Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

• Alán Alpár ^[1] ; Péter Zahola ^[1] ; János Hanics ^[1] ; Zsófia Hevesi ^[1] ; Solomiia Korchynska ^[2] ; Marco Benevento ^[2] ; Christian Pifl ^[2] ; Gergely Zachar ^[1] ; Jessica Perugini ^[3] ; Ilenia Severi ^[3] ; Patrick Leitgeb ^[2] ; Joanne Bakker ^[5] ; Andras G Miklosi ^[2] ; Evgenii Tretiakov ^[4] ; Erik Keimpema ^[2] ; Gloria Arque ^[2] ; Ramon O Tasan ^[6] ; Günther Sperk ^[6] ; Katarzyna Malenczyk ^[2] ; Zoltán Máté ^[7] ; Ferenc Erdélyi ^[7] ; Gábor Szabó ^[7] ; Gert Lubec ^[8] ; Miklós Palkovits ^[1] ; Antonio Giordano ^[3] ; Tomas GM Hökfelt ^[5] ; Roman A Romanov ^[9] ; Tamas L Horvath ^[10] ; Tibor Harkany ^[2]
  1. [1] Semmelweis University

     Semmelweis University

     Hungría

     
  2. [2] Medical University of Vienna

     Medical University of Vienna

     Innere Stadt, Austria

     
  3. [3] Marche Polytechnic University

     Marche Polytechnic University

     Ancona, Italia

     
  4. [4] Immanuel Kant Baltic Federal University

     Immanuel Kant Baltic Federal University

     Rusia

     
  5. [5] 5 Department of Neuroscience Karolinska Institutet Stockholm Sweden
  6. [6] 7 Department of Pharmacology Medical University Innsbruck Innsbruck Austria
  7. [7] 8 Institute of Experimental Medicine Hungarian Academy of Sciences Budapest Hungary
  8. [8] 9 Paracelsus Medical University Salzburg Austria
  9. [9] 3 Department of Molecular Neurosciences Center for Brain Research Medical University of Vienna Vienna Austria; 6 Immanuel Kant Baltic Federal University Kaliningrad Russia
  10. [10] 11 Program in Integrative Cell Signaling and Neurobiology of Metabolism Departments of Comparative Medicine and Neuroscience Kavli Institute for Neuroscience Yale University School of Medicine New Haven CT USA; 12 Department of Anatomy and Histology University of Veterinary Medicine Budapest Hungary

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 21, 2018, pág. 1
• Idioma: inglés
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  • Stress‐induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin‐releasing hormone‐releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal‐regulated kinase 1 and tyrosine hydroxylase with the Ca2+‐sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress‐induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate‐limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long‐lasting cortical excitability following acute stress.