(Image caption: Making “scents” of new cells in the brain’s odor-processing area. Adult-born cells travel through the thin rostral migratory stream before settling into the olfactory bulb, the large structure in the upper right of the image. Courtesy of the Belluscio Lab, NINDS)

Scientists sniff out unexpected role for stem cells in the brain

For decades, scientists thought that neurons in the brain were born only during the early development period and could not be replenished. More recently, however, they discovered cells with the ability to divide and turn into new neurons in specific brain regions. The function of these neuroprogenitor cells remains an intense area of research. Scientists at the National Institutes of Health (NIH) report that newly formed brain cells in the mouse olfactory system — the area that processes smells — play a critical role in maintaining proper connections. The results were published in the October 8 issue of the Journal of Neuroscience. 

“This is a surprising new role for brain stem cells and changes the way we view them,” said Leonardo Belluscio, Ph.D., a scientist at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the study.

The olfactory bulb is located in the front of the brain and receives information directly from the nose about odors in the environment. Neurons in the olfactory bulb sort that information and relay the signals to the rest of the brain, at which point we become aware of the smells we are experiencing. Olfactory loss is often an early symptom in a variety of neurological disorders, including Alzheimer’s and Parkinson’s diseases.

In a process known as neurogenesis, adult-born neuroprogenitor cells are generated in the subventricular zone deep in the brain and migrate to the olfactory bulb where they assume their final positions. Once in place, they form connections with existing cells and are incorporated into the circuitry.

Dr. Belluscio, who studies the olfactory system, teamed up with Heather Cameron, Ph.D., a neurogenesis researcher at the NIH’s National Institute of Mental Health, to better understand how the continuous addition of new neurons influences the circuit organization of the olfactory bulb. Using two types of specially engineered mice, they were able to specifically target and eliminate the stem cells that give rise to these new neurons in adults, while leaving other olfactory bulb cells intact. This level of specificity had not been achieved previously.    

In the first set of mouse experiments, Dr. Belluscio’s team first disrupted the organization of olfactory bulb circuits by temporarily plugging a nostril in the animals, to block olfactory sensory information from entering the brain. His lab previously showed that this form of sensory deprivation causes certain projections within the olfactory bulb to dramatically spread out and lose the precise pattern of connections that show under normal conditions. These studies also showed that this widespread disrupted circuitry could re-organize itself and restore its original precision once the sensory deprivation was reversed.

However, in the current study, Dr. Belluscio’s lab reveals that once the nose is unblocked, if new neurons are prevented from forming and entering the olfactory bulb, the circuits remain in disarray. “We found that without the introduction of the new neurons, the system could not recover from its disrupted state,” said Dr. Belluscio.

To further explore this idea, his team also eliminated the formation of adult-born neurons in mice that did not experience sensory deprivation. They found that the olfactory bulb organization began to break down, resembling the pattern seen in animals blocked from receiving sensory information from the nose. And they observed a relationship between the extent of stem cell loss and amount of circuitry disruption, indicating that a greater loss of stem cells led to a larger degree of disorganization in the olfactory bulb.

According to Dr. Belluscio, it is generally assumed that the circuits of the adult brain are quite stable and that introducing new neurons alters the existing circuitry, causing it to re-organize. “However, in this case, the circuitry appears to be inherently unstable requiring a constant supply of new neurons not only to recover its organization following disruption but also to maintain or stabilize its mature structure. It’s actually quite amazing that despite the continuous replacement of cells within this olfactory bulb circuit, under normal circumstances its organization does not change,” he said.

Dr. Belluscio and his colleagues speculate that new neurons in the olfactory bulb may be important to maintain or accommodate the activity-dependent changes in the system, which could help animals adapt to a constantly varying environment.

“It’s very exciting to find that new neurons affect the precise connections between neurons in the olfactory bulb. Because new neurons throughout the brain share many features, it seems likely that neurogenesis in other regions, such as the hippocampus, which is involved in memory, also produce similar changes in connectivity,” said Dr. Cameron.

The underlying basis of the connection between neurological disease and changes in the olfactory system is also unknown but may come from a better understanding of how the sense of smell works. “This is an exciting area of science,” said Dr. Belluscio, “I believe the olfactory system is very sensitive to changes in neural activity and given its connection to other brain regions, it could lend insight into the relationship between olfactory loss and many brain disorders.”

Mechanism that repairs brain after stroke discovered

A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.

The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.

”This is the first time that astrocytes have been shown to have the capacity to start a process that leads to the generation of new nerve cells after a stroke”, says Zaal Kokaia, Professor of Experimental Medical Research at Lund University.

The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells.

”Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells”, says Zaal Kokaia.

“This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage.”

The new nerve cells were found to form specialized contacts with other cells. It remains to be shown whether the nerve cells are functional and to what extent they contribute to the spontaneous recovery that is observed in a majority of experimental animals and patients after a stroke.

A decade ago, Kokaia’s and Lindvall’s research group was the first to show that stroke leads to the formation of new nerve cells from the adult brain’s own neural stem cells. The new findings further underscore that when the adult brain suffers a major blow such as a stroke, it makes a strong effort to repair itself using a variety of mechanisms.

The major advancement with the new study is that it demonstrates for the first time that self-repair in the adult brain involves astrocytes entering a process by which they change their identity to nerve cells.

”One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson’s disease and Huntington’s disease”, says Olle Lindvall, Senior Professor of Neurology.

Dying brain cells cue new brain cells to grow in songbird

Brain cells that multiply to help birds sing their best during breeding season are known to die back naturally later in the year. For the first time researchers have described the series of events that cues new neuron growth each spring, and it all appears to start with a signal from the expiring cells the previous fall that primes the brain to start producing stem cells.

If scientists can further tap into the process and understand how those signals work, it might lead to ways to exploit these signals and encourage replacement of cells in human brains that have lost neurons naturally because of aging, severe depression or Alzheimer’s disease, said Tracy Larson, a University of Washington doctoral student in biology. She’s lead author of a paper in the Sept. 23 Journal of Neuroscience on brain cell birth that follows natural brain cell death.

Neuroscientists have long known that new neurons are generated in the adult brains of many animals, but the birth of new neurons – or neurogenesis – appears to be limited in mammals and humans, especially where new neurons are generated after there’s been a blow to the head, stroke or some other physical loss of brain cells, Larson said. That process, referred to as “regenerative” neurogenesis, has been studied in mammals since the 1990s.

This is the first published study to examine the brain’s ability to replace cells that have been lost naturally, Larson said.

“Many neurodegenerative disorders are not injury-induced,” the co-authors write, “so it is critical to determine if and how reactive neurogenesis occurs under non-injury-induced neurodegenerative conditions.”

The researchers worked with Gambel’s white-crowned sparrows, a medium-sized species 7 inches (18 centimeters) long that breeds in Alaska, then winters in California and Mexico. Sometimes in flocks of more than 100 birds, they can be so plentiful in parts of California that they are considered pests. The ones in this work came from Eastern Washington.

Like most songbirds, Gambel’s white-crowned sparrows experience growth in the area of the brain that controls song output during the breeding season when a superior song helps them attract mates and define their territories. At the end of the season, probably because having extra cells exacts a toll in terms of energy and steroids they require, the cells begin dying naturally and the bird’s song degrades.

Gambel’s white-crowned sparrows are particularly good to work with because their breeding cycle is closely tied to the amount of sunlight they receive. Give them 20 hours of light in the lab, along with the right increase of steroids, and they are ready to breed. Cut the light to eight to 12 hours and taper the steroids, the breeding behavior ends.

“As the hormone levels decrease, the cells in the part of the brain controlling song no longer have the signal to ‘stay alive,’” Larson said. “Those cells undergo programmed cell death – or cell suicide as some call it. As those cells die it is likely they are releasing some kind of signal that somehow gets transmitted to the stem cells that reside in the brain. Whatever that signal is then triggers those cells to divide and replace the loss of the cell that sent the signal to begin with.”

The next spring, all that’s needed is for steroids to ramp up and new cells start to proliferate in the song center of the brain.

“This paper doesn’t describe the exact nature of the signals that stimulate proliferation,” Larson said. “We’re just describing the phenomenon that there is this connection between cells dying and this stem cell proliferation. Finding the signal is the next step.”

“Tracy really nailed this down by going in and blocking cell death at the end of the breeding season,” said Eliot Brenowitz, UW professor of psychology and of biology, and co-author on the paper. “There are chemicals you can use to turn off the cell suicide pathway. When this was done, far fewer stem cells divided. You don’t get that big uptick in new neurons being born. That’s important because it shows there’s something about the cells dying that turns on the replacement process.’

“There’s no reason to think what goes on in a bird brain doesn’t also go on in mammal brains, in human brains,” Brenowitz said. “As far as we know, the molecules are the same, the pathways are the same, the hormones are the same. That’s the ultimate purpose of all this, to identify these molecular mechanisms that will be of use in repairing human brains.”

In mammals, the area of the brain that controls the sense of smell and the one that is thought to have a role in memories can produce tiny numbers of new brain cells but it is not understood how or why. The numbers of new cells is so low that trying to identify and quantify whether dying cells are being replaced and if so, the steps that are involved, is much more difficult than when using a songbird like Gambel’s white-crowned sparrow, Larson and Brenowitz said.

Self-repairing mechanism helps to preserve brain function in neurodegenerative diseases

New research, led by scientists at the University of Southampton, has found that neurogenesis, the self-repairing mechanism of the adult brain, can help to preserve brain function in neurodegenerative diseases such as Alzheimer’s, Prion or Parkinson’s.

The progressive degeneration and death of the brain, occurring in many neurodegenerative diseases, is often seen as an unstoppable and irrevocable process. However, the brain has some self-repairing potential that accounts for the renewal of certain neuronal populations living in the dentate gyrus, a simple cortical region that is part of the larger functional brain system controlling learning and memory, the hippocampus. This process is known as neurogenesis.

While increased neurogenesis has been reported in neurodegenerative diseases in the past, its significance is unclear. Now a research team, led by Dr Diego Gomez-Nicola from the Centre for Biological Sciences at the University of Southampton, has detected increased neurogenesis in the dentate gyrus that partially counteracts neuronal loss.

Using a model of prion disease from mice, the research identified the time-course of the generation of these newborn neurons and how they integrate into the brain circuitry. While this self-repairing mechanism is effective in maintaining some neuronal functions at early and mid-stages of the disease, it fails at more advanced phases. This highlights a temporal window for potential therapeutic intervention, in order to preserve the beneficial effects of enhanced neurogenesis.

Dr Gomez-Nicola says: “This study highlights the latent potential of the brain to orchestrate a self-repairing response. The continuation of this line of research is opening new avenues to identify what specific signals are used to promote this increased neurogenic response, with views focused in targeting neurogenesis as a therapeutic approach to promote the regeneration of lost neurons.”

(Image caption: In this artist’s representation of the adult subependymal neurogenic niche (viewed from underneath the ependyma), electrical signals generated by the ChAT+ neuron give rise to newborn migrating neuroblasts, seen moving over the underside of ependymal cells. Credit: Illustration by O’Reilly Science Art.)

Neuron Tells Stem Cells to Grow New Neurons

Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within.

Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explains Chay Kuo, M.D. Ph.D., an assistant professor of cell biology, neurobiology and pediatrics.

In a study with mice, his team found a previously unknown population of neurons within the subventricular zone (SVZ) neurogenic niche of the adult brain, adjacent to the striatum. These neurons expressed the choline acetyltransferase (ChAT) enzyme, which is required to make the neurotransmitter acetylcholine. With optogenetic tools that allowed the team to tune the firing frequency of these ChAT+ neurons up and down with laser light, they were able to see clear changes in neural stem cell proliferation in the brain.

The findings appeared as an advance online publication June 1 in the journal Nature Neuroscience.

The mature ChAT+ neuron population is just one part of an undescribed neural circuit that apparently talks to stem cells and tells them to increase new neuron production, Kuo said. Researchers don’t know all the parts of the circuit yet, nor the code it’s using, but by controlling ChAT+ neurons’ signals Kuo and his Duke colleagues have established that these neurons are necessary and sufficient to control the production of new neurons from the SVZ niche.

"We have been working to determine how neurogenesis is sustained in the adult brain. It is very unexpected and exciting to uncover this hidden gateway, a neural circuit that can directly instruct the stem cells to make more immature neurons," said Kuo, who is also the George W. Brumley, Jr. M.D. assistant professor of developmental biology and a member of the Duke Institute for Brain Sciences. "It has been this fascinating treasure hunt that appeared to dead-end on multiple occasions!"

Kuo said this project was initiated more than five years ago when lead author Patricia Paez-Gonzalez, a postdoctoral fellow, came across neuronal processes contacting neural stem cells while studying how the SVZ niche was assembled.

The young neurons produced by these signals were destined for the olfactory bulb in rodents, as the mouse has a large amount of its brain devoted to process the sense of smell and needs these new neurons to support learning. But in humans, with a much less impressive olfactory bulb, Kuo said it’s possible new neurons are produced for other brain regions. One such region may be the striatum, which mediates motor and cognitive controls between the cortex and the complex basal ganglia.

"The brain gives up prime real estate around the lateral ventricles for the SVZ niche housing these stem cells," Kuo said. "Is it some kind of factory taking orders?" Postdoctoral fellow Brent Asrican made a key observation that orders from the novel ChAT+ neurons were heard clearly by SVZ stem cells.

Studies of stroke injury in rodents have noted SVZ cells apparently migrating into the neighboring striatum. And just last month in the journal Cell, a Swedish team observed newly made control neurons called interneurons in the human striatum for the first time. They reported that interestingly in Huntington’s disease patients, this area seems to lack the newborn interneurons.

"This is a very important and relevant cell population that is controlling those stem cells," said Sally Temple, director of the Neural Stem Cell Institute of Rensselaer, NY, who was not involved in this research. "It’s really interesting to see how innervations are coming into play now in the subventricular zone."

Kuo’s team found this system by following cholinergic signaling, but other groups are arriving in the same niche by following dopaminergic and serotonergic signals, Temple said. “It’s a really hot area because it’s a beautiful stem cell niche to study. It’s this gorgeous niche where you can observe cell-to-cell interactions.”

These emerging threads have Kuo hopeful researchers will eventually be able to find the way to “engage certain circuits of the brain to lead to a hardware upgrade. Wouldn’t it be nice if you could upgrade the brain hardware to keep up with the new software?” He said perhaps there will be a way to combine behavioral therapy and stem cell treatments after a brain injury to rebuild some of the damage.

The questions ahead are both upstream from the new ChAT+ neurons and downstream, Kuo says. Upstream, what brain signals tell ChAT+ neurons to start asking the stem cells for more young neurons? Downstream, what’s the logic governing the response of the stem cells to different frequencies of ChAT+ electrical activity?

There’s also the big issue of somehow being able to introduce new components into an existing neuronal circuit, a practice that parts of the brain might normally resist. “I think that some neural circuits welcome new members, and some don’t,” Kuo said.

Study of neurogenesis in mice may have solved mystery of childhood amnesia in humans

A team of researchers working at the University of Toronto in Canada may have found the answer to the question of why we humans tend to have little to no memory of the first few years of our lives. In their paper published in the journal Science, the team describes several experiments they ran on mice and other small mammals that revealed the impact of neurogenesis on memory and how what they learned might be applied to memory retention in people. Lucas Mongiat and Alegandro Schinder offer a review of memory studies and how the research by the team in Toronto fits in with what has already been learned in a Perspective piece in the same journal edition.

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Preparing for adulthood: thousands upon thousands of new cells are born in the hippocampus during puberty, and most survive with effortful learning

The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood.

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Depressed? Researchers identify new anti-depressant mechanisms, therapeutic approaches

Researchers at UT Southwestern Medical Center are making breakthroughs that could benefit people suffering from depression.

A team of physician-scientists at UT Southwestern has identified a major mechanism by which ghrelin (a hormone with natural anti-depressant properties) works inside the brain. Simultaneously, the researchers identified a potentially powerful new treatment for depression in the form of a neuroprotective drug known as P7C3.

The study, published online in April’s issue of Molecular Psychiatry, is notable because although a number of anti-depressant drugs and other treatments are available, an estimated one in 10 adults in the U.S. still report depression, according to the Centers for Disease Control and Prevention.

"By investigating the way the so-called ‘hunger hormone’ ghrelin works to limit the extent of depression following long-term exposure to stress, we discovered what could become a brand new class of anti-depressant drugs," said Dr. Jeffrey Zigman, Associate Professor of Internal Medicine and Psychiatry at UT Southwestern, and co-senior author of the study.

Ghrelin, a hormone produced in the stomach and intestines, has several widely known functions, including the ability to stimulate appetite. The latest research builds on a 2008 study led by Dr. Zigman, in which the team discovered that ghrelin exhibited natural anti-depressant effects that manifest when its levels rise as a result of caloric restriction or prolonged psychological stress.

The current findings identify ghrelin’s ability to stimulate adult hippocampal neurogenesis, the formation of new neurons, in animal models. In addition, Dr. Zigman and his colleagues also found that the regenerative process inside the hippocampus – a region of the brain that regulates mood, memory, and complex eating behaviors – is crucial in limiting the severity of depression following prolonged exposure to stress.

"After identifying the mechanism of ghrelin’s anti-depressant actions, we investigated whether increasing this ghrelin effect by directly enhancing hippocampal neurogenesis with the recently reported P7C3 class of neuroprotective compounds would result in even greater anti-depressant behavioral effects," Dr. Zigman said.

The P7C3 compounds were discovered in 2010 by a team of UT Southwestern researchers led by Dr. Steven McKnight, Chair of Biochemistry, Dr. Joseph Ready, Professor of Biochemistry, and Dr. Andrew Pieper, a former UT Southwestern faculty member and co-senior author of the current study. Previous research demonstrated P7C3’s promising neuroprotective abilities in instances of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and traumatic brain injury. Today, researchers hope that it can have a transformative impact on depression treatment too.

"We found that P7C3 exerted a potent anti-depressant effect via its neurogenesis-promoting properties," said Dr. Pieper, who is now Associate Professor of Neurology and Psychiatry at the University of Iowa Carver College of Medicine. "Also exciting, a highly active P7C3 analog was able to quickly enhance neurogenesis to a much greater level than a wide spectrum of currently marketed anti-depressant drugs."

Based on the study’s behavioral findings, researchers believe that individuals with depression associated with chronic stress or with altered ghrelin levels or ghrelin resistance, as has been described or theorized for conditions such as obesity and anorexia nervosa, might be particularly responsive to treatment with highly neuroprotective drugs, such as the P7C3 compounds.

Future studies will examine the ability to apply these findings to other forms of depression, including the possibility of developing clinical trials aimed at identifying whether or not P7C3 compounds have anti-depressant effects in people with major depression, as predicted. The three main types of depressive disorders include major depression, dysthymia, and bipolar disorder.