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.

Skin Cells from Alzheimer’s Disease Were Turned into Cultured Neurons Using iPSC Technology

Scientists from the University of California, San Diego School of Medicine, have created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s, using induced pluripotent stem cells from patients with the neurodegenerative disorder. This experiment provides the ability to study the precise abnormalities present in neurons that cause the pathology of this neurodegenerative disease.

Senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute investigator and director of the UC San Diego Stem Cell Program, noted that the production of highly purified, functional human Alzheimer’s neurons in culture has never been done before. Goldstein said: “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them.”

This experiment represents a new method for studying the causes of Alzheimer’s disease. These living cells provide a tool for developing and testing drugs to treat the disorder. According to Goldstein, “We’re dealing with the human brain. You can’t just do a biopsy on living patients. Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”

Goldstein and colleagues extracted skin cells called fibroblasts from skin tissues from two patients with familial Alzheimer’s disease. They also used fibroblasts from two patients with sporadic Alzheimer’s disease, and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated them into working neurons. These iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and displayed tell-tale indicators of Alzheimer’s disease. Also, they possessed higher-than-normal levels of proteins associated with Alzheimer’s disease.

With cultured neurons from Alzheimer’s patients, scientists can more deeply investigate how Alzheimer’s disease begins and chart the biochemical processes that eventually destroy brain cells and produce degeneration of elemental cognitive functions like memory. Currently, Alzheimer’s research depends heavily upon autopsies performed after the patient has died and the damage has been done. Goldstein added, “The differences between a healthy neuron and an Alzheimer’s neuron are subtle. It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”

Neurons derived from one of the two patients with sporadic Alzheimer’s disease showed biochemical changes possibly linked to the disease. Thus there may be sub-categories of the disorder and, in the future, potential therapies might be targeted to specific groups of Alzheimer’s patients.

Cultured Smooth Muscle Cells are Formed from Stem Cells

Laboratory research needs tissue as a model system. Smooth muscle is found in the urogenital system, circulatory system, digestive system, and respiratory systems of the human body. Various diseases affect smooth muscle and being able to work on cultured smooth muscle would greatly advance the ability of medical researchers to find treatments for smooth muscle disorders.

To address this need, Cambridge University scientists have devised a protocol for generating different types of vascular smooth muscle cells (SMCs) using cells from patients’ skin. This work could lead to new treatments and better screening for cardiovascular disease.

The Cambridge group used embryonic stem cells and reprogrammed skin cells. Skin cells were turned into induced pluripotent skin cells (iPSCs), which were then differentiated into SMCs. They found that they could create all the major vascular smooth muscle cells in high purity using iPSCs. This technique can also be scaled up to produce clinical-grade SMCs.

The scientists created three subtypes of SMCs from these different types of stem cells. They also showed that various SMC subtypes responded differently when exposed to substances that cause vascular diseases. They concluded that differences in the developmental origin play a role in the susceptibility of SMCs to various diseases. Furthermore, the developmental origin of specific SMCs might part some role in determining where and when common vascular diseases such as aortic aneurysms or atherosclerosis originate.

Alan Colman MD, Principle Investigator of the Institute of Medical Biology at Cambridge University, said: “This is a major advance in vascular disease modeling using patient-derived stem cells. The development of methods to make multiple, distinct smooth muscle subtypes provides tools for scientists to model and understand a greater range of vascular diseases in a culture dish than was previously available.”

Mesenchymal stem cells form heart muscle

On August 3rd, 2009, the University of Miami Miller School of Medicine released a press piece that reported the results on a study by Joshua M. Hare, who is the director of the Interdisciplinary Stem Cell Institute at the Miller School. This study examined the ability of mesenchymal stem cells to fix ailing hearts.

Mesenchymal stem cells are found in lots of different places in our bodies. They are found in bone marrow stroma, fat, connective tissue, blood vessels, umbilical cord, and lots of other places too. These cells might come from “perivascular” cells, which are cells that hang around blood vessels. Nevertheless, mesenchymal stem cells have the ability to form bone, cartilage, fat, and muscle. They also have a fascinating capacity to hide from the immune system. They have groups of surface proteins that prevent cells from the immune systems from recognizing them as foreign, and therefore, mesenchymal stem cells from one person can be transferred into an unrelated person without fear of transplantation rejection.

Several experiments have shown that mesenchymal stem cells (MSCs) can differentiate into heart muscle if treated with the right chemicals (S. Tomita, et al., Circulation 1999;100:II-247–II-256; Also see H. Okura, et al., Tissue Eng Part C Methods, 2009). Transplanting MSCs into the hearts of laboratory animals that have had heart attacks can also help the fix the heart (D. Wolf, et al., J Am Soc Echocardiogr 2007;20:512-20). However, there is a raging debate over how MSCs help broken hearts get better.

Even though MSCs can form heart muscle in culture, they seem to do so rather poorly (Y. Zhang, et al., Interact Cardiovasc Thorac Surg. 2009 Dec;9(6):943-6). Also, several studies suggest that once MSCs are transplanted into ailing hearts, they do not differentiate into heart muscle with any efficiency worth bragging about and seem to help the heart by means of the chemicals they produce (Ryota Uemura, et al., Circulation Res 98 (2006): 1414-21).

There are, however, some reasons to suspect that this is not the end of the story. Engineering MSCs with various genes or administering MSCs with certain chemicals can push then to form heart muscle at higher rates (Yigang Wang, et al. Am J Physiol Heart Circ Physiol (nov 6, 2009, doi:10.1152/ajpheart.00765.2009). Also, in particular experiments, MSCs clearly form heart muscle (J. Tang, et al., Eur J Cardiothorac Surg 30 (2006): 353-61).

Clinical studies with MSCs for heart problems have been conducted but the data are limited. Initial studies were very encouraging (S. Chen, et al., Am J Cardiol 94 (2004): 92-5 and S. Chen, et al., J. Invasive Cardiol 18 (2006): 552-6). Now a new study has shown that MSCs not only help people who have had a recent heart attack, but that they turn into heart muscle and other heart tissues.  MSCs can also help form blood vessels and the increase of blood flow to the heart also helps an ailing heart.  This seems to be one of the main ways that bone marrow-based stem cells help hearts after a heart attack.  Therefore MSCs might be one of the best ways to treat bum hearts, but certainly more work needs to be done.

The eyes have it.

Amber Dance at Nature Reports Stem Cells has a very interesting article on the use of stem cell treatments to cure blindness.

Hundreds of people have had limbal stem cell transplants to treat chemical burns or diseases that scar the cornea.  Unfortunately this therapy is not commercially available to date, since acquiring data on the efficacy of such treatments is slow.  However, 60-70% of patients who have these procedures have improved vision.

This therapy is an “adult” stem cell treatment, but treatments for other types of blindness might require a more creative strategy.

Once the light passes through the transparent cornea and is bent by the lens, it hits the retina at the back of the eye.  The retina is composed of an inner neural retina that consists of photoreceptors, bipolar cells and ganglion cells that extend axons to form the optic nerve, and an outer pigmented retina into which the photoreceptors extend.  The pigmented retina secretes growth factors and clean up cell fragments from spent photoreceptor cells.  If the photoreceptors break down, then no reception of light is possible in that portion of the retina, but if the pigmented retina breaks down, then the photoreceptors will also die, since the tissue that maintains them has died.


Age-related macular degeneration is the third-most common cause of blindness in the world, and it results from the death of the photoreceptors in the macula – that part of the retina where the concentration of photoreceptors are the highest and the resolution of the vision is the best.  In animals, scientists have been able to differentiate embryonic stem cells into retinal epithelial cells and transplant them into the retinas.  In rats that tend to suffer from sight degeneration, transplantation of retinal epithelial cells made from embryonic stem cells greatly slows loss of sight (R. Lund, et al., Cloning Stem Cells (2006) 8, 189-199).

Can such a treatment work?  Clinical studies suggest that it can.  In one study where ten patients were treated with fetal retinal cells, none of them experienced rejection (N. Radke, et al., Am. J. Ophthalmol. (2008) 146, 172-182).   The eye, you see, is sealed from the immune system, and there is no need to match tissue types before transplants.  However, injuries to the eye could sensitize the immune system to transplanted tissues, and a possibility might be using induced pluripotent stem cells (iPSCs).  As it turns out, differentiating embryonic stem cells into retinal epithelial cells is rather easy.  Therefore, the use of iPSCs might be quite easy.

There is reason for caution, however, because in animals the transplantation of neural stem cells into animal eyes can cause tumors (S. Arnhold, et al., Invest. Ophthalmol. Vis., (2004), 45, 4251-4255).  However, transplanted retinal epithelial cells made from embryonic stem cells have never formed teratomas.  Therefore, this cell type might not cause tumors at a high rate, and treatments with such cells might actually be feasible.

A recipe for heart cells from amnion

Embryonic stem cells can be made from adult cells. Such cells are called iPSCs or induced embryonic stem cells, and they have all the characteristics of embryonic stem cells made by means of the destruction of embryos.

Lately, scientists have found a way to convert one type of adult cell into another type of adult without going through any embryonic step.

Qi Zhou and his colleagues from the Melton lab at Harvard were able to transform pancreatic enzyme-secreting cells (exocrine cells) into insulin-secreting cells by inserting three transcription factors (Ngn3, also known as Neurog3), Pdx1 and Mafa into the exocrine cells and they reprogrammed themselves into beta-cells (Nature 455, 627–32 (2008)). Also, Yechoor and his colleagues used a similar technique that placed neurogenin into liver cells in a live animal. These animals shows insulin-secreting cells into their livers, which showed that the liver cells had been reprogrammed into beta cells (V. Yechoor et al., Dev. Cell 16, 358–73 (2009)).

This shows that reprogramming is vastly superior and cheaper than making cloned embryos that we subsequently kill and use to make embryonic stem cells. This is the therapeutic way of the future.

Now, Jun Takeuchi and Benoit Bruneau at the Gladstone Institute of Cardiovascular Disease in San Francisco have found that adding cardiac-specific genes to developing mouse embryos can make even some extra-embryonic parts become beating heart cells.  They made the cells from amnion, the thin layer that surrounds the embryo and fetus throughout development.  This is the sac that breaks when we say that a mother’s water breaks.  The amnion is normally medical waste, but can now be used to make heart cells.

See this link for the paper.