Responding to stress is adaptive for most complex organisms, aiding survival by temporarily mobilizing resources to let the organism better flee or defend itself in response to a perceived threat. Once the threat is ended, the response normally subsides, allowing the organism to pursue other key survival activities. But if the stress response never reverses, or is triggered inappropriately, as with extreme stressors such as trauma, it may lead to psychiatric disorders such as anxiety and PTSD. Some individuals, like Special Forces soldiers, are inherently resilient to most stressors. Such resilient individuals have higher levels of Neuropeptide Y (NPY) in their blood and CSF. Experimental injections of NPY into brain ventricles or into the amygdala of rodents can induce an acute resilience to stress and a prolonged (weeks to months) period of resilience with just a few repeated treatments. Conversely, the stress hormone, Corticotrophin Releasing Factor (CRF), respectively causes acute and prolonged vulnerability to stress when injected acutely or repeatedly into the same brain structures. Activity of projection neurons (PNs) in the basolateral amygdala (BLA) mediates fear and anxiety responses, and reducing PN activity reduces both. Earlier work from the Colmers and Urban laboratories demonstrated opposing actions of NPY and CRF on BLA PN excitability: NPY acutely hyperpolarized these cells, while CRF acutely depolarized them. The mechanism was unusual, in that NPY reduced a membrane ion current, the H-current (Ih), while CRF activated it. Because Ih is hyperpolarization-activated, it is active at the resting potential, so by closing Ih, NPY hyperpolarizes PNs, while CRF opening it depolarizes them. Repeated (5 x daily) injection of NPY causes stress resilience in rats (seen as increased social interaction) persisting longer than 4 weeks. BLA PNs from NPY-treated animals were hyperpolarized at 4W, exhibiting a relative marked loss of Ih and correlating with reductions in mRNA and protein levels for HCN1, the Ih channel subunit in these cells. shRNA knockdown of HCN1 in BLA caused long-term behavioral stress resilience, indicating HCN1s role in behavior. Using a novel organotypic slice culture system of the BLA, we studied mechanisms underlying long-term changes, mimicking the repeated application of NPY and receptor-selective agonists. Briefly, NPY did reduce Ih in these cells,but more prominently reduced the extent of BLA PN dcendrites, while CRF increased them (as is known to happen in vivo both with CRF and stress). Studies in BLA from NPY-treated rats confirmed the reduction in dendritic trees in vivo. The NPY Y5 receptor mediates the long-term changes, and requires calcineurin and the autophagic pathway to do so, while the CRFR1 receptor is involved in the increase, and requires CaMKII. Because the work wasa all done in male rats, ongoing work is determining if the same actions of NPY and CRF occur in female BLA.