Our goal is to generate a predictive model of the spinal cord nociceptive circuits that underlie the initiation of pain perception and behavior. Nociceptive signals are conveyed from the periphery to the spinal cord dorsal horn via highly specialized primary sensory neuron subtypes. These sensory neurons, as well as descending modulatory neurons, form synapses upon an array of morphologically and physiologically distinct classes of dorsal horn interneuron and projection neurons. The ascending output signals from the superficial dorsal horn to the brain are conveyed by neurons of the anterolateral tract (ALT), which project to the thalamus, periaqueductal gray, superior colliculus, lateral parabrachial nucleus, and ventral brainstem. The goal of this project is to define how critical sensory transformations and computations are achieved by these dorsal horn nociceptive circuits and how ALT circuit outputs are conveyed with spatial and contextual precision to recipient brain regions to drive pain and changes in behavior, as well as gain an understanding of the mechanisms responsible for the transition of acute to chronic pain. The premise behind this work is that predictive models of spinal cord nociceptive circuits that underlie the initiation of pain perception and behavior require: 1) defining circuit output neurons and their specific tuning properties; 2) understanding the logic of primary sensory neuron input onto these ALT output neurons; 3) determining the contributions of ALT output neuron classes to reactions to noxious and innocuous stimuli and determining how this changes in disease conditions, and; 4) defining the brain targets of dorsal horn nociceptive circuit output populations. This project will use novel ALT pathway genetic tools in mice to identify, record from, silence and activate specific ALT subpopulations, and physiological, anatomical, and novel, quantitative behavioral approaches to define the pivotal output channels of distinct dorsal horn nociceptive circuits that underlie the perception of pain and its associated affective and behavioral responses. Findings of the proposed work will establish the core logic of dorsal horn nociceptive circuitry to lay a foundation for defining novel therapeutic opportunities for disrupting this circuitry to treat and prevent chronic pain.
There is an urgent need for novel therapeutic approaches to treat chronic pain, however a major hurdle is the lack of detailed understanding of nociceptive circuitry. Our premise is that spinal cord nociceptive circuit outputs to the brain are attractive targets because pain-related signals emanating from a range of nociceptors and other sensory neuron types, descending modulatory inputs, and local interneurons, channel through only a limited number of ascending outputs pathways. Our plan is to use new mouse genetic tools and physiological and behavioral analyses to reveal the properties and functions of dorsal horn nociceptive circuit output pathways to generate a new predictive model of spinal cord nociceptive circuitry as a foundation for developing alternatives to opioids as analgesics.