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4 Janelia Publications

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    Sternson Lab
    11/02/22 | Characterization of Ultrapotent Chemogenetic Ligands for Research Applications in Nonhuman Primates.
    Raper J, Eldridge MA, Sternson SM, Shim JY, Fomani GP, Richmond BJ, Wichmann T, Galvan A
    ACS Chemical Neuroscience. 2022 Nov 02;13(21):3118-3125. doi: 10.1021/acschemneuro.2c00525

    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 studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus monkeys received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817 (0.064 mg/kg) or uPSEM792 (0.87 mg/kg), and plasma and cerebrospinal fluid samples were collected over 48 h. 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 the 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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    10/22/22 | Multimodal mapping of cell types and projections in the central nucleus of the amygdala
    Yuhan Wang , Sabine Krabbe , Mark Eddison , Fredrick E. Henry , Greg Fleishman , Andrew L. Lemire , Lihua Wang , Wyatt Korff , Paul W. Tillberg , Andreas Lüthi , Scott M. Sternson
    bioRxiv. 2022 Oct 22:. doi: 10.1101/2022.10.19.512845

    The central nucleus of the amygdala (CEA) is a brain region that integrates external and internal sensory information and executes innate and adaptive behaviors through distinct output pathways. Despite its complex functions, the diversity of molecularly defined neuronal types in the CEA and their contributions to major axonal projection targets have not been examined systematically. Here, we performed single-cell RNA-sequencing (scRNA-Seq) to classify molecularly defined cell types in the CEA and identified marker-genes to map the location of these neuronal types using expansion assisted iterative fluorescence in situ hybridization (EASI-FISH). We developed new methods to integrate EASI-FISH with 5-plex retrograde axonal labeling to determine the spatial, morphological, and connectivity properties of ∼30,000 molecularly defined CEA neurons. Our study revealed spatio-molecular organization of the CEA, with medial and lateral CEA associated with distinct cell families. We also found a long-range axon projection network from the CEA, where target regions receive inputs from multiple molecularly defined cell types. Axon collateralization was found primarily among projections to hindbrain targets, which are distinct from forebrain projections. This resource reports marker-gene combinations for molecularly defined cell types and axon-projection types, which will be useful for selective interrogation of these neuronal populations to study their contributions to the diverse functions of the CEA.

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    Sternson Lab
    06/01/22 | Development of an adrenocortical cell model of calcium signaling modulation to decipher the molecular mechanisms responsible for primary aldosteronism
    BakhtaFedlaoui , Teresa Cosentino , Zeina R. Al Sayed , Isabelle Giscos-Douriez , Fabio L. Fernandes-Rosa , Jean-SébastienHulot , Chris Magnus , Scott M. Sternson , Maria Christina Zennaro , Sheerazed Boulkroun
    Archives of Cardiovascular Diseases Supplements. 2022 Jun 01;14(2):160. doi: 10.1016/j.acvdsp.2022.04.153

    Primary aldosteronism (PA) is the most frequent form of secondary hypertension. The identification of germline or somatic mutations in different genes coding for ion channels and defines PA as a channelopathy. These mutations promote activation of calcium signaling, the main trigger for aldosterone biosynthesis.

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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.

    View Publication Page