The striatum integrates limbic and sensorimotor information to drive goal-directed behaviors. Opioid peptides and their receptors are abundant in the striatum, but a clear role for endogenous opioid signaling in action selection has not been established. This proposal aims to define key components of the striatal circuitry that process limbic information in mice and to understand how opioid peptides alter these circuits in the context of reward-guided behavior. A systematic anatomical and functional analysis of limbic projections to opioid-rich striatal microcircuits will be conducted using genetic tracing methods and ontogenetic tools in brain slices. New photochemical reagents will be employed in combination with ontogenetic to identify opioid-sensitive circuit components and determine how intercompartmental volume transmission shapes the spatiotemporal dynamics of opioid signaling. Genetically-targeted calcium imaging experiments will reveal how these actions translate into changes in network function. To provide evidence for endogenous opioid release in the context of goal-directed behaviors, activity patterns observed during reward-guided tasks will be driven in brain slices ontogenetically while electrophysiological monitoring opioid signaling in brain slices. To identify a functional role, opioid receptors will be blocked during reward-guided behavioral assays using a new photoactivatable antagonist that enables transient inhibition within discrete striatal sub-regions in vivo. To detect the release and spread of endogenous opioids with high sensitivity good spatiotemporal resolution, optical sensors will be developed by chemically modifying receptors so that they report the presence of endogenous agonists. A chemical- genetic strategy for cell-specific pharmacology will be developed to reveal which cellular targets of opioid signaling underlie behavioral responses to opioid peptides and opiate drugs. By targeting native receptors in genetically-identified cells, ths tool provides a powerful means to study opioidergic pathways in the brain. Collectively, these studies will uncover mechanisms by which opioids modulate a neural circuit involved in goal-oriented behavior. By quantifying signaling dynamics in new ways, the role of volume transmission will emerge. Although these novel techniques focus on opioids, the underlying principles are general, and should be applicable to signaling molecules beyond the nervous system. The anticipated findings should facilitate our understanding of disorders in which goal-directed actions are compromised such as Parkinson's and Huntington's diseases as well as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and addiction to substances of abuse.
Opioid peptides, such as endorphins, are naturally occurring neurotransmitters that can provide a reward signal to reinforce activities such as feeding and social interaction, whereas highly addictive opiate drugs hijack this neurochemical system to reward destructive behaviors. This proposal aims to understand how natural opioid peptides alter neural circuits to reward productive behaviors. A complete understanding of the neurochemical mechanisms that underlie behavioral reinforcement will facilitate treatments for ailments such as addiction, drug abuse and obsessive-compulsive disorder.
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