Posts Tagged ‘Neuron’

Reprinted from The Lancet Neurology,, Trapp et al, Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study, Copyright (2018), with permission from Elsevier

Bruce Trapp, Ph.D., chair of Cleveland Clinic’s Lerner Research Institute Department of Neurosciences

Cleveland Clinic researchers have discovered a new subtype of multiple sclerosis (MS), providing a better understanding of the individualized nature of the disease.

MS has long been characterized as a disease of the brain’s white matter, where immune cells destroy myelin – the fatty protective covering on nerve cells. The destruction of myelin (called demyelination) was believed to be responsible for nerve cell (neuron) death that leads to irreversible disability in patients with MS.

However, in the new findings, a research team led by Bruce Trapp, Ph.D., identified for the first time a subtype of the disease that features neuronal loss but no demyelination of the brain’s white matter. The findings, published in Lancet Neurology, could potentially lead to more personalized diagnosis and treatments.

The team’s findings support the concept that neurodegeneration and demyelination can occur independently in MS and underscore the need for more sensitive MRI imaging techniques for evaluating brain pathology in real time and monitoring treatment response in patients with the disease. This new subtype of MS, called myelocortical MS (MCMS), was indistinguishable from traditional MS on MRI. The researchers observed that in MCMS, part of the neurons become swollen and look like typical MS lesions indicative of white matter myelin loss on MRI. The disease was only diagnosed in post-mortem tissues.

“This study opens up a new arena in MS research. It is the first to provide pathological evidence that neuronal degeneration can occur without white matter myelin loss in the brains of patients with the disease,” said Trapp, chair of Cleveland Clinic’s Lerner Research Institute Department of Neurosciences. “This information highlights the need for combination therapies to stop disability progression in MS.”

In the study of brain tissue from 100 MS patients who donated their brains after death, the researchers observed that 12 brains did not have white matter demyelination. They compared microscopic tissue characteristics from the brains and spinal cords of 12 MCMS patients, 12 traditional MS patients and also individuals without neurological disease. Although both MCMS and traditional MS patients had typical MS lesions in the spinal cord and cerebral cortex, only the latter group had MS lesions in the brain white matter.

Despite having no typical MS lesions in the white matter, MCMS brains did have reduced neuronal density and cortical thickness, which are hallmarks of brain degeneration also observed in traditional MS. Contrary to previous belief, these observations show that neuronal loss can occur independently of white matter demyelination.

“The importance of this research is two-fold. The identification of this new MS subtype highlights the need to develop more sensitive strategies for properly diagnosing and understanding the pathology of MCMS,” said Daniel Ontaneda, M.D., clinical director of the brain donation program at Cleveland Clinic’s Mellen Center for Treatment and Research in MS. “We are hopeful these findings will lead to new tailored treatment strategies for patients living with different forms of MS.”

Dr. Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in MS and has published more than 240 peer-reviewed articles and 40 book chapters. He also holds the Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research. In 2017 he received the prestigious Outstanding Investigator award by the National Institute of Neurological Disorders and Stroke to examine the biology of MS and to seek treatments that could slow or reverse the disease.


When we listen to music, we often tap our feet or bob our head along to the beat – but why do we do it? New research led by Western Sydney University’s MARCS Institute suggests the reason could be related to the way our brain processes low-frequency sounds.

The study, published in PNAS, recorded the electrical activity of volunteers’ brains while they listened to rhythmic patterns played at either low or high-pitched tones. The study found that while listening, volunteer’s brain activities and the rhythmic structure of the sound became synchronized – particularly at the frequency of the beat.

Co-author of the paper, Dr Sylvie Nozaradan from the MARCS Institute, say these findings strongly suggest that the bass exploits a neurophysiological mechanism in the brain – essentially forcing it to lock onto the beat.

“There is mounting evidence supporting the hypothesis that selective synchronization of large pools of neurons of the brain to the beat frequency may support perception and movement to the musical beat”, says Dr Nozaradan.

While this research is an important step in answering the mystery of why we ‘dance to the beat of the drum’, according to co-author Dr Peter Keller from the MARCS Institute, these findings could also prove important in clinical rehabilitation.

“Music is increasingly being used in clinical rehabilitation of cognitive and motor disorders caused by brain damage and these findings, and a better understanding of the relationship between music and movement, could help develop such treatments,” says Dr Keller.

The research team – also comprising of co-authors Dr Manuel Varlet and Tomas Lenc – suggests that while this research is an important step in understanding the relationship between bass and movement, there are still many open questions about the mechanisms behind this phenomenon.

“Future research is needed to clarify what networks of brain areas are responsible for this synchronization to the beat and how it develops from early in infancy” says Dr Nozaradan.

Fresh or frozen human blood samples can be directly transformed into patient-specific neurons to study disorders such as schizophrenia and autism, Stanford researcher Marius Wernig has found.

Human immune cells in blood can be converted directly into functional neurons in the laboratory in about three weeks with the addition of just four proteins, researchers at the Stanford University School of Medicine have found.

The dramatic transformation does not require the cells to first enter a state called pluripotency but instead occurs through a more direct process called transdifferentiation.

The conversion occurs with relatively high efficiency — generating as many as 50,000 neurons from 1 milliliter of blood — and it can be achieved with fresh or previously frozen and stored blood samples, which vastly enhances opportunities for the study of neurological disorders such as schizophrenia and autism.

“Blood is one of the easiest biological samples to obtain,” said Marius Wernig, MD, associate professor of pathology and a member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “Nearly every patient who walks into a hospital leaves a blood sample, and often these samples are frozen and stored for future study. This technique is a breakthrough that opens the possibility to learn about complex disease processes by studying large numbers of patients.”

A paper describing the findings was published online June 4 in the Proceedings of the National Academy of Sciences. Wernig is the senior author. Former postdoctoral scholar Koji Tanabe, PhD, and graduate student Cheen Ang are the lead authors.

Dogged by challenges

The transdifferentiation technique was first developed in Wernig’s laboratory in 2010 when he and his colleagues showed that they could convert mouse skin cells into mouse neurons without first inducing the cells to become pluripotent — a developmentally flexible stage from which the cells can become nearly any type of tissue. They went on to show the technique could also be used on human skin and liver cells.

But each approach has been dogged by challenges, particularly for researchers wishing to study genetically complex mental disorders, such as autism or schizophrenia, for which many hundreds of individual, patient-specific samples are needed in order to suss out the relative contributions of dozens or more disease-associated mutations.

“Generating induced pluripotent stem cells from large numbers of patients is expensive and laborious. Moreover, obtaining skin cells involves an invasive and painful procedure,” Wernig said. “The prospect of generating iPS cells from hundreds of patients is daunting and would require automation of the complex reprogramming process.”

Although it’s possible to directly convert skin cells to neurons, the biopsied skin cells first have to be grown in the laboratory for a period of time until their numbers increase — a process likely to introduce genetic mutations not found in the person from whom the cells were obtained.

The researchers wondered if there was an easier, more efficient way to generate patient-specific neurons.

‘Somewhat mind-boggling’
In the new study, Wernig and his colleague focused on highly specialized immune cells called T cells that circulate in the blood. T cells protect us from disease by recognizing and killing infected or cancerous cells. In contrast, neurons are long and skinny cells capable of conducting electrical impulses along their length and passing them from cell to cell. But despite the cells’ vastly different shapes, locations and biological missions, the researchers found it unexpectedly easy to complete their quest.

“It’s kind of shocking how simple it is to convert T cells into functional neurons in just a few days,” Wernig said. “T cells are very specialized immune cells with a simple round shape, so the rapid transformation is somewhat mind-boggling.”

The resulting human neurons aren’t perfect. They lack the ability to form mature synapses, or connections, with one another. But they are able to carry out the main fundamental functions of neurons, and Wernig and his colleague are hopeful they will be able to further optimize the technique in the future. In the meantime, they’ve started to collect blood samples from children with autism.

“We now have a way to directly study the neuronal function of, in principle, hundreds of people with schizophrenia and autism,” Wernig said. “For decades we’ve had very few clues about the origins of these disorders or how to treat them. Now we can start to answer so many questions.”

Other Stanford co-authors are postdoctoral scholars Soham Chanda, PhD, and Daniel Haag, PhD; undergraduate student Victor Olmos; professor of psychiatry and behavioral sciences Douglas Levinson, MD; and professor of molecular and cellular physiology Thomas Südhof, MD.

The research was supported by the National Institutes of Health (grants MH092931 and MH104172), the California Institute for Regenerative Medicine, the New York Stem Cell Foundation, the Howard Hughes Medical Institute, the Siebel Foundation and the Stanford Schizophrenia Genetics Research Fund.

The majority of the cells in the brain are no neurons, but Glia (from “glue”) cells, that support the structure and function of the brain. Astrocytes (“start cells”) are star-shaped glial cells providing many supportive functions for the neurons surrounding them, such as the provision of nutrients and the regulation of their chemical environment. Newer studies showed that astrocytes also monitor and modulate neuronal activity. For example, these studies have shown that astrocytes are necessary for the ability of neurons to change the strength of the connections between them, the process underlying learning and memory, and indeed astrocytes are also necessary for normal cognitive function. However, it is still unknown whether astrocytic activity is only necessary, or is it may also be sufficient to induce synaptic potentiation and enhance cognitive performance.

In a new study published in Cell, two graduate students, Adar Adamsky and Adi Kol, from Inbal Goshen’s lab, employed chemogenetic and optogenetic tools that allow specific activation of astrocytes in behaving mice, to explore their role in synaptic activity and memory performance. They found that astrocytic activation in the hippocampus, a brain region that plays an important role in memory acquisition and consolidation, potentiated the synaptic connections in this region, measured in brain slices. Moreover, in the intact brain, astrocytic activation enhanced hippocampal neuronal activity in a task-dependent way: i.e. only during when it was combined with memory acquisition, but not when mice were at their home cage with no meaningful stimuli. The ability of astrocytes to increase neuronal activity during memory acquisition had a significant effect on cognitive function: Specifically, astrocytic activation during learning resulted in enhanced memory in two memory tests. In contrast, direct neuronal activation in the hippocampus induced a non-selective increase in activity (during learning or in the home cage), and thus resulted in drastic memory impairment.

The results suggest that the memory enhancement induced by astrocytic activation during learning is not simply a result of a general increase in hippocampal neuronal activity. Rather, the astrocytes, which sense and respond to changes in the surrounding neuronal activity, can detect and specifically enhance only the neuronal activity involved in learning, without affecting the general activity. This may explain why general astrocytic activation improves memory performance, whereas a similar activation of neurons impairs it.

Memory is not a binary process (remember/don’t remember); the strength of a memory can vary greatly, either for the same memory or between different memories. Here, we show that activating astrocytes in mice with intact cognition improves their memory performance. This finding has important clinical implications for cognitive augmentation treatments. Furthermore, the ability of astrocytes to strengthen neuronal communication and improve memory performance supports the claim that astrocytes are able to take an active part in the neuronal processes underlying cognitive function. This perspective expands the definition of the role of astrocytes, from passive support cells to active cells that can modulate neural activity and thus shape behavior.


by Leigh Hopper

Tnew stroke-healing gel created by UCLA researchers helped regrow neurons and blood vessels in mice whose brains had been damaged by strokes. The finding is reported May 21 in Nature Materials.

“We tested this in laboratory mice to determine if it would repair the brain and lead to recovery in a model of stroke,” said Dr. S. Thomas Carmichael, professor of neurology at the David Geffen School of Medicine at UCLA. “The study indicated that new brain tissue can be regenerated in what was previously just an inactive brain scar after stroke.”

The results suggest that such an approach could some day be used to treat people who have had a stroke, said Tatiana Segura, a former professor of chemical and biomolecular engineering at UCLA who collaborated on the research. Segura is now a professor at Duke University.

The brain has a limited capacity for recovery after stroke. Unlike the liver, skin and some other organs, the brain does not regenerate new connections, blood vessels or tissue structures after it is damaged. Instead, dead brain tissue is absorbed, which leaves a cavity devoid of blood vessels, neurons or axons — the thin nerve fibers that project from neurons.

To see if healthy tissue surrounding the cavity could be coaxed into healing the stroke injury, Segura engineered a hydrogel that, when injected into the cavity, thickens to create a scaffolding into which blood vessels and neurons can grow. The gel is infused with medications that stimulate blood vessel growth and suppress inflammation, since inflammation results in scars and impedes functional tissue from regrowing.

After 16 weeks, the stroke cavities contained regenerated brain tissue, including new neuronal connections — a result that had not been seen before. The mice’s ability to reach for food improved, a sign of improved motor behavior, although the exact mechanism for the improvement wasn’t clear.

“The new axons could actually be working,” Segura said. “Or the new tissue could be improving the performance of the surrounding, unharmed brain tissue.”

The gel was eventually absorbed by the body, leaving behind only new tissue.

The research was designed to explore recovery in acute stroke, the period immediately following a stroke — in mice, that period lasts five days; in humans, it’s two months. Next, Carmichael and Segura plan to investigate whether brain tissue can be regenerated in mice long after the stroke injury. More than 6 million Americans are living with long-term effects of stroke, which is known as chronic stroke.

The other authors of the paper are Lina Nih and Shiva Gojgini, both of UCLA.

The study was supported by the National Institutes of Health.

Scientists have just discovered that a small region of a cellular protein that helps long-term memories form also drives the neurodegeneration seen in motor neuron disease (MND). This small part of the Ataxin-2 protein thus works for good and for bad. When a version of the protein lacking this region was substituted for the normal form in fruit flies (model organisms), the animals could not form long-term memories – but, surprisingly, the same flies showed a remarkable resistance to neurodegeneration.

The popular “ice bucket challenge” highlighted the social significance of MND, as well as the need to better understand and treat neurodegenerative conditions. This new research identifies a very specific basic mechanism that facilitates progression of neuronal loss in an animal model of MND, and, by shedding light on a potential way to protect against cell death in MND, it should inform strategies for the development of therapeutics to treat or manage these devastating conditions, which are currently incurable.

The Science Foundation Ireland-funded research, involving scientists from the Trinity College Institute of Neuroscience, NCBS Bangalore and HMMI, University of Colorado, Boulder, has just been published in the leading international journal Neuron.

Professor of Neurogenetics at Trinity College Dublin, Mani Ramaswami, said: “This work, by collaborating young researchers based in Irish, Indian and American laboratories, provides a great example of the ability of fundamental research in model organisms to produce biologically and clinically interesting information.”

A common feature of neurodegenerative diseases is the presence of specific protein aggregates in nerve cells, which accumulate and clump together — usually as protein fibres called amyloid filaments. Such aggregates are believed to trigger processes that cause the neuronal death associated with these debilitating diseases. For example, amyloid-beta (Aβ) aggregates are associated with Alzheimer’s disease, while TDP-43, FUS and Ataxin-2 proteins are commonly found in MND patients.

The scientists behind the current study set out to test this “amyloid hypothesis” to see whether it may explain how MND develops. The scientists genetically engineered fruit flies with mutations designed to reduce Ataxin-2 protein assembly into aggregates without affecting other functions of the protein.

Arnas Petrauskas, Trinity, said: “The flies with this altered, non-aggregating version of the protein showed a striking resistance to neurodegeneration. This suggests the normal Ataxin-2 protein and its ability to form aggregates is required for the progression of at least some forms of MND, which means these results provide support for the amyloid hypothesis.”

“What really surprised us though was that this same protein region seems to be required for the flies to develop long-term memory, as those with the altered version of Ataxin-2 showed normal short-term but defective long-term memories.”

Fruit flies normally respond strongly to new odorants, but weakly to familiar odorants through a process called habituation. This memory of the familiar can be of the short-term kind – to an odorant encountered for half-an-hour, or of the long-term kind, to odorants encountered for days (think of it as remembering a phone number of a new acquaintance versus remembering your own phone number). Flies lacking this small domain of Ataxin-2 showed greatly reduced long-term memory.

So how is long-term memory formation and disease progression connected? It turns out that proteins like the TDP-43, FUS and Ataxin-2 found in MND are also involved in the natural control and management of protein expression in the cell. The very same region of Ataxin-2 is needed to form RNP granules that store RNAs (essentially blueprints, or recipes for specific proteins) in a silent form until they are unpackaged by a signal and used to produce molecules when they are required. This local control of RNAs is required for long-term changes at neuronal synapses that underlie long-term memory.

The new discovery shows that Ataxin-2 concentrates several RNA-binding proteins used in the process of memory storing, but in doing so, it creates a biological environment that can help these proteins aggregate into disease-causing amyloids. A “trade-off” therefore exists in nature where the Ataxin-2 gene increases the danger of neurodegeneration, but helps our cells control RNA and form long-term memories.

In a commentary on the research published in the same issue of the journal Neuron, Aaron Gitler, Professor of Genetics in the Stanford Neuroscience Institute, an independent expert in MND research said: “This data suggest that manipulating RNP granule formation by genetically manipulating ataxin-2’s IDRs, or by other means could be therapeutic in ALS. Beyond ataxin-2, the race is now on to discover additional proteins that help build RNP granules.”

By Ashley Yeager

Researchers have transferred a memory from one snail to another via RNA, they report today (May 14) in eNeuro. If confirmed in other species, the finding may lead to a shift in scientists’ thinking about how memories are made—rather than cemented in nerve-cell connections, they may be spurred on by RNA-induced epigenetic changes.

“The study suggests that RNA populations are the missing link in the search for memory,” Bridget Queenan, a neuroscientist at the University of California, Santa Barbara, who was not involved in the study, writes in an email to The Scientist. “If circulating neural RNAs can transfer behavioral states and tendencies, orchestrating both the transient feeling and the more permanent memory, it suggests that human memory—just like mood—will only be explained by exploring the interplay between bodies and brains.”

For decades, researchers have tried to pinpoint how, when, and where memories form. In the 1940s, Canadian psychologist Donald Hebb proposed memories are made in the connections between neurons, called synapses, and stored as those connections grow stronger and more abundant. Experiments in the 1960s, however, suggested RNA could play a role in making memories, though the work was largely written off as irreproducible.

Study coauthor David Glanzman of the University of California, Los Angeles, has been working on the cell biology of learning and memory for nearly 40 years, and says for the majority of that time he believed memory was stored at synapses. Several years ago, though, he and his colleagues began replicating memory-erasing research done in rodents in California sea hares (Aplysia californica), a type of marine snail also called a sea slug. The team found that the snail synapses built to “store” a memory weren’t necessarily the synapses that were removed from the neural circuits in the memory-erasing experiments.

“It was completely arbitrary which synaptic connections got erased,” Glanzman says. “That suggested maybe the memory wasn’t stored at the synapse but somewhere else.”

Glanzman turned his attention to RNA because of those earlier hints it was related to memory, and also because of recent experiments suggesting long-term memory was stored in the cell bodies of neurons, not synapses. He picked Aplysia because it has been a longtime model organism for memory studies. Like all mollusks, these snails have groups of neurons called ganglia, rather than brains. Their nervous systems comprise about 20,000 neurons, and the cells are some of the biggest and easily identifiable among nerve cells in all animals. In the snail’s gut, for example, are specific sensory and motor neurons that control the withdrawal of a fleshy, spout-like organ on the snail’s back called a siphon and the contraction of a caterpillar-looking gill, which the animal uses to breathe.

When touched lightly on the siphon, the neurons fire, retract the tissue, and contract the gill within the body cavity for a few seconds to protect it against attack. Sticking electrodes in the snail’s tail and shocking it makes this defensive response last longer, tens of seconds, and sometimes up to almost a minute. By repeatedly shocking the snail’s tail, the animal learns to stay in that defensive position when touched on the siphon, even weeks after the shocks end.

In his team’s latest experiments, Glanzman and his colleagues zapped snails’ tails, then pulled the abdominal neurons from the shocked snails, extracted their RNA, dissolved the RNA into deionized water, and injected the solution into the necks of snails that had never been shocked. (For a control, the team also took RNA from non-shocked snails and injected into naive snails.) When tapped on the siphon 24 hours later, snails that got RNA from shocked snails withdrew their siphon and gill for significantly longer (almost 40 seconds) than did snails that got RNA from non-shocked animals (less than 10 seconds).

DNA methylation appeared to be essential for the transfer of the memory among snails. When Glanzman and his colleagues blocked DNA methylation in snails getting RNA from shocked ones, the injected snails withdrew their siphons for only a few seconds when tapped on the siphon.

Glanzman wanted to know if the RNA from shocked snails actually affected the neuronal connections of the snails receiving the injections any differently than RNA from nonshocked snails. So, in a third test, he and his team removed sensory neurons from nonshocked snails, cultured the cells in a dish, and then exposed the cells to RNA from shocked snails. Zapping the culture with a bit of current excited the sensory neurons much more than neurons treated with RNA from nonshocked snails. RNA from shocked snails also enhanced a subset of synapses between sensory and motor neurons in vitro, suggesting it was indeed the RNA that transported the memory, Glanzman explains.

The idea “seems quite radical as we don’t have a specific mechanism for how it works in a non-synaptic manner,” Bong-Kiun Kaang, a neuroscientist at Seoul National University who was not involved in the study, writes in an email to The Scientist. Kaang notes there are “many critical questions that need to be addressed to further validate the author’s argument,” such as what kinds of noncoding RNAs are specifically involved, how are the RNAs transferred among neurons, and how much do RNAs at the synapse play a role? The experiments should also be replicated in organisms other than snails, he says.

Glanzman says that in his next experiments he will attempt to identify the RNAs involved, and he has an idea for the mechanism, too. The memory is not stored in the RNA itself, he speculates—instead, noncoding RNA produces epigenetic changes in the nucleus of neurons, thereby storing the memory.

“This idea is probably going to strike most of my colleagues as extremely improbable,” Glanzman says. “But if we’re right, we’re just at the beginning of understanding how memory works.”

A. Bédécarrats et al., “RNA from trained Aplysia can induce an epigenetic engram for long-term sensitization in untrained Aplysia,” eNeuro,, 2018.