ACNP 58th Annual Meeting: Panels, Mini-Panels and Study Groups

<span title="">2019</span> <i title="Springer Science and Business Media LLC"> <a target="_blank" rel="noopener" href="" style="color: black;">Neuropsychopharmacology</a> </i> &nbsp;
Like other neuromodulators, neuropeptides support the brain's ability to remain flexible in dynamic environment. Most neurons synthesize and release neuropeptides in addition to fast transmitters such as glutamate and GABA, yet our understanding of neuropeptide signaling is cursory and many fundamental questions about NP transmission remain: In what behavioral contexts does neuropeptide release occur? What activity patterns and molecular mechanisms govern release? What is the extent of volume
more &raquo; ... ansmission, and how long do peptidergic signals last? To address these questions, we are developing all-optical toolkits that © American College of Neuropsychopharmacology 2019 1234567890();,: directly and precisely measure and manipulate neuropeptide signaling in behaving animals. Recent progress has been made on probes to study interactions between the opioid neuropeptide dynorphin and the kappa opioid receptor, which are implicated in the negative aversive states associated with pain, drug addiction, stress, and depression. Methods: Photoactivatable or "caged" dynorphin derivatives were synthesized and evaluated at heterologously expressed receptors using a functional secreted alkaline phosphatase assay in HEK293 cells and at endogenous opioid receptors using brain slice electrophysiology. In parallel, two analogues were assayed in brain slices using genetically-encoded optical sensors for dynorphin developed by Lin Tian's lab at UC Davis. The kinetics of dynorphin signal activation, duration and spread were characterized in striatum using a combination of photorelease, sensor imaging and electrophysiology. Results: Caged dynorphin variants exhibited up nearly 5,000fold reductions in EC50 at the kappa, mu and delta opioid receptors depending on peptide length and caging site (e.g. at KOR: Dyn-8 = 7 nM, CYD8 = 16 µM, N-MNVOC-D8 = 33 µM, DynA-17 = 4 nM, CYD17 = 152 nM). Both caged Dyn-8 variants yielded robust photoactivation of GIRK currents in brain slices (tau-on: CYD8 = 241 ms, nMNVOC-D8 = 437 ms at 32°C). Bulk fluorescence imaging of Dyn-8 photorelease using KOR-light sensors revealed large, graded fluorescence changes that lasted for several minutes (ΔFmax = 23%, tau-off = 185 sec). Conclusions: The combination of photoactivatable neuropeptides and genetically-encoded optical neuropeptide sensors enable experiments into the spatiotemporal dynamics of neuropeptidergic signaling in the brain. Current caged dynorphin-8 variants exhibit sufficient inactivity to achieve robust, rapid and spatially-resolved receptor activation with light and are compatible with concomitant fluorescence imaging. Efforts toward in vivo application of both technologies are ongoing. Disclosure: Nothing to disclose. Abstract not included. The Influence of Periphery-To-Brain Communication in Alzheimer's Disease Abstract not included. Abstract not included. Activation of the Autophagy/Lysosomal Degradation Pathway Rescues Cognitive and Sensory Deficits in Fragile X Mice Abstract not included. ACNP 58 th Annual Meeting: Panels, Mini-Panels. . .
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="">doi:10.1038/s41386-019-0544-z</a> <a target="_blank" rel="external noopener" href="">pmid:31801977</a> <a target="_blank" rel="external noopener" href="">pmcid:PMC6957922</a> <a target="_blank" rel="external noopener" href="">fatcat:hjyvf7fcpbf2fhxit6rlhsvg2y</a> </span>
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