February 03, 2017

Meet Jonathan Fadok

Jonathan Fadok is a postdoctoral fellow in Andreas Lüthi’s group studying the neuronal networks that control fear responses. Recently, he published the results of an elaborate study that identified two types of neurons in the amygdala, each of which generates a distinct fear response – freezing or flight.

Q: You analyzed in your project how we generate a distinct fear response, either freezing or flight. What’s your fascination with fear?
Jonathan Fadok: I focus on studying behaviors related to fear and anxiety for a number of reasons. First and foremost, the lifetime prevalence of anxiety disorders is greater than 28% (at least in the U.S. – probably going to rise in the next few years) making it imperative that we understand more at the ground level about how various stimuli activate these states. Secondly, there is remarkable homology between humans and non-human animals in the types of physiological/autonomic (changes in heart rate, blood flow, and hormones, for example) and behavioral (freezing, flight, fight) reactions to threatening stimuli which provides some validity to the study of fear and anxiety-like behavior in rodents. Another nice aspect of studying fear is that the behavioral reaction to threatening stimuli is robust and relatively easy to quantify. In addition, one can use simple learning paradigms to study the mechanisms related to how neutral stimuli and contexts become associated with aversive outcomes. Overall, the study of innate and learned fear is fascinating to me because it provides insights into how learning and memory processes work, it provides vital information about how the brain generates behavior, and it can hopefully lead us toward a better understanding of the underlying mechanisms leading to anxiety disorders such as post-traumatic stress disorder, panic, and specific phobia.

Q: You studied the fear response in mice. Do you think your results can be transferred to human diseases and in what ways?
I wish I could simply say yes, but we are a long way off from that. One fundamental problem is that even though mouse brain circuits and mouse behavior are complex, they pale in comparison to the complexity of the human situation. However, as I mentioned previously, there are remarkable similarities between the fear reactions of humans and mice. Since the brain generates behavior, it is logical to think that the neuronal mechanisms that give rise to these reactions might also be conserved. Indeed, the human amygdala (and other brain areas) is activated by fearful stimuli, and the same holds true for mice. Unfortunately, given important ethical and also methodological constraints, we don’t know if the same detailed circuitry that has been discerned in the mouse is involved in generating human fear. That being said, I believe that once we have a much better understanding of brain-wide fear circuitry in mice, we can perhaps develop better models of dysfunction and in turn think of innovative ways of preventing or reversing maladaptive states.

Q: What are still the biggest obstacles for this transfer?
We simply need to know more, and not just at the level of neuronal circuits. We need collaborative and integrative research efforts that aim to understand the function of the healthy brain and the pathology underlying psychiatric disease related to fear and anxiety. To get at this, we need work at all levels, from molecules to minds. One thing that is promising is the global rise in recent years of large-scale initiatives focused on understanding the brain. These initiatives aim to take advantage of rapid and powerful technological advances by linking together and applying engineering, computational techniques, and biology to neuroscience. My hope is that the money is well spent and we get much closer in the next couple of decades to true translatability.

Q: This has been a very elaborate study. What kept you motivated during these years?
This definitely was a challenging study that required a lot of hard work from everyone involved. What keeps me motivated, and what keeps me awake at night, is the desire to understand how neuronal function gives rise to behavior, and dissecting neuronal circuits down to the underlying mechanisms is part of this. I am always thinking about my hypotheses, what the alternative explanations might be, and what is the best way to answer the questions I am interested in. Beyond my own curiosity, what keeps me motivated to keep going through periods of failure is my family and my colleagues. This might sound cheesy, but it is true. This study required talented help from 10 members of the lab, plus critical support from FMI core facilities, and this paper would not have been possible without them. And finally, Andreas has a singular approach to science, and he has kept me motivated by pushing me to do better and better science.

Q: What was the biggest challenge in this project and what helped you master it?
Within the first couple of years of my project, I had observed what would be the framework of this paper. Then came a long period of minimal results and failed experiments. I was able to persevere, again due to the support of my colleagues, friends, and family, and everything started to come together. Plus, like most academics, I am determined and intent on finding answers, which also helps.

» More about Jon’s work
» More about the interests of Andreas Lüthi’s laboratory

Fadok JP, Krabbe S, Markovic M, Courtin J, Xu C, Massi L, Botta P, Bylund K, Müller C, Kovacevic A, Tovote P, Lüthi A. (2016) A competitive inhibitory circuit for selection of active and passive fear responses. Nature, advance online publication

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