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What Is the CREB Protein and How Does It Aid in Memory Allocation?

Leonard Kelley holds a bachelor's in physics with a minor in mathematics. He loves the academic world and strives to constantly explore it.

As an educator, I am always fascinated by new frontiers in research that can impact my life. Oftentimes though the gains are by millimeters rather than the miles I wish would happen. Patience is the key to all science, but for me I am driven to understand more about how we work and why. I of course would love to have at least a template for how this is but we currently have many theories that seem to lack any cohesion at all. This article will hopefully lend some light onto at least one tiny aspect of this huge stance: how are memories allocated?

The Basics

The main ideology for memory allocation research arose in 1998 when Alcino Silva (University of California at Los Angeles) visited Yale University. There he heard about Michael Davis’ neuron mapping of specific information in different pieces of the brain with regards to the CREB gene, something that encodes proteins which activate neurons. Silva took this work, which showed that the gene was tied to emotional memories for rats and expanded the work to see how CREB played a role in long term vs. short term memory allocation. It has been shown that as we humans learn, our synapses fire between neurons and grow, with strong ties to CREB at those locations being seen. Davis’ work showed how that level of understanding could be improved upon. For instance, how did memory get hooked to those increased CREB sites in the amygdala? Does CREB lead memory formation and activate the process as well? (Silva 32-3)

Alcino Silva

Alcino Silva

CREB Studies

For his research into these questions, Silva examined the amygdala and the hippocampus with help from his assistant Sheena A. Josselyn with the goal of finding some properties of CREB in a system. They developed a virus that duplicated CREB and introduced it to a rat population. They found upon examination that those rat’s brains had neurons that fired at 4 times the rate and were that many times more likely to store memories than those without the treatment (33).

In 2007, Silva and his team found that emotional memories are not written randomly onto neurons in the amygdala but are correlated to those whose CREB levels are higher than other neurons. It was found that a competition of sorts was held by the neurons, with those whose CREB was higher were found to have a better chance of memory allocation. They followed this up to see if introducing CREB into different neurons would thus cause them to encourage memory storage, and sure enough it did. Their next target was to see if they could select memories to turn off and on and see how CREB worked with the neurons then (Silva 33, Won).

Enter the work of Yu Zhou, who worked with mouse amygdala and developed a version of CREB that had a protein attached to it that allowed the gene to be activated. Yu found that when neurons with higher CREB levels were hit off, the lower level ones were left alone and emotional memories were suppressed, pointing more evidence to CREB being a link to memory storage. Yu followed this up by changing amygdala neurons to make more CREB in the hope of spotting neurons firing at an increased pace. Not only was that found, but the activation grew easier as well. Finally, Yu looked at the synaptic connections between neurons with the elevated CREB levels, something often thought of as key to memory formation. Indeed, the connections with the higher CREB performed better when induced with a current as compared to unaltered ones (Silva 33, Zhou).

Sites of CREB expression in the brain.

Sites of CREB expression in the brain.

Predetermined Routes

Okay, so we have seen much study on emotional memories and CREB so far. Josselyn’s lab found that certain types of memories do indeed have a “predetermined set of amygdala neurons” they are associated with. Specific ion channels lead to better neuron activity for certain memories, and the surface of cells have more receptors for different firings. A similar study by Silva and Josselyn used optogenetics, which uses light to activate neurons. In this case, it was used for the CREB elevated neurons associated with fear, and once activated they could be turned off and on at will (possibly because of those altered channels with the different receptors by lowering the potential needed to activate them), but not those neurons with lower CREB (Silva 33-4, Zhou).

The New Hypothesis

So, we can see from these experiments that CREB is playing a central role with memory and in 2009 Silva developed a theory for it. Memory allocation is CREBs role but it also helps connect separate memories as well, aka the “allocate to link” hypothesis. It involves the idea of sub setting neurons and then stacking them upon one another with the aid of CREB as a link, with memory retrieval activating many neurons at once. As Silva puts it, “When two memories have many of the same neurons, they are formally linked,” therefore causing some neurons which have association with other memories to be activated as well. The main factor as to the strength of this link is time, which decays as the days after the memory are formed. Sometimes the memory is transferred to different neurons so that the present neurons can operate effectively. But how can we test this model? (Silva 34)

Testing it Out

What we require is a temporal way of tracing memories and their locations. Silva’s team along with Denise J. Cai and Justin Shobe develop a test involving mice and rooms. A mouse would be put into two different chambers within a 5-hour span, with a mild shock being applied to them in the second chamber. Later on, when placed back into that chamber, they stop because of the association of pain with the room. But when they were also put into the first chamber, they stopped as well. 7 days later, they were placed back into the first chamber and had no more association, therefore the link had been broken. But how did the neuron activity look? (Ibid)

Equipment obviously exists to see neuron activity as the subject is doing things but its restrictive. But when Silva was at a seminar at UCLA, he heard about Mark Schnitzer (Stanford) and his new microscope that totaled 2-3 grams and fit like a hat onto a mouse. The lens would be near the brain and would be capable of imaging activity given the appropriate conditions. Silva took the idea and built his own, and as for the imaging of the neurons the team engineered the neurons so that they fluoresced based on rising calcium levels in the cells. Rather than focus on the amygdala, they looked at the hippocampus, specifically the A1 region because of its role with incoming and outgoing signals (34-5).

After conducting the experiment, some interesting results came in. After the chamber exposure was conducted, the mice who were placed back 5 hours later had the same neurons fire that did the moment the pain was induced, but after 7 days a different group of neurons fired, retrieving that memory. Those memories were transferred within their own subgroup that was revealed after the memory travelled, supporting the allocate-to-link hypothesis. And the more the memory was activated later on then the more the overlapping neurons activated. Link recall is real (35).

Another test for overlapping neurons in the allocate-to-link hypothesis was developed by Mark Mayford. Called the Tet Tag System, it involves a tetracycline tag, a fluorescent marker that lasts for weeks. Clearly, this would be great for tracking which neurons are firing over a span of time. When the chamber experiment was repeated with this marker technique, the results were the same. The overlap of neurons was higher in the initial 5-hour span than after 7 days, but the link was still there (Ibid).

This field of study is in its infancy, and so treat this article as a primer. Go do more research for the latest developments in what is turning out to be an intriguing field of study. Don’t forget what we have learned here.

Works Cited

Silva, Alcino. “Memory’s Intricate Web.” Scientific American Jul. 2017. Print. 32-6.

Won, Jaejoon and Alcino Silva. “Molecular and cellular mechanism of memory allocation in neuronetworks.” Neurobiology of Learning and Memory 89 (2008) 285-292.

Zhou, Yu et al. “CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala.” Nat. Neurosci 2009 Nov 12.

© 2019 Leonard Kelley

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