their activity patterns relate to astrocyte calcium excitation. These efforts will also reveal how normal activity patterns are altered in two animal models of pain and how pharmacologic and non-pharmacologic interventions targeting astrocytes affect aberrant neuronal activity and sensory processing.
Experiments proposed here will produce a dynamic picture of the interactions between cell types in the spinal cord as animals are exposed to different kinds of somatosensory stimuli?ranging from normal to painful. These efforts will deepen our understanding of the cellular basis of sensory processing and provide new targets for treating painful conditions.
