Posts tagged neurogenesis
Articles and news from the latest research reports.
Serotonin Mediates Exercise-Induced Generation of New Neurons
Mice that exercise in running wheels exhibit increased neurogenesis in the brain. Crucial to this process is serotonin signaling. These are the findings of a study by Dr. Friederike Klempin, Daniel Beis and Dr. Natalia Alenina from the research group led by Professor Michael Bader at the Max Delbrück Center (MDC) Berlin-Buch. Surprisingly, mice lacking brain serotonin due to a genetic mutation exhibited normal baseline neurogenesis. However, in these serotonin-deficient mice, activity-induced proliferation was impaired, and wheel running did not induce increased generation of new neurons. (Journal of Neuroscience)
Scientists have known for some time that exercise induces neurogenesis in a specific brain region, the hippocampus. However, until this study, the underlying mechanism was not fully understood. The hippocampus plays an important role in learning and in memory and is one of the brain regions where new neurons are generated throughout life.
Serotonin facilitates precursor cell maturation
The researchers demonstrated that mice with the ability to produce serotonin are likely to release more of this hormone during exercise, which in turn increases cell proliferation of precursor cells in the hippocampus. Furthermore, serotonin seems to facilitate the transition of stem to progenitor cells that become neurons in the adult mouse brain.
For Dr. Klempin and Dr. Alenina it was surprising that normal baseline neurogenesis occurs in mice that, due to a genetic mutation, cannot produce serotonin in the brain. However, they noted that some of the stem cells in serotonin-deficient mice either die or fail to become neurons.
Yet, these animals seem to have a mechanism that allows compensation for the deficit, in that progenitor cells, an intermediate stage in the development from a stem cell to a neuron, divide more frequently. According to the researchers, this is to maintain the pool of these cells.
However, the group of wheel-running mice that do not produce serotonin did not exhibit an exercise-induced increase in neurogenesis. The compensatory mechanism failed following running. The researchers concluded: “Serotonin is not necessarily required for baseline generation of new neurons in the adult brain, but is essential for exercise-induced hippocampal neurogenesis.”
Hope for new approaches to treat depression and memory loss in the elderly
Deficiency in serotonin, popularly known as the “molecule of happiness”, has been considered in the context of theories linking major depression to declining neurogenesis in the adult brain. “Our findings could potentially help to develop new approaches to prevent and treat depression as well as age-related decline in learning and memory,” said Dr. Klempin and Dr. Alenina.
Producing new neurones under all circumstances: a challenge that is just a mouse away …
Improving neurone production in elderly persons presenting with a decline in cognition is a major challenge facing an ageing society and the emergence of neuro-degenerative conditions such as Alzheimer’s disease. INSERM and CEA researchers recently showed that the pharmacological blocking of the TGFβ molecule improves the production of new neurones in the mouse model. These results incentivise the development of targeted therapies enabling improved neurone production to alleviate cognitive decline in the elderly and reduce the cerebral lesions caused by radiotherapy.
The research is published in the journal EMBO Molecular Medicine.
New neurones are formed regularly in the adult brain in order to guarantee that all our cognitive capacities are maintained. This neurogenesis may be adversely affected in various situations and especially:
- in the course of ageing,
- after radiotherapy treatment of a brain tumour. (The irradiation of certain areas of the brain is, in fact, a central adjunctive therapy for brain tumours in adults and children).
According to certain studies, the reduction in our “stock” of neurones contributes to an irreversible decline in cognition. In the mouse, for example, researchers reported that exposing the brain to radiation in the order of 15 Gy is accompanied by disruption to the olfactive memory and a reduction in neurogenesis. The same happens in ageing in which a reduction in neurogenesis is associated with a loss of certain cognitive faculties. In patients receiving radiotherapy due to the removal of a brain tumour, the same phenomena can be observed.
Researchers are studying how to preserve the “neurone stock”. To do this, they have tried to discover which factors are responsible for the decline in neurogenesis.
Contrary to what might have been believed, their initial observations show that neither heavy doses of radiation nor ageing are responsible for the complete disappearance of the neural stem cells capable of producing neurones (and thus the origin of neurogenesis). Those that survive remain localised in a certain small area of the brain (the sub-ventricular zone (SVZ)). They nevertheless appear not to be capable of working correctly.
Additional experiments have made it possible to establish that in both situations, irradiation and ageing, high levels of the cytokine TGFβ cause the stem cells to become dormant, increasing their susceptibility to apoptosis (PCD) and reducing the number of new neurones.
“Our study concluded that although neurogenesis reduced in ageing and after a high dose of radiation, many stem cells survive for several months, retaining their ‘stem’ characteristics”, explains Marc-Andre Mouthon, one of the main authors of the research, that was conducted in conjunction with José Piñeda and François Boussin.
The second part of the project demonstrated that pharmacological blocking of TGFβ restores the production of new neurones in irradiated or ageing mice.
For the researchers, these results will encourage the development of targeted therapies to block TGFβ in order to reduce the impact of brain lesions caused by radiotherapy and improving the production of neurones in the elderly presenting with a cognitive decline.
![Every science writer loves a good challenge to dogma. I wish I had been in the working world in the spring of 1992, when one such intellectual overhaul happened in neuroscience. The dogma: Neurons, unlike most of the body’s cells, can’t be replenished. You’re born with just 100 billion of them and you better use them wisely. The challenge: Samuel Weiss and Brent Reynolds reported in Science that brain tissue taken from adult mice could be chemically coaxed into making new neurons.
“It left us speechless,” Weiss told the New York Times. Everybody else was pretty stunned, too. Over the next six years, other researchers confirmed that this so-called neurogenesis happens in the adult hippocampus of many animals, including tree shrews, marmosets, Old World monkeys and people. Today, more than two decades since the splashy Science report, adult neurogenesis is a bona fide subfield, with hundreds of labs studying it around the world.
But after all this time, researchers still don’t really know what it’s for. Studies have uncovered a wide variety of environmental stimuli — what you might think of as inputs — that affect neurogenesis in the dentate gyrus, a part of the hippocampus. Running and antidepressants can ramp up neurogenesis, for example, while stress, social isolation, sleep deprivation and aging can shut it down. Scientists have also looked at the outputs of neurogenesis, showing that a boost of new neurons may be important for exploratory behavior and certain kinds of learning, such as navigating a new space. But how do the inputs lead to the outputs?
“I like to think of the dentate as an association machine,” says Sam Pleasure, a neuroscientist at the University of California, San Francisco. All day long, he says, we’re walking around the world trying to associate various sensations and emotions — big dog with fangs, small screaming toddler, perilous traffic intersection — so that we can remember them later. “All these stimuli are happening and converge on this circuit, and they somehow affect how new neurons are recruited into the circuit, and that ends up coming out as the ability to form new memories.” But how it all works on the molecular level is a black box.
Two papers published in Cell Stem Cell [1 , 2]open that box a little bit. They identify molecular inhibitors — what Pleasure calls “wet blankets” — that turn off neurogenesis in certain contexts.
Opening the Black Box of Neurogenesis by Virginia Hughes](http://40.media.tumblr.com/cc38202eb4074d2eedac252402664440/tumblr_mj35te3xQf1rog5d1o1_500.jpg)
Every science writer loves a good challenge to dogma. I wish I had been in the working world in the spring of 1992, when one such intellectual overhaul happened in neuroscience. The dogma: Neurons, unlike most of the body’s cells, can’t be replenished. You’re born with just 100 billion of them and you better use them wisely. The challenge: Samuel Weiss and Brent Reynolds reported in Science that brain tissue taken from adult mice could be chemically coaxed into making new neurons.
“It left us speechless,” Weiss told the New York Times. Everybody else was pretty stunned, too. Over the next six years, other researchers confirmed that this so-called neurogenesis happens in the adult hippocampus of many animals, including tree shrews, marmosets, Old World monkeys and people. Today, more than two decades since the splashy Science report, adult neurogenesis is a bona fide subfield, with hundreds of labs studying it around the world.
But after all this time, researchers still don’t really know what it’s for. Studies have uncovered a wide variety of environmental stimuli — what you might think of as inputs — that affect neurogenesis in the dentate gyrus, a part of the hippocampus. Running and antidepressants can ramp up neurogenesis, for example, while stress, social isolation, sleep deprivation and aging can shut it down. Scientists have also looked at the outputs of neurogenesis, showing that a boost of new neurons may be important for exploratory behavior and certain kinds of learning, such as navigating a new space. But how do the inputs lead to the outputs?
“I like to think of the dentate as an association machine,” says Sam Pleasure, a neuroscientist at the University of California, San Francisco. All day long, he says, we’re walking around the world trying to associate various sensations and emotions — big dog with fangs, small screaming toddler, perilous traffic intersection — so that we can remember them later. “All these stimuli are happening and converge on this circuit, and they somehow affect how new neurons are recruited into the circuit, and that ends up coming out as the ability to form new memories.” But how it all works on the molecular level is a black box.
Two papers published in Cell Stem Cell [1 , 2]open that box a little bit. They identify molecular inhibitors — what Pleasure calls “wet blankets” — that turn off neurogenesis in certain contexts.
Opening the Black Box of Neurogenesis by Virginia Hughes
Neuroscientist Sheds Light on Cause for ‘Chemo Brain’
Study finds fog-like condition related to chemotherapy’s effect on new brain cells and rhythms.
It’s not unusual for cancer patients being treated with chemotherapy to complain about not being able to think clearly, connect thoughts or concentrate on daily tasks. The complaint – often referred to as chemo-brain – is common. The scientific cause, however, has been difficult to pinpoint.
New research by Rutgers University behavioral neuroscientist Tracey Shors offers new clues for this fog-like condition, medically known as chemotherapy-induced cognitive impairment. In a featured article published in the European Journal of Neuroscience, Shors and her colleagues argue that prolonged chemotherapy decreases the development of new brain cells, a process known as neurogenesis, and disrupts ongoing brain rhythms in the part of the brain responsible for making new memories. Both, she says, are affected by learning and in some cases are necessary for learning to occur.
“One of the things that these brain rhythms do is to connect information across brain regions,” says Shors, Professor II in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers. “We are starting to have a better understanding of how these natural rhythms are used in the process of communication and how they change with experience.”
Working in the Shors laboratory, postdoctoral fellow Miriam S. Nokia from the Department of Psychology at the University of Jyvaskyla in Finland and Rutgers neuroscience graduate student Megan Anderson treated rats with a chemotherapy drug – temozolomide (TMZ) – used on individuals with either malignant brain tumors or skin cancer to stop rapidly dividing cells that have gone out of control and resulted in cancer.
In this study, scientists found that the production of new healthy brain cells treated with the TMZ was reduced in the hippocampus by 34 percent after being caught in the crossfire of the drug’s potency. The cell loss, coupled with the interference in brain rhythms, resulted in the animal being unable to learn difficult tasks.
Shors says the rats had great difficulty learning to associate stimulus events if there was a time gap between the activities but could learn simple task if the stimuli were not separated in time. Interestingly, she says, the drug did not disrupt the memories that were already present when the treatment began.
For cancer patients undergoing long-term chemotherapy this could mean that although they are able to do simple everyday tasks, they find it difficult to do more complicated activities like processing long strings of numbers, remembering recent conversations, following instructions and setting priorities. Studies indicate that while most cancer patients experience short-term memory loss and disordered thinking, about 15 percent of cancer patients suffer more long-lasting cognitive problems as a result of the chemotherapy treatment.
“Chemotherapy is an especially difficult time as patients are learning how to manage their treatment options while still engaging in and appreciating life. The disruptions in brain rhythms and neurogenesis during treatment may explain some of the cognitive problems that can occur during this time. The good news is that these effects are probably not long-lasting,” says Shors.
(Source: news.rutgers.edu)
Researchers identify potential target for age-related cognitive decline
Cognitive decline in old age is linked to decreasing production of new neurons. Scientists from the German Cancer Research Center have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.
The hippocampus – a structure of the brain whose shape resembles that of a seahorse – is also called the “gateway” to memory. This is where information is stored and retrieved. Its performance relies on new neurons being continually formed in the hippocampus over the entire lifetime. “However, in old age, production of new neurons dramatically decreases. This is considered to be among the causes of declining memory and learning ability”, Prof. Dr. Ana Martin-Villalba, a neuroscientist, explains.
Martin-Villalba, who heads a research department at the German Cancer Research Center (DKFZ), and her team are trying to find the molecular causes for this decrease in new neuron production (neurogenesis). Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.
"We find considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. We therefore suspected this signaling molecule to be responsible for the fact that hardly any young neurons are generated any more in old age." The scientists tested their assumption in mice whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs had developed these animals at DKFZ. The term "Dickkopf" (from German "dick" = thick, "Kopf" = head) also goes back to Niehrs, who had found in 1998 that this signaling molecule regulates head development during embryogenesis.
Treatment to prevent Alzheimer’s disease moves a step closer
A new drug to prevent the early stages of Alzheimer’s disease could enter clinical trials in a few years’ time according to scientists.
Alzheimer’s is the most common type of dementia, which currently affects 820,000 people in the UK, with numbers expected to more than double by 2050. One in three people over 65 will die with dementia.
The disease begins when a protein called amyloid-β (Aβ) starts to clump together in senile plaques in the brain, damaging nerve cells and leading to memory loss and confusion.
Professor David Allsop and Dr Mark Taylor at Lancaster University have successfully created a new drug which can reduce the number of senile plaques by a third, as well as more than doubling the number of new nerve cells in a particular region of the brain associated with memory. It also markedly reduced the amount of brain inflammation and oxidative damage associated with the disease.
The drug was tested on transgenic mice containing two mutant human genes linked to inherited forms of Alzheimer’s, so that they would develop some of the changes associated with the illness. The drug is designed to cross the blood-brain barrier and prevent the Aβ molecules from sticking together to form plaques.
Professor Allsop, who led the research and was the first scientist to isolate senile plaques from human brain, said: “When we got the test results back, we were highly encouraged. The amount of plaque in the brain had been reduced by a third and this could be improved if we gave a larger dose of the drug, because at this stage, we don’t know what the optimal dose is.”
The drug needs to be tested for safety before it can enter human trials, but, if it passes this hurdle, the aim would be to give the drug to people with mild symptoms of memory loss before they develop the illness.
“Many people who are mildly forgetful may go on to develop the disease because these senile plaques start forming years before any symptoms manifest themselves. The ultimate aim is to give the drug at that stage to stop any more damage to the brain, before it’s too late.”
Support for the research was given by Alzheimer’s Research UK, and the results are published in the open access journal PLOS ONE.
Induction of adult cortical neurogenesis by an antidepressant
The production of new neurons in the adult normal cortex in response to the antidepressant, fluoxetine, is reported in a study published online this week in Neuropsychopharmacology.
The research team, which is based at the Institute for Comprehensive Medical Science, Fujita Health University, Aichi, has previously demonstrated that neural progenitor cells exist at the surface of the adult cortex, and, moreover, that ischemia enhances the generation of new inhibitory neurons from these neural progenitor cells. These cells were accordingly named “Layer 1 Inhibitory Neuron Progenitor cells” (L1-INP). However, until now it was not known whether L1-INP-related neurogenesis could be induced in the normal adult cortex.
Tsuyoshi Miyakawa, Koji Ohira, and their colleagues employed fluoxetine, a selective serotonin reuptake inhibitor, and one of the most widely used antidepressants, to stimulate the production of new neurons from L1-INP cells. A large percentage of these newly generated neurons were inhibitory GABAergic interneurons, and their generation coincided with a reduction in apoptotic cell death following ischemia. This finding highlights the potential neuroprotective response induced by this antidepressant drug. It also lends further support to the postulation that induction of adult neurogenesis in cortex is a relevant prevention/treatment option for neurodegenerative diseases and psychiatric disorders.
(Source: eurekalert.org)
Lithium rescues synaptic plasticity and memory in Down syndrome mice
Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.
Lipid metabolism regulates the activity of adult neural stem cells
Neural stem cells generate thousands of new neurons every day in two regions of the adult brain: the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus. This process, called adult neurogenesis, is critical for a number of processes implicated in certain forms of learning and memory. Impaired adult neurogenesis has been associated with a number of diseases such as depression, epilepsy, and Alzheimer’s disease.
A team led by Sebastian Jessberger, Professor of Neurosciences at the Brain Research Institute, has now identified a novel mechanism that plays a key role in adult neurogenesis and is required for the life-long activity of neural stem cells. Prof. Jessberger believes that “this finding will hopefully give us a new target to develop novel drugs against depression or neurodegenerative diseases”. The results of this study were published on December 2nd in the scientific journal Nature.
Stem cells produce their own lipids
Researchers in his group could show that stem cells depend on glucose-derived production of new fatty acids and lipids. When the key enzyme of this pathway, fatty acid synthase (Fasn), is blocked in neural stem cells, they loose their ability to divide which results in a reduction in newborn neurons.
To prevent the constant division of neural stem cells, this pathway is regulated by a protein called Spot14, which inhibits lipid synthesis. Controlling Fasn activity is important to make sure that stem cells do not divide too often, which could lead to a premature exhaustion or depletion of the stem cell pool. Surprisingly, the metabolic state of neural stem cells seems to be fundamentally distinct from their daughter cells (newborn neurons) and other dividing cells in the central nervous system. These other cell types are able to take up lipids from the blood stream and use them as important structural components of cell membranes but also for signaling events and as an energy source.
Potential target for new drugs
The study published by the Jessberger group has identified a novel target to pharmacologically enhance the activity of neural stem cells in diseases that are associated with reduced levels of newborn neurons, such as depression.
Marlen Knobloch, postdoc in the Jessberger lab and first author of the study, says: “Currently, we have to understand in much greater detail why neural stem cells are in this distinct metabolic state; to this end, we are currently performing experiments in the lab with the aim to enhance neurogenesis through manipulation of lipid metabolism”. However, one must not place too high expectations for the quick development of novel drugs, although for Simon Braun, co-first author of the study, “the hope certainly is to increase the number of newborn neurons by targeting lipid metabolism in the human brain”.
Newborn Neurons — Even in the Adult Aging Brain - are Critical for Memory
Newly generated, or newborn neurons in the adult hippocampus are critical for memory retrieval, according to a study led by Stony Brook University researchers published online in Nature Neuroscience. The functional role of newborn neurons in the brain is controversial, but in “Optical controlling reveals time-dependent roles for adult-born dentate granule cells,” the researchers detail that by ‘silencing’ newborn neurons, memory retrieval was impaired. The findings support the idea that the generation of new neurons in the brain may be crucial to normal learning and memory processes.
Previous research by the study’s lead investigator Shaoyu Ge, PhD, Assistant Professor in the Department of Neurobiology & Behavior at Stony Brook University, and others have demonstrated that newborn neurons form connections with existing neurons in the adult brain. To help determine the role of newborn neurons, Dr. Ge and colleagues devised a new optogenetic technique to control newborn neurons and test their function in the hippocampus, one of the regions of the brain that generates new neurons, even in the adult aging brain.
“Significant controversy has surrounded the functional role of newborn neurons in the adult brain,” said Dr. Ge. “We believe that our study results provide strong support to the idea that new neurons are important for contextual fear memory and spatial navigation memory, two essential aspects of memory and learning that are modified by experience.
“Our findings could also shed light on the diagnosis and treatment of conditions common to the adult aging brain, such as dementia and Alzheimer’s disease,” he said.