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195 Publications

Showing 191-195 of 195 results
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    01/10/21 | A neuropeptidergic circuit gates selective escape behavior of Drosophila larvae.
    Imambocus BN, Zhou F, Formozov A, Wittich A, Tenedini FM, Hu C, Sauter K, Macarenhas Varela E, Herédia F, Casimiro AP, Macedo A, Schlegel P, Yang C, Miguel-Aliaga I, Wiegert JS, Pankratz MJ, Gontijo AM, Cardona A, Soba P
    Current Biology. 2022 Jan 10;32(1):149-63. doi: 10.1016/j.cub.2021.10.069

    Animals display selective escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximizing chances of survival, yet the underlying network mechanisms are so far not fully understood. Using synapse-level reconstruction of the Drosophila larval network paired with physiological and behavioral readouts, we uncovered a circuit that gates selective escape behavior for noxious light through acute and input-specific neuropeptide action. Sensory neurons required for avoidance of noxious light and escape in response to harsh touch, each converge on discrete domains of neuromodulatory hub neurons. We show that acute release of hub neuron-derived insulin-like peptide 7 (Ilp7) and cognate relaxin family receptor (Lgr4) signaling in downstream neurons are required for noxious light avoidance, but not harsh touch responses. Our work highlights a role for compartmentalized circuit organization and neuropeptide release from regulatory hubs, acting as central circuit elements gating escape responses.

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    Sternson Lab
    01/07/22 | Characterization of ultrapotent chemogenetic ligands for research applications in non-human primates
    Jessica Raper , Mark A. G. Eldridge , Scott. M. Sternson , Jalene Y. Shim , Grace P. Fomani , Barry J. Richmond , Thomas Wichmann , Adriana Galvan
    bioRxiv. 2022 Jan 07:. doi: 10.1101/2022.01.06.475241

    Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of “Pharmacologically Selective Actuator Modules” (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent “Pharmacologically Selective Effector Molecules” (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus macaques received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817(0.064 mg/kg) or uPSEM792 (0.87 mg/kg) and plasma and CSF samples were collected over the course of 48 hours. Both compounds exhibited good brain penetrance, relatively slow washout and negligible conversion to potential metabolites - varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

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    01/05/22 | Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus.
    Zhao X, Hsu C, Spruston N
    Neuron. 2022 Jan 05;110(1):96-108.e4. doi: 10.1016/j.neuron.2021.10.003

    To successfully perform goal-directed navigation, animals must know where they are and what they are doing-e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this "where/what" code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on available cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

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    Looger Lab
    01/04/22 | Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands.
    Nichols AL, Blumenfeld Z, Fan C, Luebbert L, Blom AE, Cohen BN, Marvin JS, Borden PM, Kim CH, Muthusamy AK, Shivange AV, Knox HJ, Campello HR, Wang JH, Dougherty DA, Looger LL, Gallagher T, Rees DC, Lester HA
    eLife. 2022 Jan 04;11:. doi: 10.7554/eLife.74648

    Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters ('iDrugSnFRs') for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

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    01/01/22 | ER proteins decipher the tubulin code to regulate organelle distribution.
    Zheng P, Obara CJ, Szczesna E, Nixon-Abell J, Mahalingan KK, Roll-Mecak A, Lippincott-Schwartz J, Blackstone C
    Nature. 2022 Jan 01;601(7891):132-138. doi: 10.1038/s41586-021-04204-9

    Organelles move along differentially modified microtubules to establish and maintain their proper distributions and functions. However, how cells interpret these post-translational microtubule modification codes to selectively regulate organelle positioning remains largely unknown. The endoplasmic reticulum (ER) is an interconnected network of diverse morphologies that extends promiscuously throughout the cytoplasm, forming abundant contacts with other organelles. Dysregulation of endoplasmic reticulum morphology is tightly linked to neurologic disorders and cancer. Here we demonstrate that three membrane-bound endoplasmic reticulum proteins preferentially interact with different microtubule populations, with CLIMP63 binding centrosome microtubules, kinectin (KTN1) binding perinuclear polyglutamylated microtubules, and p180 binding glutamylated microtubules. Knockout of these proteins or manipulation of microtubule populations and glutamylation status results in marked changes in endoplasmic reticulum positioning, leading to similar redistributions of other organelles. During nutrient starvation, cells modulate CLIMP63 protein levels and p180-microtubule binding to bidirectionally move endoplasmic reticulum and lysosomes for proper autophagic responses.

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