Can we manipulate memory to treat addiction?
Manipulating memory via optogenetics mitigated addiction-related behaviors... sounds like a complex, labyrinthian and highly controversial topic. But this is precisely the route I believe - as a neuroscientist in the making - we should be focusing our future research on. Why manipulate and twist brain functionality and form with drugs when we can use the body we already have, after all?
Starting with some statistics, in the United States alone, over 14 million adults suffer from alcohol addiction, which is otherwise referred to as an alcohol usage disorder - or AUD for short.
For the individuals who dane to explore the realm of recovery and seek active help and engage with present treatment resources, 90% will experience at least one relapse within the first four years.
One highly profound reason for this is that alcohol withdrawal directly impacts the brain’s stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors - thus why addiction of any format is so very difficult to shake off.
However, consider the possibility of more research being conducted on on how the human memory map works, and how we could potentially hijack it to treat disorders of the brain.
Recently, some ongoing studies have been examining whether the effects of alcohol addiction in the brain could be modified through memory manipulation. To do this, researchers primarily study alcohol exposure and withdrawal in mice to see if they were able to affect their responses to traumatic experiences.
Using optogenetics, a technique that uses light and genetic engineering to control the cells of the brain, the researchers were able to artificially dampen fear responses in mice and mitigate addiction-related behaviors.
How exactly did the researchers pull this off and what are the future implications? Read my short Q&A of essential questions below which highlight the motivation behind these studious works, the findings, and what we hope to study next...
1) What happens to a person’s brain when they are addicted to alcohol and go through withdrawal?
When an individual consumes alcohol, the alcohol enters your bloodstream and crosses into your brain where there’s a cascade of effects across many regions.
Alcohol is considered a depressant, meaning it slows down your brain, and various regions and pathways can change and adapt (structurally and functionally) following chronic, heavy drinking.
After a person develops a dependency, going through withdrawal results in a negative affective state, where the individual can experience increased stress and anxiety, likely leading the individual to crave and seek alcohol.
Withdrawal from alcohol tends to increase negative emotions which can compromise the ability to properly process aversive events. In other words, these aversive events can be perceived to be even more negative than usual as a result of withdrawal.
2) What did we aim to study with this research? Alcohol is known to have effects on the brain’s stress and memory systems. Something I am personally interested in is the intersection of memory and addiction research. Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are often researched in isolation, however in the real world the comorbidity of these two disorders is a huge public health concern.
Depending on which populations are taken into account, the comorbidity of AUD and PTSD can range from 30-60%.
For this type of study ckncept, the interest should draw focus on looking at the effects of alcohol exposure and withdrawal on how mice and how they are seemingly able to process and attenuate their responses to a traumatic experience. Moreover, looking to mitigate these effects artificially will enhance the ability to transfer this knowledge to human trials.
The use of animal models, in particular rodents, allow researchers to better understand and dissect not only how the brain functions, but also how it malfunctions.
Exposure therapy is a common clinical approach used to treat stress, memory, and addiction related disorders, where patients are continually exposed to a specific anxiety trigger in a safe, controlled environment.
In research we call this extinction training.
The intention is that continuous exposure will help to overcome stress-related anxieties, and over time the animal will update their fear memories and learn that the context is safe again.
However, in rodent models of alcohol use disorder, studies have shown significant impairments in the ability of an alcohol-withdrawn rodent to attenuate fear memories and behaviors by extinction learning.
The neural circuits that underlie this impairment in rodents likely exist in individuals who struggle with PTSD and AUD.
How do you give a mouse PTSD?
To give mice PTSD, we utilize contextual fear conditioning. To do this, we place a mouse in a small chamber they’ve never seen before.
Mice are naturally inquisitive and will explore novel environments if there is no threat. After giving them a few minutes to explore, the mice receive four mild footshocks about a minute apart.
Mice, when scared, will exhibit an innate fear-response behavior known as “freezing.” Mice tend to stay in the corner of the box, hunched over, and completely still.
Extinction training consists of continually placing the mouse back into this same box, and over time the mouse will freeze less and less as they update their memory and re-learn that the chamber is no longer a threatening place.
3) A walk through of experiments thus far and their corresponding findings...
The mice were first administered to chronicle ethanol to generate an addiction-related state and they began showing abnormally heightened fear responses.
Next, researchers proceeded to find and define the cells involved in processing a fear memory in particular, and genetically engineered those cells to become light-sensitive so that we could optically activate them using optogenetics.
Then, further processes of activating these cells are performed repeatedly in an attempt to artificially dampen the fear responses. The studies ultinately proved that cells can be optogenetically mitigated to these addiction-related behaviors in general.
4) What was the most surprising finding?
The “replication crisis” is a well known issue within academia, especially in psychology and behavioral neuroscience. Or in short; getting the same results twice and more times again to prove validity and accuracy.
The first experiment researchers performed was all about replicating findings in a lab setting, however the extinction paradigm which was used was different from any previous studies already conducted.
In the literature, we have thus far only been able to illustrate extinction paradigms that involved putting the mice in the context once per day, whereas we placed our mice in the chamber two times every day.
Comparing the primary and secondary experiments however, a noticeable “zig-zag” effect with freezing levels was identified- whereby mice froze higher in the morning session than in the afternoon. This illustrates well that PTSD has a memory basis to it and links the what and where of trauma and addiction related activities to the how and the when of a scenario.
Greater prominence of this correlation was identified with the alcohol-exposed mice in Experiment 1, as they froze significantly higher than saline control animals in the morning sessions, but not in the afternoon session.
Further curiosity has been engaged within the neuro community now as to whether it could be possible to alter, shift and record the effects of time of day, reconsolidation (or the “updating” of a memory that can occur once a memory itself is recalled), which would in theory show that the alcohol exposed mice do not necessarily have an extinction-learning impairment, but rather an extinction-recall impairment.
In all of the images above, blue represents all cells, green represents cells that were active and tagged during a fearful experience and red cells are those active when a mouse was recalling the fearful experience
5) What is the significance of these findings?
Optogenetic technology as it stands today is too invasive to be used in humans, however there are some other groups working on developing non-invasive optogenetic tools.
Nonetheless, discoveries made will continue to expand society’s knowledge of neural circuits and in turn, inform future treatments and change how we treat patients with disorders such as PTSD and AUD.
6) What does the neuro community hope to study next?
By establishing whether optogenetics have any true validity, I'd like to witness and potentially be a part of more research that commences analysis of the behavioral effect in mice withdrawn from alcohol - which is presently referred to more "scientificqlly" as: maladaptive “generalization.”
Mice that are fear conditioned in one context should not exhibit fear responses in a novel, safe context. However, mice that have been exposed to and withdrawn from alcohol will generalize their fear memories across novel contexts.
In this new project, I’m looking to better understand the hippocampal dynamics of fear generalization, first by tagging and inhibiting the fear engrams in different contexts, and also by implanting mice with miniature microscopes so that I can view and analyze the cells in awake, behaving, freely moving mice as the mice are exposed to different contexts.