NPY Induces Stress Resilience via Downregulation ofI_hin Principal Neurons of Rat Basolateral Amygdala

Abstract

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 Y receptors hyperpolarizes BLA principal neurons (PNs) through inhibition of the hyperpolarization-activated, depolarizing H-current, The present studies tested whether NPY treatment induces stress resilience by modulating NPY (10 pmol) was delivered daily for 5 d bilaterally into the BLA to induce resilience; thereafter, the electrophysiological properties of PNs and the expression of in the BLA were characterized. As reported previously, increases in social interaction (SI) times persisted weeks after completion of NPY administration. intracellular recordings showed that repeated intra-BLA NPY injections resulted in hyperpolarization of BLA PNs at 2 weeks (2W) and 4 weeks (4W) after NPY treatment. At 2W, spontaneous IPSC frequencies were increased, whereas at 4W, resting was markedly reduced and accompanied by decreased levels of HCN1 mRNA and protein expression in BLA. Knock-down of HCN1 channels in the BLA with targeted delivery of lentivirus containing HCN1-shRNA increased SI beginning 2W after injection 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 knock-down mimicked the increases in SI and stress resilience observed with NPY, indicating the importance of in stress-related behavior. Resilience 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 that decrease the activity of pyramidal output neurons. One key mechanism is a reduction in levels of the excitatory ion channel HCN1. Moreover, shRNA knock-down of HCN1 expression in BLA recapitulates some of the actions of NPY and causes potent resilience to stress, indicating that this channel may be a possible target for therapy.

Moderate maternal separation mitigates the altered synaptic transmission and neuronal activation in amygdala by chronic stress in adult mice

“…Overexcitation of principal neurons in BLA has been shown to be highly associated with stress-related behavior [23], while decreasing the excitability of amygdala neurons by NPY induces resilience [43]. We here observed that stress inoculation attenuated CSDS-induced increase of intrinsic excitability in BLA PNs in the present study.…”

A Possible Link Between HCN Channels and Depression

“…In a recent report, a single or multiple injections of neuropeptide Y (NPY) into basolateral amygdala produced resilience to stress in rats through a reduction of functional I h . 28 Importantly, we also found that a reduction of I h in dorsal CA1 region before the CUS-induced onset of depression is sufficient to provide resilient effects to CUS (Figure 2). Before onset of CUS-induced depression, a reduction of functional I h in dorsal CA1 region/neurons led to (1) changes in intrinsic membrane properties, (2) an increase in neuronal excitability, (3) an enhancement of the BDNF-mTOR signaling pathways, (4) an increase in field excitatory postsynaptic potentials, and (5) an increase in dorsal hippocampal activity 9 (Figure 2).…”

Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of Ih current in VTA dopaminergic neurons

“…Thus, for instance, I h current appeared increased in VTA DA neurons of resilient rodents subject to adult stress protocol ( Friedman et al, 2014 ), but was reduced in animals subjected to chronic mild stress ( Zhong et al, 2018 ). Further, I h was found to be down-regulated in the principal neurons of the basolateral amygdala of stress-resilient rats ( Villarroel et al, 2018 ) and in the dorsal CA1 region, where its reduction was sufficient to provide resilience to chronic unpredictable stress in rats ( Kim and Johnson, 2018 ). We add to this scenario by reporting for the first time that the I h current of DA neurons in the iVTA of resilient female mice exposed to early life adversity is significantly reduced.…”