Deconstructing the network mechanisms of chronic pain and reward in the amygdala

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Summary Chronic pain is not merely a persistent sensory disorder, but a neurological disease of affective dysfunction that negatively impacts the mental state, professional goals, and personal relationships of over 100 million Americans. Emotionally-guided behaviors, such as avoiding pain and seeking pleasure, are derived from valence information generated by the limbic brain. The ability of valence circuits to categorize external and internal sensory information as either ‘pleasant’ or ‘unpleasant’ is essential for behavior selection, protective learning, and survival. However, miscoding of sensory information due to pathological plasticity within these valence circuits can produce unwanted psychological effects, including the suffering and depression associated with chronic pain. The amygdala is a brain region critical for processing emotional valence and influencing motivational drive. However, the functional relevance of amygdalar valence processing to the generation of hedonic perception and behavior-selection is defined primarily by its output connectivity with effector structures in limbic and cortical regions. Recent evidence proposes the existence of innate and distinct neuronal circuits for opposing positive and negative valence processing in the basolateral nucleus of the amygdala (BLA) that also diverge based on the downstream target structures, such as the nucleus accumbens (NAc). However the network-level interface between these opposing BLA valence circuits has been largely unexplored. Here, I propose to uncover the dynamic interactions of BLA valence circuits to determine their contribution to pain and hedonic affect, both locally within the BLA and at their long-range targets in the NAc. During the mentored K99 phase, my career development and training will be supervised by my co-mentors, Drs. Gregory Scherrer and Mark Schnitzer, with additional support from Drs. Robert Malenka, Sean Mackey, and Brian Kobilka. To investigate the neural network mechanisms driving pain unpleasantness and comorbid anhedonia, I will receive expert training in optogenetic-guided brain slice electrophysiology and time-lapse in vivo Ca2+ imaging in freely behaving mice to uncover the functional interactions of neural ensembles encoding nociceptive and appetitive sensory information throughout the development of chronic pain. During the independent R00 phase, I will determine whether BLA valence circuits that differently innervate the NAc define functionally and anatomically distinct “hedonic zones” within opioidergic circuits. I will further investigate the relevance of these zones to behavior-selection and reinforcement during acute and chronic pain, and during drug use conditions. The advanced training I will receive during this K99/R00 award will lay the foundations for my future research program and NIH grant applications. This award will help me advance my own scientific capabilities, and bolster my career as a successful, independent research scientist and mentor. The successful completion of this work will also have important public health benefits as it will guide future efforts on novel analgesic strategies to reduce pain and lessen the need for prescription opioids.