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Learning to Forget: Epigenetic Mechanisms and Inherited Phobias

Past experiences can lead to fundamental physiological and psychological changes to how we perceive and react to future events. When we go through a frightening experience we are designed to store such memories so we can recall them when encountering similar scenarios. We are designed to move away from noxious stimuli, avoiding encounters that will be detrimental to our wellbeing, but when we cannot keep such responses at bay, they start interfering with our normal responses.

If one experiences a fearful or painful reaction to a context-specific stimuli, one will try to avoid such context in the future, in order to avoid the behavioural response and to stop one from getting hurt. One such known example from an evolutionary perspective is ophiophobia, or fear of snakes, which has been suggested to be a survival response some of us share, which we have inherited from our ancestors. It makes sense then to have such processes, keeping us at check from perilous adventures, and in turn ensuring our evolution.

As with majority of processes that occur in our brain, fear is a complex process in which varied cellular and structural compartments come together to give rise to our behavioural and physiological responses. Maintaining a balance within our internal processes is key to our ability to normally function. When the balance shifts, such as overexpression of fear responses in the wrong context, it leads to dysfunctional processes and in many instances develops to chronic mood and anxiety disorders. This phenomena is normally observed in people that suffer from post-traumatic stress disorder (PTSD), since they no longer can discriminate which cues are deleterious, showing overactive responses to situations formerly perceived innocuous.

For us not to be paralysed with fear in unnecessary situations, which would be detrimental to our wellbeing and capacity to correctly react, we have opposing mechanisms to discern what may truly be noxious to us and what not. Our capacity to learn and unlearn responses to certain cues, falls within the realm of neural plasticity - our ability to adapt to our environment and adjust our biological parameters so they match the stimuli at hand.

Such cellular processes occuring in our brain are related to epigenetic mechanisms, where chemical tags will be added the DNA within our neurons in the brain areas responsible for the fear-related behavioural responses, aiming to achieve a balanced state between the inducing the learned responses to fear but without overexpressing them in the wrong context. For such a task, unlearning the detrimental responses comes into play.

Learning what may be perceived as a danger to us induces epigenetic modifications, turning on and off certain genes to adjust our response to the scenario. It has been known for some time that specific chemical tags induce fearful response to dangerous stimuli. These tags, namely 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5mhC), appear highly dynamic in neurons compared to other cells, for they respond to learning processes.

It has also been shown in animal studies, that these epigenetic modifications vary between males and females, inducing different processes on how fear will be perceived. In a study in rats by Sase and colleagues, they found that one such epigenetic tag had a specific role in females; repressing fear-induced memories, whereas the activation of such same tag in males did not cause that effect. It seemed easier to attenuate recalling fear-related memories in females due to how the epigenetic tag was positioned and the role it had compared to males, where that same tag did not attenuate recalling such events. This finding sheds light into how a variety of factors could alter how fearful experiences are perceived.

Another important study was carried out by Li and colleagues in a recently published paper in Nature Neuroscience. They discovered the presence of another epigenetic tag not previously known to be involved in fear extinction processes. Fear extinction is the contrary process of forming a fearful memory and conditioning our response to it, it is the opposite pathway of a bidirectional system. Fear extinction relies on gene expression across varied brain regions, particularly from the infralimbic prefrontal cortex (ILPFC). This ensures we have the tools to unlearn what may become a detrimental response if cued in the wrong context.

Exploring how this system functions has allowed scientists to understand better the neural mechanisms that take place in emotional learning and memory and how fear-related memories can be reversed. What the scientists found, is that the epigenetic tag N6-methyl-2’-deoxyadenosine (m6dA) is necessary to activate the needed genes to correctly extinguish fear memories. The researchers investigated this by placing mice in a box in which after a tone was played a mild electric shock was delivered to the mice. This led the mice to associate such tone with the electric shock, causing them to stay still whenever they heard the tone. To allow removing the recently formed fear-related memory, the researchers put the mice in a new box, where the tune was repeatedly on but without its former accompanying electric shock. Straight after this, the mice were put back into the initial box, in which they no longer showed fearful behaviours in response to the tune.

But to explore further the cellular components involved in giving rise to such processes, they examined the DNA from the mice neurons and found that indeed the m6dA tag appeared across large parts of the genome. The tags were highly concentrated at genes for brain-derived neurotrophic factor, which is associated with learning and memory processes. The m6dA tag appeared to increase this gene activity during fear extinction processes. This study sheds light in the importance of not only exploring how the epigenetic tags vary across cellular populations, but also how they vary in context-dependent events, such as removing fear-related memories, reconditioning our learning.

These epigenetic mechanisms are pivotal to understanding how debilitating disorders such as PTSD or anxiety are formed. Coupling our understanding of such mechanisms with more tailored therapies will prove invaluable to bringing the much needed tools to dismantle such systems and stop such disorders from perturbing our normal functioning. Fear-related memories are essential to notice and react dangerous situations, albeit when the system is dysregulated and we no longer can discern what may pose a danger, we become constrained by our inability to normally react. For this reason, grasping all the factors that contribute to enabling fear extinction processes is crucial to developing adequate therapies.

Claudia Ghezzou

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