Impact of Amygdala Lateralization on Processing and Modulation of Bladder Pain

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PROJECT SUMMARY Urologic chronic pelvic pain syndrome (UCPPS) represents the most common type of chronic visceral pain disorder. Although dysregulation of peripheral inputs from the viscera likely account for a number of the symptoms UCPPS, a failure to understand and treat central nervous system (CNS) changes likely prevents complete recovery for affected patients. The long-term goal of our lab is to understand the extent to which areas in the brain are responsible for the development and maintenance of persistent pain and accompanying affective disturbances that exist within urologic conditions. Recent evidence has suggested that the central amygdala in the CNS may be an important locus for the interaction between visceral pain and anxiety, potentially serving as a driver for chronic conditions like UCPPS. By determining the role of the amygdala in animal models of bladder pain, insight will be provided into the underlying physiology of the human condition. Evidence from human and animal models has shown that the left and right amygdala may differentially regulate pain. Variances in left and right hemisphere activation are well described in human language production, visual processing, and complex planning tasks. Functional lateralization exists in emotional processing areas of the brain, including the amygdala, across multiple taxa where the right brain serves as a reactive center to stress and injury. This conservation suggests that lateralization of limbic circuits is an evolutionarily important phenomenon. The idea that dysregulation in lateralization might also play a significant role in disease is a novel concept with clinical relevance. UCPPS patients show lateralized changes in amygdala gray matter and lateralized amygdala functional connectivity to other areas in the CNS. We recently identified a key molecular mediator through which lateralization of the amygdala modulates bladder pain bi- directionally in mice depending on the side of the brain this neuropeptide is applied. The objective of this proposal is to dissect the impact of this neuropeptide during the transition of acute to persistent bladder pain in a rodent model including exploring the efferent circuits from the amygdala that mediate brain-induced analgesia or hyperalgesia for bladder pain. This objective will be met through three distinct but complementary specific aims. In Aim 1, we will determine the extent to which the development of persistent bladder pain alters left versus right amygdala lateralization. In Aim 2, we will manipulate specific efferent outputs from the amygdala to identify the unique analgesic versus hyperalgesic pathways. In Aim 3, we will incorporate new and existing physiology data to develop a realistic 3-dimensional computational model of the amygdala that can be used to predict laboratory results to progress bladder pain studies and therapies. Overall, this proposal will help determine the extent and mechanisms of amygdala activation during painful bladder stimulation and the mechanisms by which an overactive amygdala may contribute to bladder pain as seen in UCPPS.