reposted love this glial cell interactions with PwPD....

Reprogrammed Glia Improve Symptoms in a Mouse Model of Parkinson’s

By converting glial cells into dopaminergic neurons, scientists were able to partially rescue motor behavior in mice.

By Diana Kwon | April 10, 2017

A human astrocyteWIKIMEDIA, BRUNO PASCAL

Parkinson’s, a neurodegenerative disease that primarily affects the motor system, is marked by a progressive loss of dopaminergic neurons in the brain. While current treatments are aimed at replenishing dopamine levels, none are able to restore the lost cells. Now, scientists have devised a way to reprogram glial cells into active dopamine neurons that can partially restore motor function in a mouse model of Parkinson’s. This proof-of-principle study could pave the way to a new treatment for the disease, researchers reported today (April 10) in Nature Biotechnology.

“In Parkinson’s disease, dopamine neurons die, but at the same time, because of inflammation . . . some glial cells become reactive and proliferate,” said coauthor Ernest Arenas, a molecular neurobiologist at the Karolinska Institute in Sweden. “So we thought that one interesting possibly for reprogramming could be to turn these [glial] cells . . . into the cells that are missing in the disease.”

Arenas and colleagues first tested this technique in vitro, by infecting human astrocytes—star-shape glial cells that are abundant in the brain—with viruses containing three transcription factors involved in neuronal identity and growth, a dopaminergic neuron-specific microRNA, and several small molecules that promote chromatin remodeling and aid brain development.

The researchers were able to successfully transform up to 16 percent of human astrocytes into dopaminergic neurons that were capable of firing action potentials in vitro. “We were really amazed by the physiological properties of the cells,” Arenas told The Scientist. “The reprogrammed cells had fantastic electrophysiology that is difficult to get in stem cell–derived cells.”

When the team applied this protocol to a mouse model of Parkinson’s (in which dopaminergic neurons in the striatum are killed by a toxin), the rodents displayed improved motor behavior and gait control. “The major achievement of this study is that, for the very first time, they show a behavioral effect achieved by reprogrammed neurons,” Magdalena Götz, a neuroscientist at the Ludwig-Maximilians-University Munich in Germany who was not involved with this study, told The Scientist. While many groups have converted various glial cells into neurons both in vitro and in vivo, she added, none had reported a corresponding change in behavior, until now.

“Generating in vivo dopaminergic neurons is an excellent way to replace the current L-dopa approach [to treating Parkinson’s],” said Gong Chen, a life sciences professor at Pennsylvania State University who was not involved in the work. L-dopa, or Levodopa, is a dopamine precursor that is commonly prescribed to treat the symptoms of Parkinson’s disease. “By regenerating dopaminergic neurons locally, you can greatly reduce the desensitization of dopamine receptors all over the brain,” Chen added. However, he pointed out that the reprogramming efficiency in the current study was relatively low. In a recent study, Chen’s group was able to reprogram up to 90 percent of astrocytes in mouse cortices in vivo.

Arenas acknowledged that because his team’s method is still an early prototype, there is still significant room for progress. “Our first focus will be to improve the reprogramming efficiency,” he said. He also noted that the group currently requires transgenic mice to selectively express the injected genes in astrocytes. In order to make this technique feasible for human testing, the team plans to explore ways to allow the virus to specifically target glial cells without a genetically modified host.

Over the last decade, glial reprogramming has piqued the interest of many researchers who see it as a promising method to treat neurodegenerative disease and brain injury by replenishing lost neurons. “During the last 10 to 15 years, this field moved incredibly fast from a strange approach to a fairly accepted approach attracting many researchers,” said Götz, who was one of the first to successfully convert glia into neurons in vitro.

“I predict that this is going to be the next frontier in regenerative medicine—we don’t need to inject any external stem cells anymore, we can just use internal glial cells,” Chen said. “I think this field will continue to thrive.”

P. Rivetti di Val Cervo et al., “Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model,” Nature Biotechnol.,doi:10.1038/nbt.3835, 2017.

Tags

reprogramming, Parkinson, neuroscience, neuron, glia, dopamine and cellular reprogramming

reposted from

Altered circadian rhythm worsens Parkinson's disease, researchers show

Date:

April 5, 2016

Source:

Temple University Health System

Summary:

Chronic lack of sleep and irregular sleep-wake cycles may be risk factors of Parkinson's disease, new work suggests. In an animal model, the researchers show that disturbances in circadian rhythm that exist before Parkinson's onset dramatically worsen motor and learning deficits brought on by the disease.

Share:

FULL STORY

---

This is Domenico Praticò, MD, Professor in the Departments of Pharmacology and Microbiology and the Center for Translational Medicine at Lewis Katz School of Medicine at Temple University

Credit: Lewis Katz School of Medicine at Temple University

Chronic lack of sleep and irregular sleep-wake cycles may be risk factors of Parkinson's disease, new work by researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) suggests. In an animal model, the researchers show that disturbances in circadian rhythm that exist before Parkinson's onset dramatically worsen motor and learning deficits brought on by the disease.

The new work, led by Domenico Praticò, MD, Professor in the Departments of Pharmacology and Microbiology and the Center for Translational Medicine at LKSOM, is the first to demonstrate that an environmental factor -- chronic daily exposure to long periods of light with brief exposure to dark, which alters circadian rhythm -- can exacerbate Parkinson's symptoms and pathology. The findings appear online April 5 in the journal Molecular Psychiatry.

Patients with Parkinson's disease often suffer from recurrent sleep disorders and disturbances in circadian rhythm, the roughly 24-hour biological cycle of humans. But whether those disturbances impact the development and progression of Parkinson's has been unclear. "Many think that sleep disturbances are secondary to Parkinson's disease," Dr. Praticò explained. "But circadian rhythm disturbances are increasingly reported before the onset of Parkinson's, suggesting that they could be risk factors."

After age 60, the majority of Parkinson's disease cases are idiopathic, their cause unknown. According to Dr. Praticò, it is probable that in those cases, the disease arises as a result of interactions between genes and environmental risk factors. The latter include chronic stress, sleep disorders, and circadian disturbances, all of which affect the function of the central nervous system, potentially contributing to the pathology that characterizes Parkinson's disease.

Dr. Praticò and colleagues investigated the role of altered circadian rhythm using a well-established mouse model of Parkinson's disease, in which treatment with MPTP, a neurotoxin, reproduces aspects of the disease in mice. The researchers divided animals into two groups.

The first, the control group, was maintained on a regular circadian schedule, being exposed to 12 hours of light followed by 12 hours of dark each day. In the second group, circadian rhythm was altered through daily exposure to 20 hours of light followed by just four hours of dark. After 60 days, some animals from each group were treated with MPTP.

Assessments of movement and behavior showed that all mice treated with MPTP developed Parkinson's disease, but animals with altered circadian rhythm experienced significant learning impairments. They also exhibited severe motor deficits, with drastic reductions in motor coordination and motor learning skills -- far worse than the deficits observed in MPTP-treated mice with normal circadian rhythm.

To understand why circadian rhythm disturbance worsens Parkinson's disease, Dr. Praticò and his team examined the brains of affected mice. In a region known as the substantia nigra, they observed significant reductions in neurons that produce dopamine, the loss of which is a major molecular feature of Parkinson's disease. "The substantia nigra is the epicenter of Parkinson's disease," Dr. Praticò said. "Cells normally die in that region of the brain, but our study shows that circadian rhythm disturbance accelerates cell death there."

In addition, cells known as microglia, which normally protect neurons, were superactive in circadian-disrupted MPTP-treated mice. The overactivation of microglia can actually worsen neuroinflammation and potentially speed the progression of Parkinson's disease.

The next challenge is to see if the findings can be replicated in other animal models. "If those studies are successful, we'll then try to reestablish normal circadian rhythm in circadian-disrupted animals to explore the possibility of reversing brain inflammation and cell death," Dr. Praticò said.

The outcomes of those studies could have important implications for the prevention and treatment of Parkinson's disease in persons with chronic sleep disorders.

---

Story Source:

Materials provided by Temple University Health System. Note: Content may be edited for style and length.

---

Journal Reference:

1. E Lauretti, A Di Meco, S Merali, D Pratic�. Circadian rhythm dysfunction: a novel environmental risk factor for Parkinson’s disease. Molecular Psychiatry, 2016; DOI: 10.1038/MP.2016.47

reposted from

How Experience Shapes Adult Neurogenesis

Interneurons and mature granule cells in the adult mouse brain are critical for newborn neurons’ responses to novel environments.

By Ruth Williams | October 27, 2016

Granule neurons in the mouse dentate gyrusWIKIMEDIA, AVILA, J.Newly made cells in the brains of mice adopt a more complex morphology and connectivity when the animals encounter an unusual environment than if their experiences are run-of-the-mill. Researchers have now figured out just how that happens. According to a study published today (October 27) in Science, a particular type of cell—called an interneuron—in the hippocampus processes the animals’ experiences and subsequently shapes the newly formed neurons.

“We knew that experience shapes the maturation of these new neurons, but what this paper does is it lays out the entire circuit through which that happens,” said Heather Cameron, a neuroscientist at the National Institute of Mental Health in Bethesda who was not involved with the work. “It’s a really nicely done piece of work because they go step-by-step and show all of the cells that are involved and how they’re connected.”

Most of the cells in the adult mammalian brain are mature and don’t divide, but in a few regions, including an area of the hippocampus called the dentate gyrus, neurogenesis occurs. The dentate gyrus is thought to be involved in the formation of new memories. In mice, for instance, exploring novel surroundings electrically activates the dentate gyrus and can affect the production, maturation, and survival of the newly born cells. Now, Alejandro Schinder and his team at the Leloir Institute in Buenos Aires, Argentina, have investigated the process in detail.

Newborn dentate gyrus neurons, which are called granule cells, take six weeks to fully develop and integrate into the mouse brain’s existing neural networks, said Schinder. To examine these cells’ development, the team labeled newborn granule cells with red fluorescent protein in the brains of mice and then either left the animals in their regular cages (controls) or exposed them to enriched environments—cages with tunnels and other unusual objects—for different 48 hour periods. Three weeks after the new cells were labeled, the team examined their morphology and activity.

The researchers found that in animals who had been exposed to the enriched environment during a particular period (9 to 11 days after labeling), the young granule cells had longer dendrites with evidence of increased connections with other neurons. Specifically, these cells had a greater number of dendritic spines, the sites of incoming synapses, and more detectable electrical inputs.

Granule cells receive different inputs from surrounding neurons at different stages of their development, Schinder said, which may explain why they are apparently receptive to experiential input only within a short period (day 9 to 11), rather than throughout their development.

The team went on to analyze these neuronal inputs more closely. Through a series of optogenetic and chemogenetic experiments, the researchers showed that mature granule cells activated their younger counterparts via intermediary cells called interneurons. Artificially stimulating either the mature granule cells or the interneurons could recapitulate the effects of environmental enrichment on the young granule cells. Moreover, the team showed that blocking the activity of the interneurons during the animals’ exposure to enriched environments prevented the expected experience-induced morphology in the young granule cells.

“The take home message is that experience can change how these young cells are incorporating into the brain and how they are contributing to brain circuitry,” said Hongjun Song, who studies neurogenesis at the Johns Hopkins University School of Medicine in Baltimore and who did not participate in the research. But, he asked, “what’s the functional impact? Does this process make the mice better learners? Or if you block the process, do they get worse [at learning]?”

As yet, those questions remain unanswered.

D. D. Alvarez et al., “A disynaptic feedback network activated by experience promotes the integration of new granule cells,” Science, 354:459-65, 2016.

Tags

neuroscience, neurogenesis, learning, hippocampus and behavior

reposted from

The smart mouse with the half-human brain

• 12:45 01 December 2014 by Andy Coghlan
• For similar stories, visit the The Human Brain Topic Guide

What would Stuart Little make of it? Mice have been created whose brains are half human. As a result, the animals are smarter than their siblings.

The idea is not to mimic fiction, but to advance our understanding of human brain diseases by studying them in whole mouse brains rather than in dishes.

The altered mice still have mouse neurons – the "thinking" cells that make up around half of all their brain cells. But practically all the glial cells in their brains, the ones that support the neurons, are human.

"It's still a mouse brain, not a human brain," says Steve Goldman of the University of Rochester Medical Center in New York. "But all the non-neuronal cells are human."

Rapid takeover

Goldman's team extracted immature glial cells from donated human fetuses. They injected them into mouse pups where they developed into astrocytes, a star-shaped type of glial cell.

Within a year, the mouse glial cells had been completely usurped by the human interlopers. The 300,000 human cells each mouse received multiplied until they numbered 12 million, displacing the native cells.

"We could see the human cells taking over the whole space," says Goldman. "It seemed like the mouse counterparts were fleeing to the margins."

Astrocytes are vital for conscious thought, because they help to strengthen the connections between neurons, called synapses. Their tendrils (see image) are involved in coordinating the transmission of electrical signals across synapses.

Human astrocytes are 10 to 20 times the size of mouse astrocytes and carry 100 times as many tendrils. This means they can coordinate all the neural signals in an area far more adeptly than mouse astrocytes can. "It's like ramping up the power of your computer," says Goldman.

Intelligence leap

A battery of standard tests for mouse memory and cognition showed that the mice with human astrocytes are much smarter than their mousy peers.

In one test that measures ability to remember a sound associated with a mild electric shock, for example, the humanised mice froze for four times as long as other mice when they heard the sound, suggesting their memory was about four times better. "These were whopping effects," says Goldman. "We can say they were statistically and significantly smarter than control mice."

Goldman first reported last year that mice with human glial cells are smarter. But the human cells his team injected then were mature so they simply integrated into the mouse brain tissue and stayed put.

This time, he injected the precursors of these cells, glial progenitor cells, which were able to divide and multiply. That, he says, explains how they were able to take over the mouse brains so completely, stopping only when they reached the physical limits of the space.

Species cross

"It would be interesting to find out whether the human astrocytes function the same way in the mice as they do in humans," says Fred Gage, a stem cell researcher at the Salk Institute in La Jolla, California. "It would show whether the host modifies the fate of cells, or whether the cells retain the same features in mice as they do in humans," he says.

"That the cells work at all in a different species is amazing, and poses the question of which properties are being driven by the cell itself and which by the new environment," says Wolfgang Enard of Ludwig-Maximilians University Munich in Germany, who has shown that mice are better at learning if they have the human Foxp2 gene, which has been linked with human language development.

In a parallel experiment, Goldman injected immature human glial cells into mouse pups that were poor at making myelin, the protein that insulates nerves. Once inside the mouse brain, many of the human glial cells matured into oligodendrocytes, brain cells that specialise in making the insulating material, suggesting that the cells somehow detected and compensated for the defect.

This could be useful for treating diseases in which the myelin sheath is damaged, such as multiple sclerosis, says Goldman, and he has already applied for permission to treat MS patients with the glial progenitor cells, and hopes to start a trial in 12 to 15 months.

Still a mouse

To explore further how the human astrocytes affect intelligence, memory and learning, Goldman is already grafting the cells into rats, which are more intelligent than mice. "We've done the first grafts, and are mapping distributions of the cells," he says.

Although this may sound like the work of science fiction – think Deep Blue Sea, where researchers searching for an Alzheimer's cure accidently create super-smart sharks, or Algernon, the lab mouse who has surgery to enhance his intelligence, or even the pigoons, Margaret Atwood's pigs with human stem cells – and human thoughts – Goldman is quick to dismiss any idea that the added cells somehow make the mice more human.

"This does not provide the animals with additional capabilities that could in any way be ascribed or perceived as specifically human," he says. "Rather, the human cells are simply improving the efficiency of the mouse's own neural networks. It's still a mouse."

However, the team decided not to try putting human cells into monkeys. "We briefly considered it but decided not to because of all the potential ethical issues," Goldman says.

Enard agrees that it could be difficult to decide which animals to put human brain cells into. "If you make animals more human-like, where do you stop?" he says.

Journal reference: Journal of Neuroscience, DOI: 10.1523/JNEUROSCI.1510-14.2014

Clearly a Mouse

reposted from

Clearly a Mouse

December 2014's Scientist to Watch, Viviana Gradinaru, helped develop CLARITY, a method for making transparent mice.

By Kerry Grens | December 1, 2014

• Comment
• Print

• Link this
• Stumble
• Tweet this

Read the full story.

Tags

tissue clearing, neuroscience, mouse models and CLARITY