Intrinsic Mechanisms of Stress Resilience in the Basolateral Amygdala
Material below summarizes the article NPY Induces Stress Resilience via Downregulation of Ih in Principal Neurons of Rat Basolateral Amygdala, published on May 9, 2018, in JNeurosci and authored by Heika Silveira Villarroel, Maria Bompolaki, James P. Mackay, Ana Pamela Miranda Tapia, Sheldon D. Michaelson, Randy J. Leitermann, Robert A. Marr, Janice H. Urban, and William F. Colmers.
Stress is a key and inescapable component of life. Our physiology is tuned to accommodate stress, by anticipating and responding reflexively to physical or emotional threats and challenges.
An appropriate stress response maintains homeostasis, the healthy state, and prevents harm to the individual. But responding to stress mobilizes considerable physiological resources. Thus, it is important the stress response is terminated and emotional recalibration is achieved once the threat has gone so life can proceed.
Nonetheless, complementary innate mechanisms allow these stressful experiences to form strong, long-lasting memories, shaping future behaviors and providing an adaptive and situational advantage for survival. So fundamentally, we are made to deal with stress and overcome it.
As efficient as the stress response is, this system has its limits. Unrelenting and/or overwhelming stress often intensifies stress reactivity, resulting in less effective or even maladaptive responses to stress. A pathological result of stress exposure is hyperactivity of the amygdala, the brain region responsible for emotional processing. This phenomenon underlies the etiology of many psychiatric disorders, such as depression, anxiety, post-traumatic stress disorder (PTSD) and phobias.
Fortunately, most people are stress resilient and do not develop such disorders, even if they experience stress similar to the stress levels experienced by stress-vulnerable people who develop stress-related disorders. Resilience imparts an evolutionary advantage in dealing with stress. Understanding the neural and physiological mechanisms underlying resilience may aid in developing ways to help individuals with stress-related disorders.
While we have considerable information about the stress response, the understanding of endogenous systems of resilience has lagged. We do know some of the chemical messengers and brain circuits important for this process.
One endogenous signal that correlates positively with resilience in human populations is neuropeptide Y (NPY). In a recent clinical trial, intra-nasal administration of NPY ameliorated symptoms of anxiety in patients suffering from PTSD. Furthermore, in the basolateral complex of the amygdala (BLA), NPY has consistently been found to promote stress buffering, fear recalibration, and resilience in animal models.
More specifically, we have previously shown acute application of NPY decreases the activity of BLA output neurons by inhibiting the H current, which is important for regulating the baseline activity of these cells. Increased activity in these neurons signals stress to the rest of the brain. NPY thus curtails stress-induced hyperexcitability of BLA neurons in the short term.
But resilience is a long-term state. Therefore, we wanted to learn how NPY could promote lasting pro-resilient behaviors.
We used an established animal model of resilience, generated by repeatedly (once daily for five days) injecting NPY into the BLA of male rats. In this model, animals are assessed for resilience in the social interaction test with a similar but unfamiliar partner rat. This behavioral test reflects the emotional state of the animal and thus reflects BLA activity.
It was previously reported NPY-induced resilient animals interact more with their partner rat after stress than do control animals. NPY-treated rats are resilient for up to eight weeks past the end of the peptide injections. Not coincidentally, decreased sociability is associated with stress-related mental illnesses, which supports the notion that a pro-resilient behavior is measured in this model.
Our recent experiments were designed to examine long-lasting cellular and molecular changes in BLA neurons that correlate with the development of resilient behavior in the model of NPY-induced resilience.
Based on our earlier findings that the H current was important for the actions of NPY in the BLA, we assayed H currents in BLA neurons in brain slices from NPY- and vehicle-treated animals at different times after injection and measured the expression of the HCN1 (hyperpolarization-activated, cyclic nucleotide-gated subunit 1) channels that carry the H current.
Consistent with the short-term actions of NPY, there were significant reductions in the H current and in HCN1 expression (messenger RNA and protein) relative to vehicle-treated animals. This suggested a straightforward link between NPY treatment and HCN1 levels in BLA neurons.
Can this loss of neuronal HCN1 explain the behavioral phenotype of NPY-induced resilience? To test this, we reduced HCN1 expression specifically within the BLA, using a knockdown strategy.
Consistent with our hypothesis, knockdown of HCN1 within the BLA increased social interaction and promoted stress resilience like repeated NPY treatment did.
These findings offer enticing new avenues to possible treatments for stress-related psychiatric disorders. Indeed, there are already small molecule blockers of HCN1, although they are not specific enough to use as medicines.
From our work, we have identified HCN1 channels to be physiologically relevant for emotional homeostasis and stress resilience. Their activity can be modified by the endogenous pro-resilient agent, NPY, to control amygdala activity.
Importantly, the stress hormone corticotrophin releasing factor (CRF) increases the activity of the H-current, exciting the same neurons NPY inhibits. By reducing HCN1 expression in BLA neurons, repeated NPY treatment also impairs activation of these cells by CRF, an additional pro-resilient action.
As mentioned above, we already know a great deal about stress. However, this unique model of NPY-induced resilience has allowed us to identify novel cellular mechanisms underlying an endogenous system that normally helps terminate stress responses and enhance resilience.
Understanding this and perhaps other innate mechanisms that promote the establishment and maintenance of resilience over stress vulnerability, may help lead to the treatment or prevention of stress-related psychiatric illnesses.
NPY Induces Stress Resilience via Downregulation of Ih in Principal Neurons of Rat Basolateral Amygdala. Heika Silveira Villarroel, Maria Bompolaki, James P. Mackay, Ana Pamela Miranda Tapia, Sheldon D. Michaelson, Randy J. Leitermann, Robert A. Marr, Janice H. Urban, William F. Colmers. JNeurosci May 2018, 38 (19) 4505-4520; DOI: https://doi.org/10.1523/JNEUROSCI.3528-17.2018