Can negative memories be accurately deleted? Peking University’s research team did this with gene editing.

After discovering that his ex-girlfriend had used advanced instruments to remove the unpleasant memories of two people in her brain, she also decided to wash it. This is the plot of the 2005 Academy Award for Best Original Screenplay for the film “The Eternal Sunshine of a Beautiful Mind.” Now, the technology of deleting memories has moved from film to reality.

On March 18, 2020, local time, A team of Yiming researchers and professors from the Institute of Neuroscience, Peking University, published an online opinion entitled Development of a CRISPR-SaCas9 system for Science Advances A paper on the development of the CRISPR-SaCas9 system for projection and functional-specific gene editing in the projection-and function-specific gene in the rat brain.

Based on CRISPR-Cas9 gene editing, researchers are known to develop a CRISPR-SaCas9 system that enables precise deletion of specific memories in the brains of experimental rats.

Can negative memories be accurately deleted? Peking University's research team did this with gene editing.

Development of the CRISPR-SaCas9 system

Stabilizing the gene of a particular neuron subgroup is challenging, a challenge for researchers and the starting point for this study.

In fact, complex networks of neurons in the mammalian brain are formed by a collection of neurons with different genetic, morphological, and functional characteristics. Even in the same brain region, the assembly of neurons is not uniform in anatomy or function, divided into different subgroups, which is a kind of “heterogeneity”.

This heterogeneity requires gene editing of specific neurons — and precise genetic manipulation in specific neuronal subtypes and circuits is essential to determine the relationship between neuronal activity and behavior.

However, in neuronsubs with specific connectivity or functional characteristics, especially in rats and non-human primates, it is not easy to achieve stable gene knock-down (Gene knock-down, which prevents gene expression by degrading mRNA with a homologous sequence target gene) or gene modification.

CrispR-Cas9 gene editing technology has found a breakthrough for researchers.

CRISPR-Cas9 gene editing technology, in layman’s way, is to “modify” the wrong site gene in the genome to restore normal functioning to human cells. The technique is a game-changer in the field of biosciences, where a specially programmed enzyme called Cas9 discovers, removes, and replaces specific parts of DNA.

In fact, the CRISPR-Cas9 gene editing technique is known as the “gene magic scissors” and it is thought that gene editing is to modify genes with the gene scissors that come with a “navigator”.

However, the limited capacity of viral vectors is an obstacle to the application of CRISPR-Cas9 in the nervous system.

In fact, one of the most commonly used viral vectors is adeno-related viruses (AAV, adeno-associated virus), a type of single-stranded DNA-defective virus. The Cas9 ortholog from Staphylococcus aureus (SaCas9), by contrast, is more than 1 kb shorter edits the genome with an efficiency similar to SpCas9

The high versatile nucleic acid endoenzyme Cas9 (SpCas9) from purulent streptococcus is limited by the capacity of the AAV delivery carrier (usually less than 4.4-4.7kb) and inefficient packaging. In contrast, the Cas9 direct congener SaCas9 delivery vector from Staphylococcus aureus has a capacity of more than 1kb smaller than SpCas9, but the efficiency of gene editing is not significant.

Combining these factors, the team proposed a CRISPR-SaCas9 system, based on CRISPR-Cas9 technology, combining smooth/retrograde AAV vector and cell marker technology.

Accurately delete rat-specific memories

Experiments show that this system achieves projection and functional specific gene editing in the rat brain.

Specifically, the team first induced the rat’s fear of memory of two different laboratory boxes, and then, using the CRISPR-SaCas9 system, accurately deleted the rat’s memory of one of the boxes, while the rat’s memory of the other box remained intact.

Can negative memories be accurately deleted? Peking University's research team did this with gene editing.

Neuron excitability and memory formation, a transcriptional co-activation factor with the activity of histone acetyl transferase, is cbp (CREB binding protein) in a specific neuron subgroup of the inner frontal cortex.

Based on this, the team targeted cbp and performed gene knock-downs that confirmed the significance of projection and functionalspecific CRISPR-SaCas9 systems in revealing the neurons and circuit bases of memory, which also suggests that the high efficiency and specificity of CRISPR-SaCas9 systems can be widely used in neural loop research.

At the same time, the above process also shows that the system, combined with electrophysiology, behavioral analysis, flow cell fluorescence sorting technology FACS and deep sequencing methods, can provide an important reference for precise genomic interference of brain function under physiological and pathological conditions. One of the authors of the paper, Yi Ming, a researcher at the Cognitive Neuroscience Laboratory at Peking University’s Institute of Neuroscience, said:

Memory coding is important to storage, but forgetting negative memories is just as important. If negative memories are too stubborn, they can sometimes be burdened and even sick. Chronic pain, drug addiction, chronic stress and other diseases, in essence, patients after experiencing pain, drug-related feelings or stress, the production of difficult to clear, long-term existence of “pathological memory.” Therefore, this system may also provide new ideas for the treatment of these diseases.

Delete memory, block and long

Prior to this breakthrough, many scientists had done research on memory editing and deletion.

In previous studies, researchers often considered the following:

Starting from the study of the hippocampus: located between the ceaphin and inner temporal lobes of the brain, the main functions are memory processing storage and spatial information processing. At the beginning of the 20th century, scientists recognized that the hippocampus had a fundamental role in certain memory and learning;

Using optogenetics: Using photonic sins, select and open specific cells of a creature, designed to activate a single neuron in a sober mammal. In the context of studying the brain and memory, the technique is biotechnology that uses light to turn on or off neuronal groups in the brain;

Aim at treating diseases such as depression: patients with depression have a memory preference for negative events, but do not have the corresponding memory ability for positive information. Therefore, the deletion of negative memories will contribute to the treatment of this type of disease.

In fact, there are some specific memory-cancellation methods that have emerged. In May 2019, for example, a team of researchers at Boston University used optogenetics to stimulate specific areas of the experimental rat hippocampus to “eliminate” negative memories; It mimics the way the brain stores and deletes information.

It is not difficult to find, and whether or not the deletion of memories will trigger a new round of ethical discussions, from a technical point of view, there is still a lot of room for development in this field.

So, if the above method one day enters the application stage, will you choose to delete a memory?