Brain stem cells in the dentate gyrus make new memories and help keep old ones

When you sit down to study something new and try to commit it to memory, you find yourself retaining some things, but forgetting others. However, learning new material does not tend to prevent you from recalling older material. How do neurons, the cells that are responsible for neural impulse in the nervous system, do this? How do they form new memories without compromising old ones?

To answer this question, neuroscientists at the RIKEN-MIT Center for Neural Circuit Genetics examined neural stem cells to dissection the function of a specific portion of the brain known to be involved in forming new memories. Their results are remarkable, and will be published in the March 30th issue of the journal, Cell. This study connects the cellular basis of memory formation with the birth of new neurons. This discovery could offer new strategies for drug makers to make new classed of drugs to treat memory disorders.

Specific neurons in region of the brain called the “dentate gyrus” play a peculiar role in memory formation. The dentate gyrus is part of a larger structure called the “hippocampus.” The hippocampus is also part of a complex circuit called the limbic system. The limbic system supports a wide variety of functions that include emotion, long-term memory, behavior, and the sense of smell. There are several brain structures in the limbic system, and they have all had function mapped to them. These structures are shown in the figure below and their functions are as follows:

1. Hippocampus – This is required for long-term memories and maintains cognitive maps for navigation.
2. Fornix – transmits neural signals from the hippocampus to the mammillary bodies and septal nuclei.
3. Mammillary body – these structures are essential for the formation of memories.
4. Septal nuclei provide essential interconnections between various parts of the limbic system.
5. Amygdala – signals the cerebral cortex when complex stimuli are received, such as fear, rewards, or sexual mating behaviors.
6. Parahippocampal gyrus – this plays an important role in spatial memory.
7. Cingulate gyrus – regulates bodily functions like the heart rate, blood pressure and the ability of pay attention to particular things.
8. Dentate gyrus – contributes to new memories.

The hippocampus, and in particular the dentate gyrus is the site of stem cell populations in the brain (see Ming GL and Song H, Neuron 2011 70(4):687-702). This stem cell population has been thought to contribute to the production of new memories. However, one remarkable new find is that decreased neurogenesis in the dentate gyrus leads to depression. To read more about this, see this site here.

In the present study from the RIKEN-MIT group, the ability of the dentate gyrus to form new memories depends on whether or not the neural stem cells in the dentate gyrus are old or young. These findings also suggest that imbalances between young and old neurons in the dentate gyrus and possibly other regions of the brain as well could potentially disrupt the formation of memories during post-traumatic stress disorder (PTSD) and aging. This could also explain the link between depression and poor memory formation in patients with depression.

Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center, and lead author of this study said, “In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging.”

In this study, researchers tested two types of memory processed in mice. The first is called “pattern separation,” which the means by which the brain distinguishes differences between different events that are similar, but different. For example, remembering two pepperoni pizzas that have different tastes would be one such example, since the two pizzas might look similar, but they have very different gustatory outcomes. The second, “pattern completion” remembers detailed content with few clues. For example, when you memorize lines from a play, you can start anywhere in the play if someone only gives you the first few words on one sentence. Alternatively, if we stick with our pizza example, remembering who was with you and what they were wearing when you had that great pizza would be an example of using pattern completion.

The formation of new memories on the basis of pattern separation utilizes differences between experiences. Pattern completion, on the other hand, recalls memories by detecting similarities. In patients with brain injury or specific types of trauma, cannot remember people they encounter every day. Others with PTSD cannot forget horrific events. According the Dr. Tonegawa, “Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients.

It has been largely accepted that pattern completion and pattern separation are the work for separate neural circuits in the brain. Pattern separation has been mapped to the dentate gyrus. The dentate gyrus also is involved in depression, epilepsy and also traumatic brain injury. A second region in the hippocampus called the “CA3 region” was suspected to be involved in pattern completion. However, as is often the case in science, a long-held idea has to be abandoned in the face of new data; the MIT group found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.In the picture below, you can see that the CA3 region is part of the hippocampus (see circled bit in the cross-section).  CA3 stands for “cornu ammonis later 3.”

Pattern separation was assessed in mice that had learned to different, but similar chambers. One of these chambers was safe, but the other was dangerous, since upon entering it the mice received an electric shock in their feet. Since these mice had discriminated between to similar but different chambers, the group tested their pattern completion capabilities. To do this, they gave the mice limited cues to scurry through a maze that they had previously learned. Normal mice were compared with mice that had deficits or either old or new neurons in their dentate gyruses. Interestingly, mice exhibited defects in either pattern completion or separation depending on whether the old or the new neurons were missing.

Study co-author Toshiaki Nakashiba said, “”By studying mice genetically modified to block neuronal communication from old neurons — or by wiping out their adult-born young neurons — we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it. Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”

This remarkable study will almost certainly be the beginning of an entirely new way of looking at depression. Collaborators in this work included researchers from the laboratories of Michael S. Fanselow at the University of California at Los Angeles; and Chris J. McBain at the National Institute of Child Health and Human Development.