{"doi":"10.1523/jneurosci.1035-18.2018","title":"α<sub>2A</sub>-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity<i>In Vivo</i>","abstract":"<jats:p>Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α<jats:sub>2A</jats:sub>-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α<jats:sub>2A</jats:sub>-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α<jats:sub>2A</jats:sub>-AR is a G<jats:sub>i</jats:sub>-linked GPCR, we assessed the impact of activating the G<jats:sub>i</jats:sub>-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced<jats:italic>Fos</jats:italic>in BNST<jats:italic>Crh</jats:italic>neurons. Further, using<jats:italic>Prkcd</jats:italic>as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of<jats:italic>Prkcd/Crh</jats:italic>in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α<jats:sub>2A</jats:sub>-AR activation suppresses the<jats:italic>in vivo</jats:italic>activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α<jats:sub>2A</jats:sub>-AR agonist guanfacine reduces activity of these cells<jats:italic>in vivo</jats:italic>, and reduces excitatory PBN inputs onto these cells<jats:italic>ex vivo</jats:italic>. Additionally, we uncover a novel sex-dependent coexpression of<jats:italic>Prkcd</jats:italic>with<jats:italic>Crh</jats:italic>in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.</jats:p>","journal":"The Journal of Neuroscience","year":2019,"id":676911,"datarank":0.5837730447165941,"base_score":3.8918202981106265,"endowment":3.8918202981106265,"self_citation_contribution":0.5837730447165941,"citation_network_contribution":0.0,"self_endowment_contribution":0.5837730447165941,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":48087,"name":"Aakash Basu","orcid":"0000-0003-2446-4937","position":1,"is_corresponding":false},{"id":1225393,"name":"Bretton P. Nabit","orcid":"0000-0001-9459-2462","position":2,"is_corresponding":false},{"id":1768620,"name":"Elias Awad","orcid":null,"position":3,"is_corresponding":false},{"id":651297,"name":"Kellie M. Williford","orcid":"0000-0002-7405-6459","position":4,"is_corresponding":false},{"id":548320,"name":"Samuel W. Centanni","orcid":"0000-0002-3941-7677","position":5,"is_corresponding":false},{"id":605815,"name":"Robert T. Matthews","orcid":"0000-0002-1235-3802","position":6,"is_corresponding":false},{"id":320868,"name":"Yuval Silberman","orcid":"0000-0002-4694-4053","position":7,"is_corresponding":false},{"id":318608,"name":"Danny G. Winder","orcid":"0000-0002-6185-4769","position":8,"is_corresponding":false},{"id":651296,"name":"Tracy L. Fetterly","orcid":"0000-0002-8856-4833","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"α<sub>2A</sub>-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity<i>In Vivo</i>","abstract":"<jats:p>Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α<jats:sub>2A</jats:sub>-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α<jats:sub>2A</jats:sub>-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α<jats:sub>2A</jats:sub>-AR is a G<jats:sub>i</jats:sub>-linked GPCR, we assessed the impact of activating the G<jats:sub>i</jats:sub>-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced<jats:italic>Fos</jats:italic>in BNST<jats:italic>Crh</jats:italic>neurons. Further, using<jats:italic>Prkcd</jats:italic>as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of<jats:italic>Prkcd/Crh</jats:italic>in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α<jats:sub>2A</jats:sub>-AR activation suppresses the<jats:italic>in vivo</jats:italic>activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α<jats:sub>2A</jats:sub>-AR agonist guanfacine reduces activity of these cells<jats:italic>in vivo</jats:italic>, and reduces excitatory PBN inputs onto these cells<jats:italic>ex vivo</jats:italic>. Additionally, we uncover a novel sex-dependent coexpression of<jats:italic>Prkcd</jats:italic>with<jats:italic>Crh</jats:italic>in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30478032","pmcid":"PMC6335747","openalex_id":null,"authors":[],"funders":[{"funder_name":"NIAAA NIH HHS","grant_id":"R00 AA022937","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R01 DA042475","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA068485","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"T32 MH064913","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R25 GM062459","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P30 DK020593","title":null},{"funder_name":"NEI NIH HHS","grant_id":"P30 EY008126","title":null},{"funder_name":"NIAAA NIH HHS","grant_id":"R37 AA019455","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM007628","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"U24 DK059637","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"U2C DK059637","title":null},{"funder_name":"NICHD NIH HHS","grant_id":"U54 HD083211","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P30 DK058404","title":null}],"total_grants":13,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"bronze","license":"https://creativecommons.org/licenses/by-nc-sa/4.0/","oa_locations":[{"url":"https://www.jneurosci.org/content/jneuro/39/3/472.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1523/JNEUROSCI.1035-18.2018","host_type":"publisher"}],"fields_of_study":[],"mesh_terms":["Septal Nuclei","Neurons","Animals","Mice, Inbred C57BL","Mice","Norepinephrine","Guanfacine","Corticotropin-Releasing Hormone","Receptors, G-Protein-Coupled","Receptors, Adrenergic, alpha-2","Restraint, Physical","Ovariectomy","Patch-Clamp Techniques","Stress, Psychological","Gene Expression","Genes, fos","Female","Male","Protein Kinase C-delta","Adrenergic alpha-2 Receptor Agonists","Parabrachial Nucleus"],"keywords":["Stress","Norepinephrine","CRF","BNST","Parabrachial"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T03:20:03.095505Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}