Optogenetics Allow Neuroscientists to Turn Fear Off and On

Manipulating neural circuitry can erase fear-based associations of a memory.

Posted Apr 30, 2015

Pixabay/Free Image
Source: Pixabay/Free Image

Webster's Dictionary defines fear as, "an unpleasant emotion caused by the belief that someone or something is dangerous, likely to cause pain, or a threat." When was the last time you experienced fear? Is there are a person, place, or activity that fills you with fear? How do you cope with your fear? 

As an endurance athlete, I faced many fearful situations such as: swimming an Ironman triathlon leg in the shark infested waters of South Africa, running through Death Valley in 130° F during the Badwater Ultramarathon, and knowing that I had to run non-stop for 24 hours on a treadmill at a busy Manhattan intersection. 

Instead of hiding under the covers or avoiding fearful situations, I learned how to "face the dragon" head-on by using a variety of techniques that I've written about in Psychology Today blog posts like, "5 Neuroscience Based Ways to Clear Your Mind" and "Returning to an Unchanged Place Reveals How You Have Changed." 

Are There People, Places, or Physical Activities that Fill You With Fear? 

I was excited this morning to read about a method that neuroscientists at the Massachusetts Institute of Technology (MIT) have developed for turning off fear-conditioned responses in mice. Their findings open the door for revolutionary methods that humans might use some day to re-wire their minds to negate fear-conditioning and avoidance learning.

The April 2015 study, "A Circuit Mechanism for Differentiating Positive and Negative Associations," was published in the journal Nature.

The MIT neuroscientists used cutting-edge optical-genetic tools to pinpoint the mechanisms of fear-conditioned avoidance and reward-driven behavior which are both critical to the survival of a species. Using "optogenetics" allowed the researchers to manipulate individual neurons projecting to both the "context-storing hippocampus" and the "emotion-storing amygdala." 

Praneeth Namburi, Anna Beyeler, Ph.D., Kay M. Tye, Ph.D., Massachusetts Institute of Technology
Neuronal circuitry of negative (red) and positive (green) associations are often intertwined, 
Source: Praneeth Namburi, Anna Beyeler, Ph.D., Kay M. Tye, Ph.D., Massachusetts Institute of Technology

In an unexpected finding, Kay Tye, PhD and colleagues at MIT found that the crossroads of convergent circuits in the basolateral amygdala, are involved in both fear and reward learning. Initially, they were stumped as to how the amygdala could orchestrate such opposing behaviors—like seeking a reward and avoidance.

The answer to this riddle appears to be that one neural circuit projects to a reward center, the nucleus accumbens, and the other projects to a nearby fear center, the centromedial amygdala, which is the “output station” of the brain’s emotional hub.

Optically stimulating the reward center projection can enhance positive reinforcement and a feeling of safety. On the flip side, stimulating the fear center projection promoted negative reinforcement. Similarly, blocking the fear center projection impaired fear learning and enhanced reward learning.

The neuroscientists found that each circuit projection is composed of separate populations of intertwined neurons. Using fluorescent bead tracers of optogenetics they were able to differentiate which neurons belonged to each circuit.

For this study, mice underwent classic fear or reward conditioning and were trained to either fear a sound paired with a shock or to associate the tone with a sugar reward. The MIT researchers measured the strength of the neural connections in both “fearful” and “safe” environments.

The most striking discovery of this research was that the neuronal connectivity to reward center projections decreased after fear learning and increased with reward learning. Conversely, the connectivity to fear center projections increased with fear learning and decreased after reward learning.

“These converging mechanisms in anatomically intertwined circuits could hold clues to teasing apart how positive and negative emotional associations may influence each other,” Tye concluded in a press release.

Negative Emotions Can Be Replaced by Positive Emotions at a Neurobiological Level

In a similar study by researchers at MIT, Susuma Tonegawa and colleagues were able to transform a negative memory into a positive memory. The August 2014 study, “Bidirectional Switch of the Valence Associated with a Hippocampal Contextual Memory Engram,” was also published in the journal Nature.

In a press release, Tonegawa says, "There is some evidence from pyschotherapy that positive memory can suppress memories of negative experience. We have shown how the emotional valence of memories can be switched on the cellular level."

The ecstatic and traumatic episodes of your life are stored in specific neural networks called an engram as unique memories in your brain. Do you have any symptoms of post-traumatic stress disorder linked to a fear-conditioned response? 

Back in the days when Manhattan still had some rough neighborhoods, I was jumped by three guys who beat me up one night as I was walking home to my apartment in the East Village. The event left deeply seeded fear conditioning that would cause my palms to sweat and heart to race any time I got within a few blocks of the crime. It took me months to be able to walk home along the same route where I had been beaten up. 

On the flip side, encoding a specific location as being safe, secure and feeling like home can create that reality. As an athlete, I was able to create positive associations regardless of the reality of the situation and mastered the psychologcal finesse needed to negate any fear-conditioning I might associate with facing tempests out on a race course. 

Since I sort of consider myself a human lab rat, it's fun to read Tonegawa describe how this type of contextual information is recorded in the brain's hippocampus, whereas the emotional component of the memory is stored separately, in the amygdala. As he explains it, "The amygdala can store information with either a positive or negative valence, and associate it with a memory." 

Tonegawa and his colleagues were curious to see if they could alter a memory that was already strongly associated with an emotion. The million dollar question was, "Once an animal had developed fear of a place, could the memory of that place be made pleasurable instead?"

To find the answer, Tonegawa et al placed mice in a chamber that delivered a mild shock. As the mouse formed of fear-based memory of this dangerous place, they used optogenetics to insert a light-sensitive protein into the cells that stored the information.

By linking the production of the light-sensitive protein with the activation of a gene that is switched on as memories are encoded, they were able to target light-sensitivity to the cells that housed the newly formed memory.

The mice were then removed from the chamber and a few days later, the scientists artificially reactivated the memory by shining a light into the cells holding the memory of the fearful place. As expected, the animals responded by freezing in place, and avoiding further explorations which indicated they were afraid.

Then the scientists set out to overwrite the fear by giving the mice positive associations to the fearful chamber, despite their negative associations tied to the location. So, they placed the mice in a new environment, but instead of a shock they had the opportunity to interact with female mice which made them feel safe. 

As the mice bonded in a safe environment, the researchers activated their fear memory-storing neurons again using optogenetic light. But this time, they only activated one subset of memory-storing neurons at a time—either those in the hippocampus or those in the amygdala.

When the researchers reactivated the memory-storing cells in the hippocampus while the mice interacted with females, the memory cells in the hippocampus acquired a new positive emotional association. Interestingly, the mice now sought out the environments that had previously been linked to fear.

This is proof positive that negative memories can be rewired using classical conditioning and interweaving positive associations into the neural networks associated with negative environments. 

Conclusion: What are the Human Implications of Optogenetic Research on Mice? 

Tonegawa emphasizes that the success the MIT researchers have had with switching the emotions of a memory on and off in mice won't translate immediately into human therapies or interventions.

Unfortunately, there isn't any existing technology that can presently manipulate human neurons the way MIT researchers can in mice experiments. However, Tonegawa believes that a better understanding of the neural circuits connecting the hippocampus and the amygdala might lead to the development of better pharmaceuticals and other interventions in the future. 

This video from MIT shows how optogentics allow neuroscientists to control the activity of specific neurons. 

If you'd like to read more on this topic, check out my Psychology Today blog posts:

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