The EMBO Journal / Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

Stressinduced 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 corticotropinreleasing hormonereleasing 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 signalregulated 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 stressinduced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is ratelimited by CNTF volume transmission and poised to directly convert hypothalamic activation into longlasting cortical excitability following acute stress. Synopsis A multimodal signaling pathway initiated by CRH neurons using aqueductal CNTF volume transmission explains how acute stress is communicated from the hypothalamus to the cerebral cortex. Hypothalamic CRH output gates cortical norepinephrine (NE) signaling upon stress. CRH neurons induce ciliary neurotrophic factor (CNTF) release from ventricular ependyma. CNTF primes NE neurons by volume transmission. CNTF signaling recruits secretagogin to activate tyrosine hydroxylase for NE production. CNTF infusion or driving secretagogin+ NE neuron excitability accentuates stressinduced freezing.(VLID)340657