Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress.

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. © 2018 The Authors.

Citation

Alán Alpár, Péter Zahola, János Hanics, Zsófia Hevesi, Solomiia Korchynska, Marco Benevento, Christian Pifl, Gergely Zachar, Jessica Perugini, Ilenia Severi, Patrick Leitgeb, Joanne Bakker, Andras G Miklosi, Evgenii Tretiakov, Erik Keimpema, Gloria Arque, Ramon O Tasan, Günther Sperk, Katarzyna Malenczyk, Zoltán Máté, Ferenc Erdélyi, Gábor Szabó, Gert Lubec, Miklós Palkovits, Antonio Giordano, Tomas Gm Hökfelt, Roman A Romanov, Tamas L Horvath, Tibor Harkany. Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress. The EMBO journal. 2018 Nov 02;37(21)

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PMID: 30209240

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