From the poignant discomfort of being alone in a dark alley to the dull anguish one can feel towards an uncertain future, fear takes on different flavors. If this emotion comes to us from a basic survival mechanism (to protect oneself from mortal dangers), many psychological disorders related to fear go beyond this initial function: panic attacks, social phobias, post-traumatic stress disorders, to name a few. quote them. These disorders all have in common the emotion of fear and symptoms of reaction to some form of threat.
Technological advances in neuroscience now make it possible to analyze how the brain creates states of fear and defense. Techniques for identifying and manipulating specific brain areas of living organisms have led to the discovery of new brain areas involved in fear-related cognitive processes, as well as the identification of neural-scale mechanisms that govern our "fear memory", i.e. the recall of fear-related events that occurred in the past.
When faced with a threat, our brain promotes defense mechanisms to try to lessen the consequences of the threat and improve the chances of survival. The result is both cognitive and behavioral: it is this combination that we consciously perceive as fear.
When faced with a dangerous situation, such as animals, we have three options: fight, flee, or stand still (to go unnoticed). From an evolutionary perspective, these three responses have different implications. For example, many predators detect their prey by seeing them move – for the species that make up their prey, it makes sense to freeze. This reaction is often observed in rodents, for example. In fact, much of our scientific knowledge about fear and the brain comes from behavioral experiments on animals.
Historically, much research aimed at understanding the brain mechanisms of fear has been done using a procedure called "fear conditioning", or "Pavlov conditioning". As we will see, these conditioning experiments allow us to explore certain mechanisms involved in fear. However, it is essential to understand that there is a distinction between the different components of fear, and how these mechanisms can be studied.
Indeed, in Pavlov's paradigm, a neutral stimulus (a sound for example) and an aversive stimulus (like an electric shock) are repeated. Over time, these neutral and aversive stimuli become associated, so much so that the mere sound can trigger a behavioral response of fear, even in the absence of an electric shock.
This type of conditioning procedure has often been used on rodents, which then freeze in response to sound. Researchers use the characteristics of this immobilization, such as its duration and the delay to the sound, to quantify the behavioral response elicited by the sound.
What this conditioning allows us to study is different from the conscious feeling of fear: when sound occurs, it activates in the brain a learned association between sound and pain and leads to the expression of species-typical defensive responses to face danger. In other words, when researchers study fear conditioning in animals, they are actually assessing defensive responses elicited by a threat, rather than feelings of fear. This component of the defensive response is a cognitive process within the domain of emotions and, as with other emotions, its understanding is primarily through human studies.
Fear itself can be defined as a "conscious emotional experience", or in other words, the awareness that one, oneself, is in danger. Additionally, while fear can be thought of as arising from a response to an external stimulus, anxiety is a more long-lasting phenomenon that occurs in response to vaguer, less imminent threats.
Different brain circuits are involved in fear responses, each for different components.
The amygdala plays a major role in threat perception: it receives sensory input from the thalamus and other sensory regions, allowing it to quickly identify potential threats. Once a threat is detected, the amygdala activates the sympathetic nervous system, which triggers the release of adrenaline and other stress hormones. This leads to a series of physiological responses, such as increased heart rate, rapid breathing and sweating, which help prepare the body for immediate action.
In turn, these physiological responses also contribute to our conscious feelings of fear.
Details of the threat encounter are encoded and stored in the hippocampus, a region of the brain involved in forming and retrieving memories. So when we encounter a similar situation afterwards, the hippocampus retrieves the stored memory and helps us recognize the threat.
The prefrontal cortex, involved in decision making, planning, and problem solving, is responsible for regulating and controlling emotional and behavioral responses. In situations where the threat is not immediate or dangerous, the prefrontal cortex can override the amygdala-initiated fear response, allowing us to remain calm and rational.
Fear conditioning has also been studied in humans, including humans with accidental brain injury. For example, patients with hippocampal damage do not recall being conditioned, but express defensive responses. Indeed, the memory of having been conditioned is a form of explicit memory, which requires the intervention of the hippocampus. On the other hand, the learning of the defensive response is a form of implicit memory, which is based on the joint action of several regions of the brain.
In contrast, damage to the amygdala impairs the ability to acquire a defensive response, but does not affect conscious memory of having been conditioned to do so.
Thus, before the 2000s, studies exploited the presence of lesions to understand which regions are involved in the fear response, and how. But by damaging entire brain regions, the researchers couldn't study the functions of the different types of neurons present in those brain regions, preventing a scale understanding of brain circuitry.
Nowadays, different techniques allow researchers to precisely activate or deactivate specific populations of neurons in a short time, using techniques such as "chemogenetics". This technique uses specially designed proteins located inside neurons in the brains of research animals. When a specific chemical compound is administered, it can specifically turn on or off neurons expressing the specially designed protein – which in our case would be linked to a fear response, for example.
Thus, how we regulate our fear memories is an important aspect of fear response, which researchers have focused on, because turning off these fear memories is crucial for recovery from anxiety or traumatic disorders. Also known as "fear extinction", this form of learning (or unlearning) relies primarily on the prefrontal cortex, which controls emotional and behavioral responses.
In a recent study, our team at the École Normale Supérieure in Paris identified a new brain region connected to the prefrontal cortex, and showed that this connection is involved in the extinction of fear. This is the "fastigial nucleus", part of the cerebellum. The latter is so called because it has a large number of neurons ("little brain" in Latin), and is a recent region of interest in fear research.
The researchers in our team trained mice in a Pavlovian-like fear conditioning task. Normally, after some time without the presence of the electric shock, the mice stop immobilizing when they hear the sound. This indicates the extinction of the association between the sound stimulus and the electric shock, i.e. the fear memory fades. But interestingly, when the researchers inhibited the neurons in the prefrontal cortex that communicate with the fastigial nucleus using chemogenetics, these mice continued to immobilize – longer than normal mice.
This suggests that the manipulated mice were unable to properly extinguish their fear memories, highlighting the importance of this communication between prefrontal cortex and fastigial nucleus in regulating fear memory extinction.
This is just one of many recent studies that take advantage of new technologies available in neuroscience to explore fear and the brain. In fact, putting together the puzzle pieces of the brain circuits underlying the acquisition and expression of defensive behaviors is crucial to gaining a comprehensive view of the complexity of these processes. This will encourage more research into new therapeutic approaches for the treatment of fear-related disorders in humans.
* Ana Margarida Pinto, PhD student, Ecole Normale Supérieure (ENS) – PSL
