While anxiety disorders are the brain disorders with the highest prevalence and constitute a major burden for the society, a considerable number of affected people are still treated insufficiently. Here, we identified two neuropeptide receptors in the mammalian brain that were able to inhibit fear expression and facilitate fear extinction. Targeting these receptors with specific drugs may support cognitive behavioral therapies for human anxiety disorders.
More importantly, we also demonstrate a crucial interaction between food intake and fear, two life-sustaining survival circuits. Our data identifies thus, not only two novel drug targets for treating anxiety-related disorders but also provides a framework for the development of novel therapeutic approaches by linking energy homeostasis to fear-related behavior.
Neuropeptide Y (NPY) is a highly conserved neuropeptide that is specifically expressed in fear-relevant brain areas. We demonstrated that NPY Y2 and Y4 receptors are crucially involved in the processing of fear memories. In particular, the synergistic action of Y1 and Y2 receptors was a novel finding that considerably changed established concepts. We further demonstrated that NPY, by acting on Y2 receptors in the amygdala (a center of emotional processing), promotes fear extinction and generates a long-term suppression of fear, two important preconditions that could support cognitive behavioral therapies in human patients.
Electrophysiological characterizations of Y2 receptor activation in the central amygdala suggests that Y2 receptors inhibit also long-range amygdala output and input neurons and may thus serve as an essential modulator of neuronal fear pathways. Interestingly, we also identified a fear extinction-promoting effect after activation of Y4 receptors. These receptors are targeted not only by NPY but also by peripherally released pancreatic polypeptide and are generally known for their involvement in feeding. Since the NPY system is controlling both, emotional-affective behavior and energy homeostasis, it appears, from an evolutionary point of view, reasonable that fear and feeding circuits are in fact mutually influencing each other to produce an adaptive behavioral response. We investigated this putative interaction of survival circuits for fear and hunger and demonstrated that short-term fasting suppresses fear and promotes the extinction of fear by inhibiting excitability in an amygdala microcircuit.
Thus, modulators of appetite, hunger and food intake may as well serve as potent fear- reducing drug-targets by interacting within distinct microcircuits in the mammalian brain.
These data highlight the importance of integrating peripheral, hormonal signals with survival- dedicated brain circuits to modify and adapt fear-related emotional responses.
