A parabrachial hub for the prioritization of pain and other survival behaviors - Our long-standing goal is to understand how the brain resolves competing needs to determine optimal survival behavior. In this project we ask the question, can circuits activated in different need states suppress the activity of neurons that signal chronic pain? Thus, the experiments outlined will monitor and manipulate neural circuits that reduce chronic pain during competing need states. We focus on the lateral parabrachial nucleus (lPBN), which integrates ascending nociceptive information from the spinal cord with competing survival information. The activity of lPBN neurons is amplified in multiple injury models and activity of PBN neurons correlates with behavioral measures or responses to inflammatory or neuropathic pain. Our ongoing studies indicate that the lPBN receives a dense innervation from neuropeptide Y (NPY) neurons in the arcuate nucleus (that contributes to hunger, ARC), the subparafascilular nucleus (that contributes to fear, SFP), and the ventral periaqueductal grey (that contribute to thirst, vPAG). We show that hunger, thirst, and fear reduce stimulus-evoked activity of lPBNY1 neurons. Importantly, we find that blocking signaling at Npy1r (Y1) receptors in lPBN prevents the ability of hunger, thirst, and fear to reduce behavioral signs of neuropathic pain. This provides the premise for an overarching conceptual framework that Y1-expressing lPBN neurons (lPBNY1) serve as a hub for the integration of multiple needs states with chronic pain. Our research will define the neural inputs that underlie how internal needs (hunger and thirst) and external threats (fear) evoke the release of NPY (Aim 1A) that reverses the hyper-responsiveness of lPBNY1 neurons to sensory stimulation in mouse models of early inflammatory pain, latent sensitization models of chronic inflammatory pain, and nerve injury models of neuropathic pain (Aim 1B). We will use Y1 receptor pharmacology and mouse genetics to definitively demonstrate the cellular target of NPY in the lPBN (Aim 2) and will determine the functional role of each NPY input from the ARC, SPF, and PAG in mediating pain-response behaviors and negative affect associated with chronic inflammatory and neuropathic pain (Aim 3). These will be the first studies to implement assays of NPY release, microendoscopy lPBNY1 recordings, and conditioned place aversion to explore the neural circuits that determine how multiple needs engage distinct, previously unstudied NPY-expressing neurons to suppress chronic pain. Taken together, our experiments will chart the endogenous neural network that modulates the transmission of pain signals through the brain. Ultimately, these studies will reveal important insights into how the brain ranks and responds to competing survival needs in a dynamic environment.
