RT Journal Article SR Electronic T1 NPY induces stress resilience via down-regulation of Ih in principal neurons of rat basolateral amygdala JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 3528-17 DO 10.1523/JNEUROSCI.3528-17.2018 A1 Heika Silveira Villarroel A1 Maria Bompolaki A1 James Mackay A1 Ana Pamela Miranda Tapia A1 Sheldon D. Michaelson A1 Randy J. Leitermann A1 Robert A. Marr A1 Janice H. Urban A1 William F. Colmers YR 2018 UL http://www.jneurosci.org/content/early/2018/04/12/JNEUROSCI.3528-17.2018.abstract AB Neuropeptide Y (NPY) expression is tightly linked with the development of stress resilience in rodents and humans. Local NPY injections targeting the basolateral amygdala (BLA) produce long-term behavioral stress resilience in male rats via an unknown mechanism. Previously, we showed that activation of NPY Y1 receptors hyperpolarizes BLA principal neurons (PNs) through inhibition of the hyperpolarization-activated, depolarizing H-current, Ih. The present studies tested whether NPY treatment induces stress resilience by modulating Ih.NPY (10 pmol) was delivered daily for 5 days bilaterally into the BLA to induce resilience; thereafter the electrophysiological properties of PNs and the expression of Ih in the BLA were characterized. As reported previously, increases in social interaction (SI) times persisted weeks after completion of NPY administration. In vitro intracellular recordings showed that repeated intra-BLA NPY injections resulted in hyperpolarization of BLA PNs at 2 (2W) and 4 weeks (4W) post NPY treatment. At 2W, spontaneous IPSC frequencies were increased, while at 4W, resting Ih was markedly reduced and accompanied by decreased levels of HCN1 mRNA and protein expression in BLA. Knockdown of HCN1 channels in the BLA with targeted delivery of lentivirus containing HCN1-shRNA increased social interaction beginning 2W postinjection and induced stress resilience.NPY treatment induced sequential, complementary changes in the inputs to BLA PNs and their postsynaptic properties that reduce excitability, a mechanism that contributes to less anxious behavior. Furthermore, HCN1 knockdown mimicked the increases in SI and stress resilience observed with NPY, indicating the importance of Ih in stress-related behavior.SIGNIFICANCE STATEMENTResilience improves mental health outcomes in response to adverse situations. Neuropeptide Y (NPY) is associated with decreased stress responses and the expression of resilience in rodents and humans. Single or repeated injections of NPY into the basolateral amygdala (BLA) buffer negative behavioral effects of stress and induce resilience in rats, respectively. Here we demonstrate that repeated administration of NPY into the BLA unfolds several cellular mechanisms which decrease activity of pyramidal output neurons. One key mechanism is a reduction in levels of the excitatory ion channel, HCN1; moreover, shRNA knockdown of HCN1 expression in BLA recapitulates some of the actions of NPY and causes potent resilience to stress, indicating this channel may be a possible target for therapy.