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      Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons

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          Abstract

          Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses in mice, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRP PBN neurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRP PBN neurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar projections elicit assorted unconditioned threat responses including autonomic arousal, anxiety, and freezing behavior, while thalamic and basal forebrain projections generate freezing behavior and, unexpectedly, contribute to associative fear learning. Moreover, the unconditioned responses generated by individual projections are complementary, with simultaneous activation of multiple sites driving profound freezing behavior and bradycardia that are not elicited by any individual projection. This semi-parallel, scalable connectivity schema likely contributes to flexible control of threat responses in unpredictable environments.

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          Most cited references50

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          Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat.

          A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
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            The amygdala: vigilance and emotion

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              Targeting cells with single vectors using multiple-feature Boolean logic.

              Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                28 August 2020
                2020
                : 9
                : e59799
                Affiliations
                [1 ]Department of Biochemistry, University of Washington SeattleUnited States
                [2 ]Howard Hughes Medical Institute, University of Washington SeattleUnited States
                [3 ]Graduate Program in Neuroscience, University of Washington SeattleUnited States
                [4 ]Center for Integrative Brain Research, Seattle Children’s Research Institute SeattleUnited States
                RIKEN Center for Brain Science Japan
                University Medical Center Hamburg-Eppendorf Germany
                RIKEN Center for Brain Science Japan
                RIKEN Center for Brain Science Japan
                Author information
                https://orcid.org/0000-0002-8911-2572
                http://orcid.org/0000-0002-3986-8785
                http://orcid.org/0000-0003-1589-5575
                https://orcid.org/0000-0001-6587-0582
                Article
                59799
                10.7554/eLife.59799
                7556873
                32856589
                d667821a-d282-4b06-ab87-aca9282e4e62
                © 2020, Bowen et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 08 June 2020
                : 28 August 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: T32NS099578
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01-DA24908
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                Parabrachial neurons expressing CGRP relay affective components of ascending pain information via distinct thalamic and amygdalar pathways, which together contribute to complementary aspects of adaptive threat responses.

                Life sciences
                affect,learning,pain,fear,thalamus,parabrachial,mouse
                Life sciences
                affect, learning, pain, fear, thalamus, parabrachial, mouse

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