Action Potential

Where Do Your Fears Lie?

This is a guest post in our #NPGsfn11 blog series and posted on behalf of Tara LeGates.

It is something we have all experienced and the memories it produces are some of the strongest and longest-lasting we know. Fear is evolutionarily-conserved and significantly influences behavior in response to danger. However, chronic fear, or fear elicited by non-threatening cues, is maladaptive and the hallmark of several disorders such as anxiety, phobias, and posttramatic stress disorder. Knowledge of the circuitry underlying fear will hopefully assist in the understanding and treatment of these types of disorders.

Andreas Lüthi presented some of his eloquent work dissecting this circuitry in a Special Lecture entitled: Defining the Neuronal Circuitry of Fear. This was a fantastic talk that I’m afraid may be difficult to fully capture in a blog post.

Lüthi’s group used auditory fear conditioning to elicit fear behavior in mice. This is a form of classical conditioning where an auditory stimulus (tone) is paired with footshock, which will elicit fear behavior (freezing). Eventually, providing the tone alone will elicit this fear response. If the tone is continuously presenting with no shock, the fear behavior can be extinguished, considered a separate learning experience. Think about it this way: Let’s say your boss jingles his or her keys. Normally, that’s not very threatening right? Well, now s/he comes into the lab, jingling those keys and yelling indiscriminately. Perhaps this becomes a regular occurrence. Eventually, just the sound of those keys, as s/he approaches the lab, will have you running for the cold room for cover. Classical conditioning.


Using auditory fear conditioning and a variety of genetic and electrophysiological techniques, his lab has examined the role of amygdala circuitry in fear conditioning. The amygdala is considered to be a region of the brain that is ‘front and center’ when it comes to thinking about the neural control of fear. The amygdala is made up of subdivisions, including the lateral nucleus (LA), basal nucleus (BA) and the central nucleus, which can be further divided into medial (CEm) and lateral (CEl). Each nucleus has been associated with different aspects of receiving and processing information in fear learning and memory. In an oversimplified view, the LA is thought to receive sensory input, which in turn projects to the central nucleus. The CEm is thought to be the source of output to regions like the brainstem and hypothalamus, controlling the physiological response to fear.

A section through the central nucleus of the amygdala, stained with antibodies against three markers that distinguish largely non-overlapping populations of neurons. See also Haubensak et al. (2010). Photo credit: Prabhat Kunwar, from the David Anderson lab.


Lüthi’s work focused on the ability of the central nucleus to gate conditioned fear behavior. In particular, he showed that increasing activity of CEm (either through optogenetic stimulation or by relieving inhibition from the CEl,) induced freezing behavior (fear). Additionally, his group characterized two separate subpopulations of CEl cells, including how each influences CEm activity, with clever genetic techniques.

He has also focused on context-dependent modulation of fear. Briefly, a mouse learns to be fearful in one context (A,) but the fear association is extinguished in a different context (B.) If the mouse is placed back into context B, the mouse will obviously not exhibit a fear response. However, when the mouse is placed in context A, the original fear association still elicits a response. In the basal amygdala, Lüthi and colleagues found one set of neurons exhibiting increased activity after fear conditioning, but reduced firing after extinction (fear neurons.) The other set exhibited increased firing after extinction (extinction neurons). The opposing firing patterns of each neuronal population beautifully correlated with the observed behavior. These experiments, as well as others that I don’t have time to discuss, have positioned the basal amygdala as a potential “switch” for fear/extinction behavior.

[For more, see Ciocchi, et al.]

There has been a great deal of excellent work that has gone into understanding fear circuitry. It was clear from the lecture that this pathway is incredibly intricate, but also tractable to observation and manipulation, driving us closer to understanding where (in the brain) our fears lie.

Tara LeGates

Ph.D. Candidate, Johns Hopkins University

tlegate1@jhu.edu

Tara received her B.S. from Rider University and is currently a Ph.D. candidate in the Cellular, Molecular, Developmental Biology, and Biophysics Program at Johns Hopkins University. She is hoping to find a postdoc or job after graduating. Please give her a job.

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