Corticotropin-releasing factor promotes growth of brain norepinephrine neuronal processes through Rho GTPase regulators of the actin cytoskeleton in rat

Cognitive aspects of the acute stress response are partly mediated through activation of the locus coeruleus (LC)-norepinephrine (NE) system via corticotropin-releasing factor (CRF). Apart from mediating the acute responses to stress, CRF can mediate the long-term impact of stress on the brain through its potent modulation of neuronal morphology. Importantly, the cellular pathways engaged by stress in general, and CRF in particular, in remodeling neuronal structure are poorly understood. Here, we demonstrate that apart from its well-established acute effects on LC neuronal activity, CRF also stimulates growth and arborization of LC neuronal processes. By contrast, urocortin 2 (UCN 2), a related peptide, inhibits outgrowth of such processes. These opposing effects are transduced by a common receptor (CRF(1)) but distinct intracellular signaling pathways. The structural effects of CRF required protein kinase A and mitogen-activated protein kinase, as well as Rac1, a member of the Rho family of GTPases that regulates the actin and microtubule cytoskeleton. By contrast, the effects of UCN II were mediated by the protein kinase C and RhoA pathways. This is the first study to link stress-related substrates to molecular mediators of actin cytoskeletal remodeling in the LC. We propose a model of dynamic LC neuronal plasticity that is reciprocally controlled by CRF and UCN II, eventually determining actin rearrangement by Rho-specific pathways. By regulating the extension of processes into pericoerulear regions where limbic afferents terminate, these peptides may determine the degree to which the LC-NE system is influenced by limbic structures that mediate emotional expression.