Control of Fear Extinction

What happens in the brain when we are faced with threat and how does it suppress fear caused by traumatic experiences? A new paper by the groups of Daria Peleg-Raibstein and Denis Burdakov shows the involvement of a specific group of hypothalamic neurons in flexibility expression of fear behavior. Their results were published in the September issue of PNAS.

Anxiety and stress-related disorders, including post-traumatic stress disorder (PTSD), are among the most prevalent and debilitating neuropsychiatric disorders worldwide. These disorders pose an enormous burden on public health, economy and society. Therefore, the understanding of the psychological and neurobiological underlying mechanisms of this disorder is important.  It is important both for studying brain circuits involved in anxiety and fear responses when the threat is present, and those involved in diminishing fear once the threat is gone.

In the past years, research has focused on unravelling the underlying mechanisms involved in inhibiting fear responses after a traumatic event. However, the effectiveness of extinction-based therapies is limited and often PTSD patients experience relapse of fear. Melanin-concentrating hormone (MCH) neurons which are a population of relatively underexplored hypothalamic neurons, were recently implicated in learning and memory.

Here, we characterized fear learning, extinction and fear-relapse in rodents to further our understanding of the neural machinery of fear disorders and advancing their treatments. More specifically, we investigated whether and to which extend MCH neurons are involved in learning processes related to traumatic experience.

MCH neurons are involved in long-term flexibility of fear behavior

We could demonstrate that traumatic event-associated brain signals generated by hypothalamic MCH neurons which were not previously implicated in fear processing are essential for normal extinction of fear behavior. We showed that the brain converts fear-inducing events into MCH neurons’ signals. These brief signals are necessary for healthy long-term flexibility of fear behavior. Without them, a fearful experience leads to abnormal treatment-resistant, relapsing fear reminiscent of PTSD.

These findings demonstrate that traumatic event-associated MCH neuron activity is mandatory for subsequent normal extinction of fear behavior. Given that MCH neurons are present in the human brain, our findings may offer new insight into the pathophysiology of persistent anxiety and impaired extinction in disorders such as PTSD and anxiety disorder.

By: Dr. Daria Peleg-Raibstein and Prof. Denis Burdakov, Department of Health Sciences and Technology, ETH Zurich

Concetti C, Bracey EF, Peleg-Raibstein D, Burdakov D. Control of fear extinction by hypothalamic melanin-concentrating hormone-expressing neurons. Proc Natl Acad Sci U S A. 2020;117(36):22514-22521. Pdf