nerve cells

Making Sense of the Senses: ‘Context’ Matters When the Brain Interprets Sounds

The brain’s interpretation of sound is influenced by cues from other senses, explaining more precisely how we interpret what we hear at a particular moment, according to a report published online October 31 in Nature Neuroscience.

In the new study in mice, researchers at NYU Langone Medical Center found that nerve cells dedicated to hearing also rely on surrounding context to properly interpret and react to familiar sounds.

“What the brain ‘hears’ depends on what is ‘seen’ in addition to specific sounds, as the brain calculates how to respond,” says study senior investigator and neuroscientist Robert Froemke, PhD, an assistant professor at NYU Langone and its Skirball Institute of Biomolecular Medicine.

Froemke says his team’s latest findings reveal that while mammals recognize sounds in the auditory cortex of their brains, the signaling levels of nerve cells in this brain region are simultaneously being strengthened or weakened in response to surrounding context.

“Our study shows how the same sound can mean different things inside the brain depending on the situation,” says Froemke. “We know, for instance, that people learn to respond without alarm to the honk of a car horn if heard from the safety of their homes, but are startled to hear the same honk while crossing a busy street.”

If further experiments find similar activity in human brains, the researchers say their work may lead to precise explanations of situation-specific behaviors, such as anxiety brought on during math exams; sudden post-traumatic stress among combat veterans hearing a car backfire; and the ability of people with dementia to better remember certain events when they hear a familiar voice or see a friend’s face.

To map how the same sense can be perceived differently in the brain, the NYU Langone team, led by postdoctoral fellow Kishore Kuchibhotla, PhD, monitored nerve circuit activity in mice when the animals expected, and did not expect, to get a water reward through a straw-like tube (that they see) after the ringing of a familiar musical note.

When mice were exposed to specific auditory cues, researchers observed patterns based on a basic divide in the nature of nerve cells. Each nerve cell “decides” whether a message travels onward in a nerve pathway. Nerve cells that emit chemicals which tell the next cell in line to amplify a message are excitatory; those that stop messages are inhibitory. Combinations of the two strike a counterbalance critical to the function of the nervous system, with inhibitory cells sculpting “noise” from excitatory cells into the arrangements behind thought and memory.

Furthermore, the processing of incoming sensory information is achieved in part by adjusting signaling levels through each type of nerve cell. Theories hold that the brain may attach more importance to a given signal by turning up or down excitatory signals, or by doing the same with inhibitory nerve cells.

In the current study, researchers found to their surprise that most of the nerve cells in auditory cortex neurons that stimulate brain activity (excitatory) had signaled less (had “weaker” activity) when the mice expected and got a reward. Meanwhile, and to the contrary, a second set of remaining “excitatory” neurons saw greater signaling activity when mice expected a reward based on exposure to the two sensory cues and got one.

Further tests showed that the activation of specific inhibitory neurons—parvalbumin, somatostatin, and vasoactive intestinal peptide—was responsible for these changes and was in turn controlled by the chemical messenger, or neurotransmitter, acetylcholine. Chemically shutting down acetylcholine activity cut in half the number of times mice successfully went after their water reward when prompted by a ring tone. Some studies in humans have linked acetylcholine depletion to higher rates of Alzheimer’s disease.

Froemke, who is also a faculty scholar at the Howard Hughes Medical Institute, says the team next plans to assess how the hormones noradrenaline and dopamine affect auditory cortex neurons under different situations.

“If we can sort out the many interactions between these chemicals and brain activity based on sensory perception and context, then we can possibly target specific excitatory and inhibitory neurological pathways to rebalance and influence behaviors,” says Froemke.

Karl von Frisch - The Human Body and Types of Tissue Cells, “Man and the Living World”, 1965.

Upper left, nerve cell and its fibers; below, in order, muscle cells of the arm, connective tissue surrounding muscle, tough fibrous connective tissue of a tendon. Upper right, cells of cartilage; below, in order, outer cells of skin, structure of bone, and cells of the fatty tissue.

'SpongeBob' creator says he has Lou Gehrig's disease

The creator of Nickelodeon’s “SpongeBob SquarePants” says he has been diagnosed with Lou Gehrig’s disease.

Stephen Hillenburg tells Variety that he will continue to work on the show and his other passions for as long as he’s able.

Lou Gehrig’s disease, also known as ALS, is a progressive disease that attacks nerve cells that control the muscles. There is no known cure.

The 55-year-old Hillenburg is a former marine biology teacher who created the series featuring an animated sponge that lives in a pineapple under the sea in 1999.

Nickelodeon says in a statement to Variety that Hillenburg “is a brilliant creator who brings joy to millions of fans” and that the network’s “thoughts and support” are with Hillenburg and his family.

The Associated Press

pondering of the day: can robots have mental illnesses?

my personal opinion is yes. from webmd: “Some mental illnesses have been linked to abnormal functioning of nerve cell circuits or pathways that connect particular brain regions.” human brains run on circuits; so would a robot brain, correct? just different, more literal circuits. but theres no reason to think that every robot would be built “perfectly” all the time. abnormalities in the functioning of their brain, just like in humans, could easily lead to conditions that mirror human mental illnesses. especially considering the sheer complexity of a brain, it seems very plausible to me that robots could be manufactured with many unexpected traits, differing uniquely from robot to robot

in short, just like how all humans are unique

and then, of course, some mental illness can be brought about by environmental factors (traumatic events, etc.) that case gets an even more resounding “yes” from me: a sentient robot with human or above human intelligence would naturally react and change according to events happening around them. and assuming they are programmed with emotions, trauma would affect them just like it does anything else that is alive and able to think and feel

thoughts?

Supporting the damaged brain

A new study shows that embryonic nerve cells can functionally integrate into local neural networks when transplanted into damaged areas of the visual cortex of adult mice.

(Image caption: Neuronal transplants (blue) connect with host neurons (yellow) in the adult mouse brain in a highly specific manner, rebuilding neural networks lost upon injury. Credit: Sofia Grade, LMU/Helmholtz Zentrum München)

When it comes to recovering from insult, the adult human brain has very little ability to compensate for nerve-cell loss. Biomedical researchers and clinicians are therefore exploring the possibility of using transplanted nerve cells to replace neurons that have been irreparably damaged as a result of trauma or disease. Previous studies have suggested there is potential to remedy at least some of the clinical symptoms resulting from acquired brain disease through the transplantation of fetal nerve cells into damaged neuronal networks. However, it is not clear whether transplanted intact neurons can be sufficiently integrated to result in restored function of the lesioned network. Now researchers based at LMU Munich, the Max Planck Institute for Neurobiology in Martinsried and the Helmholtz Zentrum München have demonstrated that, in mice, transplanted embryonic nerve cells can indeed be incorporated into an existing network in such a way that they correctly carry out the tasks performed by the damaged cells originally found in that position. Such work is of importance in the potential treatment of all acquired brain disease including neurodegenerative illnesses such as Alzheimer‘s or Parkinson’s disease, as well as strokes and trauma, given each disease state leads to the large-scale, irreversible loss of nerve cells and the acquisition of a what is usually a lifelong neurological deficit for the affected person.

In the study published in Nature, researchers of the Ludwig Maximilians University Munich, the Max Planck Institute of Neurobiology, and the Helmholtz Zentrum München have specifically asked whether transplanted embryonic nerve cells can functionally integrate into the visual cortex of adult mice. “This region of the brain is ideal for such experiments,” says Magdalena Götz, joint leader of the study together with Mark Hübener. Hübener is a specialist in the structure and function of the mouse visual cortex in Professor Tobias Bonhoeffer’s Department (Synapses – Circuits – Plasticity) at the MPI for Neurobiology. As Hübener explains, “we know so much about the functions of the nerve cells in this region and the connections between them that we can readily assess whether the implanted nerve cells actually perform the tasks normally carried out by the network.” In their experiments, the team transplanted embryonic nerve cells from the cerebral cortex into lesioned areas of the visual cortex of adult mice. Over the course of the following weeks and months, they monitored the behavior of the implanted, immature neurons by means of two-photon microscopy to ascertain whether they differentiated into so-called pyramidal cells, a cell type normally found in the area of interest. “The very fact that the cells survived and continued to develop was very encouraging,” Hübener remarks. “But things got really exciting when we took a closer look at the electrical activity of the transplanted cells.” In their joint study, PhD student Susanne Falkner and Postdoc Sofia Grade were able to show that the new cells formed the synaptic connections that neurons in their position in the network would normally make, and that they responded to visual stimuli.

The team then went on to characterize, for the first time, the broader pattern of connections made by the transplanted neurons. Astonishingly, they found that pyramidal cells derived from the transplanted immature neurons formed functional connections with the appropriate nerve cells all over the brain. In other words, they received precisely the same inputs as their predecessors in the network. In addition, they were able to process that information and pass it on to the downstream neurons which had also differentiated in the correct manner. “These findings demonstrate that the implanted nerve cells have integrated with high precision into a neuronal network into which, under normal conditions, new nerve cells would never have been incorporated,” explains Götz, whose work at the Helmholtz Zentrum and at LMU focuses on finding ways to replace lost neurons in the central nervous system. The new study reveals that immature neurons are capable of correctly responding to differentiation signals in the adult mammalian brain and can close functional gaps in an existing neural network.

There should be more posts honouring and remembering Rita Levi Montalcini. I know she’s atypical for those “women in science” posts, because her work was honoured in her later life, with a Nobel too, and she was nominated as a senator for life, one of the highest honours that Italy can grant. But she studied as a Jewish woman in the 1930s, under fascism, and when antisemitic laws prevented her from retaining her job as an academic assistant, she set up a home laboratory where she studied the growth of nerve cells throughout ww2. There cannot ever be enough appreciation for such a great woman.

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naobro’s “Medical Tidbits” blog #7; 05/22/2013

The top image from dd.dynamicdiagrams.com, the middle one from flickr.com/photos/bethscupham/7362405446 & the bottom from en.wikipedia.org/wiki/Wilder_Penfield. The top 2 images show the Motor & the Sensory Homunculus created by Dr. Wilder Penfield, a Canadian neurosurgeon (the bottom image; while he was at Princeton). The middle image shows the brain area responsible for moving the body in pink. It also shows the brain area responsible for feeling the body in orange. These areas sit next to each other, at the top down to the middle of the brain. The 2 Homunculi show how big an area of the brain (how many nerve cells) is dedicated to each body part. The Homunculi were created by superimposing the images of our body parts onto those brain areas according to the representation. They hang upside down on our brain; with their feet at the top & their faces at the bottom. See how big brain areas are dedicated to moving/feeling our hands & face, especially the lips!

anonymous asked:

Your vagina is a self cleansing muscular tract with over 50,000 nerve cells ready to act! In fact, 6.5 inches side to side and with a PH value of 4.5! When you become aroused blood flow increases to the vagina, labia and clitoris, the inner walls of the vulva expand, as well as increasing vaginal lubrication!

Thank you for these interesting anatomical facts! Vaginas are really cool.

Quick fact. Ready?
Concussions often result with a decrease in neuronal functioning. Why? The brain tries to protect itself by creating more stabilizing proteins for its neurons, however too many of these proteins eventually leads to nerve cell death.

I’m a mutant, I guess.

I’d always known that my tentative diagnosis of myasthenia gravis was… tentative. Meaning, because of elements of my personal and family histories, there’s always been a suspicion that I (and other living family members) might have a form of congenital myasthenia. Complicating things of course, is the fact that there have been recent discoveries of hereditary myasthenia that is autoimmune.

So… normally the way they classify myasthenia is into two basic categories:

  1. Myasthenia gravis, which is more common, not generally hereditary, and is caused by an autoimmune disease. Autoimmune diseases happen when your immune system mistakes part of your body for a dangerous foreign invader and attacks it. For instance, in Hashimoto’s disease (which runs in my family, but I don’t have any sign of it — yet, anyway), your immune system attacks your thyroid. In multiple sclerosis, your immune system attacks the protective myelin covering around your nerve cells. And in myasthenia gravis, your immune system attacks the neuromuscular junction, which is the area where the nerve meets the muscle.

  2. Congenital myasthenia. Congenital myasthenia is genetic and hereditary, and is not autoimmune. With congenital myasthenia, you’re born with at least some degree of the problems inherent in any kind of myasthenia. Sometimes it stays mild throughout your life, and sometimes it gets worse over time (or suddenly worsens and stays worse), and sometimes it starts out very obvious and stays very obvious. Congenital myasthenia is rare. Some forms of it are so rare that each family that has the condition has it from a totally unique genetic configuration that are not found in other families.

And recently, they have discovered that there are some forms of myasthenia that are both inherited and autoimmune. I don’t know a lot about genetic autoimmune diseases, but I assume it works a lot like Hashimoto’s in my family, where many of the biological women in one branch of the family seem to develop it at some point in their lifetimes, but at what time some event triggers it into becoming active, varies greatly. Like, one person might get a totally ordinary virus at the age of twenty, that somehow triggers their immune system along with whatever genetic predisposition they have, to attack their thyroid. But in another person, the same sort of thing happens, only in their fifties. So there’s the gene that determines a body is going to react this way to certain physiological events, but which physiological events trigger the onset of the active disease varies. Understand, I’m not a medical professional, this is just how I’ve heard it described by relatives and by other people with hereditary Hashimoto’s in their families. I don’t know if all forms of hereditary autoimmune disease work this way. And hereditary myasthenia gravis is barely being discovered right now, so there’s a lot they don’t know.

Meanwhile, there’s a lot they don’t know about congenital myasthenia because there just aren’t a lot of people who have it.

Anyway, until now, we’d been in one sort of unknown territory with my diagnosis. Now, we seem to be in a completely new sort of unknown territory. Lots of unknowns here. Nothing is certain, even my genetic testing provides as many questions as answers. (And no, I’m not going to go into details about what testing I’ve had. That information is private.)

So anyway, to clear up some confusion… myasthenia gravis refers specifically to autoimmune myasthenia. Congenital myasthenia is the term for non-autoimmune, genetic myasthenia. I don’t know WTF they’re going to call hereditary autoimmune myasthenia — congenital myasthenia gravis, hereditary myasthenia gravis, hereditary autoimmune myasthenia, WTF? As I said, no clue. Anyway, a lot of people just refer to all myasthenia as myasthenia gravis and abbreviate it to MG. This is because most people have only heard of MG and not of congenital myasthenia, even people who are diagnosed with MG. And because congenital myasthenia is rare enough that often support groups for all people with all kinds of myasthenia have MG as part of the name and people with congenital myasthenia are welcome, but people are just used to saying MG when they mean myasthenia in general.

So… I’ve gotten genetic testing. And I do have a rare mutation in a gene associated with one form of congenital myasthenia. My symptoms, now and throughout my lifetime, are well within the range of case reports I’ve read about this variety. Only thing is, so far they’ve only studied people with myasthenia who have two copies of the gene, and have not studied people with only one who have myasthenia, so they’ve assumed that two copies are required. My doctors think it would be way too unlikely a coincidence for me to have traits consistent with congenital myasthenia, other immediate family members with these traits as well, and to have a mutation in this gene, and have that all just be random coincidence with no relation to each other just because I only have one copy of the gene. So their working hypothesis is that, as with other recessive conditions, most people with one copy would not have symptoms, but some people, me probably included, have myasthenia from only one copy, but simply not as severe as it would be if we had two copies. They say this sort of thing happens with other recessive conditions, that genetics can be more complicated than a layperson’s view of them can make them out to be, and that… yeah, it would just be an ultra-weird, or more like close-to-impossible coincidence for me to have a rare mutation that’s usually connected with a disease I and several close relatives have symptoms of (and diagnostic testing and response to meds both showing we have neuromuscular junction problems) and have been diagnosed with, and then, for those things to just be two totally unrelated random things that have nothing to do with each other. So current hypothesis is that I have incompletely expressed congenital myasthenia.

This means I get to go off of the immune suppressants I was on (and it was scary being on something that’s normally a transplant rejection drug), and may never have to go on plasmapheresis. Meanwhile I will be switched to a treatment regimen more consistent with the recommendations for congenital myasthenia. Until proven otherwise, we’ll assume I have congenital myasthenia. Which, to me, suggests that the evidence for congenital myasthenia is now pretty strong, because most people with myasthenia, me previously included, are treated as if we have myasthenia gravis unless there’s a definite reason to believe otherwise. This is because myasthenia gravis is way more common therefore more likely. Even knowing it seemed to run in my family, they were using myasthenia gravis as the working hypothesis. So for them to change their minds suggests to me that, while we may never know exactly what’s going on (being realistic, the research may never catch up to people like me within my lifetime, if what we suspect is true), there’s strong evidence at this point for congenital myasthenia, strong enough to justify changing all my meds around.

So if you ever hear me saying I have myasthenia gravis, it’s probably just force of habit. Probably the most neutral term I could use is just myasthenia. But I do strongly suspect congenital myasthenia now, and so do my neurologist (who’s well-respected both by doctors and patients, and seems better at teasing out difficult diagnoses than most, because he just methodically goes through every possibility, even remote ones, rather than leaping to conclusions) and my GP (also very well-respected by both doctors and patients). It’s just not the sort of thing we’ll necessarily be able to prove. Especially since, as my neurologist pointed out, they haven’t even found all the genes for congenital myasthenia, not even close, just as they haven’t found all the antibodies involved in myasthenia gravis. Congenital myasthenia would also explain, though, why I (and family) tests positive for myasthenia on single-fiber EMGs but show no sign of the usual antibodies found with MG.

Anyway, either way, I appear to be a mutant. But having muscles that go floppy with exercise doesn’t seem like much of a superpower. Oh well.

I also appear to be weirdly panicky when I think about all this too directly. I’m not sure why. It’s not like anything’s changed. But something about this is feeling like one of those “Shit, my entire view of huge chunks of my entire life is totally different now and I’m going to be sifting through this information for a long time.” And for whatever reason, that kind of thing can be mind-blowingly terrifying at times. I can’t even read about congenital myasthenia right now, it’s one reason I’m relying on memory for a lot of my facts, so don’t 100% trust what I say about all the different kinds of myasthenia and stuff, I’m going entirely on memory. When I first got the test results back, I was able to read just enough to realize I fit more of the congenital myasthenia profile than I thought I did (there’s nothing all that unusual about my personal history, for someone with congenital myasthenia), but since then I haven’t been able to stand looking at the research or even summaries of the research, without freaking out.

Scientists Keep a Molecule from Moving Inside Nerve Cells to Prevent Cell Death

Amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is a progressive disorder that devastates motor nerve cells. People diagnosed with ALS slowly lose the ability to control muscle movement, and are ultimately unable to speak, eat, move, or breathe. The cellular mechanisms behind ALS are also found in certain types of dementia.

A groundbreaking scientific study published in Nature Medicine has found one way an RNA binding protein may contribute to ALS disease progression. Cells make RNA to carry instructions for making proteins from DNA to protein-constructing machinery.

The culprit protein, TDP-43, normally binds to small pieces of newly read RNA and helps shuttle the fragments around inside nerve cell nuclei. The study describes for the first time the molecular consequences of misplaced TDP-43 inside nerve cells, and demonstrates that correcting its location can restore nerve cell function. Misplacement of TDP-43 in nerve cells is a hallmark of ALS and other neurological disorders including frontotemporal dementia (FTD), Alzheimer’s, Parkinson’s, and Huntington’s diseases. Studies that characterize common mechanisms behind these diseases could have widespread implications and may also accelerate development of broad-based therapies.

To find the misplaced TDP-43, the researchers viewed nerve cells donated by people who died from ALS or FTD under high powered microscopes. They discovered TDP-43 accumulates in nerve cell mitochondria, critical structures responsible for generating the enormous amount of energy nerve cells require. By physically isolating the affected mitochondria the researchers were able to pinpoint TDP-43’s exact location inside the subcellular structures. They were also able to characterize variations of the protein most likely to get misplaced.

This important work was led by Xinglong Wang, PhD, from the department of pathology at Case Western Reserve University School of Medicine and a team of scientists from his laboratory.

“By multiple approaches, we have identified the mitochondrial inner membrane facing matrix as the major site for mitochondrial TDP-43,” explained Wang. “Mitochondria might be major accumulation sites of TDP-43 in dying neurons in various major neurodegenerative diseases.”

The researchers discovered that once inside the mitochondria, TDP-43 resumes its RNA binding role and attaches itself to mitochondrial genetic material. This disrupts the mitochondria’s ability to generate energy for the cell. Wang’s team was able to precisely identify the RNA in mitochondria that was bound by TDP-43 and observe the resultant disassembly of mitochondrial protein complexes. This finding provides much needed clarity on the consequences of TDP-43 misplacement inside nerve cells and opens the door for deeper studies involving a range of neurological disorders. Although the study focused on ALS and FTD, according to Wang “mislocalization of TDP-43 represents a key pathological feature correlating strongly with symptoms in more than half of Alzheimer’s disease patients.”

Mutations in the gene encoding TDP-43 have long been linked to neurodegenerative diseases like ALS and FTD. Wang’s team found that disease-associated mutations in TDP-43 enhance its misplacement inside nerve cells. The researchers also identified sections of TDP-43 that are recognized by mitochondria and serve as signals to let it inside. These sections could serve as therapeutic targets, as the study found blocking them prevents TDP-43 from localizing inside mitochondria. Importantly, Wang’s team was able to keep TDP-43 out of nerve cell mitochondria in mice using small proteins which “almost completely” prevented nerve cell toxicity and disease progression.

“We, for the first time, provide the novel concept that the inhibition of TDP-43 mitochondrial localization is sufficient to prevent TDP-43-linked neurodegeneration,” said Wang. “Targeting mitochondrial TDP-43 could be a novel therapeutic approach for ALS, FTD and other TDP-43-linked neurodegenerative diseases.”

Wang has begun to develop small proteins that prevent TDP-43 from reaching mitochondria in human nerve cells, and has a patent pending for the therapeutic molecule used in the study.

There is no treatment currently available for ALS or FTD. The average life expectancy for people newly diagnosed with ALS is just three years, according to The ALS Association.

The Brain’s Gardeners: Immune Cells ‘Prune’ Connections Between Neurons

A new study, published in the journal Nature Communications, shows that cells normally associated with protecting the brain from infection and injury also play an important role in rewiring the connections between nerve cells. While this discovery sheds new light on the mechanics of neuroplasticity, it could also help explain diseases like autism spectrum disorders, schizophrenia, and dementia, which may arise when this process breaks down and connections between brain cells are not formed or removed correctly.

(Image caption: Microglia (green) with purple representing the P2Y12 receptor which the study shows is a critical regulator in the process of pruning connections between nerve cells)

“We have long considered the reorganization of the brain’s network of connections as solely the domain of neurons,” said Ania Majewska, Ph.D., an associate professor in the Department of Neuroscience at the University of Rochester Medical Center (URMC) and senior author of the study. “These findings show that a precisely choreographed interaction between multiple cells types is necessary to carry out the formation and destruction of connections that allow proper signaling in the brain.”

The study is another example of a dramatic shift in scientists’ understanding of the role that the immune system, specifically cells called microglia, plays in maintaining brain function. Microglia have been long understood to be the sentinels of the central nervous system, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up dead cell tissue. However, scientists are now beginning to appreciate that, in addition to serving as the brain’s first line of defense, these cells also have a nurturing side, particularly as it relates to the connections between neurons.

The formation and removal of the physical connections between neurons is a critical part of maintaining a healthy brain and the process of creating new pathways and networks among brain cells enables us to absorb, learn, and memorize new information.  

“The brain’s network of connections is like a garden,” said Rebecca Lowery, a graduate student in Majewska’s lab and co-author of the study. “Not only does it require nourishment and a healthy environment, but every once in a while you need to prune dead branches and pull up weeds in order to allow new flowers to grow.”

While this constant reorganization of neural networks – called neuroplasticity – has been well understood for some time, the basic mechanisms by which connections between brain cells are made and broken has eluded scientists.

Performing experiments in mice, the researchers employed a well-established model of measuring neuroplasticity by observing how cells reorganize their connections when visual information received by the brain is reduced from two eyes to one.

The researchers found that in the mice’s brains microglia responded rapidly to changes in neuronal activity as the brain adapted to processing information from only one eye. They observed that the microglia targeted the synaptic cleft – the business end of the connection that transmits signals between neurons. The microglia “pulled up” the appropriate connections, physically disconnecting one neuron from another, while leaving other important connections intact.

This is similar to what occurs during an infection or injury, in which microglia are activated, quickly navigate towards the injured site, and remove dead or diseased tissue while leaving healthy tissue untouched.

The researchers also pinpointed one of the key molecular mechanisms in this process and observed that when a single receptor – called P2Y12 – was turned off the microglia ceased removing the connections between neurons.

These findings may provide new insight into disorders that are the characterized by sensory or cognitive dysfunction, such as autism spectrum disorders, schizophrenia, and dementia. It is possible that when the microglia’s synapse pruning function is interrupted or when the cells mistakenly remove the wrong connections – perhaps due to genetic factors or because the cells are too occupied elsewhere fighting an infection or injury – the result is impaired signaling between brain cells.

“These findings demonstrate that microglia are a dynamic and integral component of the complex machinery that allows neurons to reorganize their connections in the healthy mature brain,” said Grayson Sipe, a graduate student in Majewska’s lab and co-author of the study. “While more work needs to be done to fully understand this process, this study may help us understand how genetics or disruption of the immune system contributes to neurological disorders.”

anonymous asked:

Would it be okay if I used the symptoms of synesthesia you said your grandfather had for a character in a fic I'm writing? I don't want to do it if it will offend you or you don't feel comfortable with me doing it (but let's face it: I'm an awful writer and I don't have synesthesia so I don't know what it's like and even if I didn't have that in there it would still turn out awful so really telling me no isn't going to change anything so feel free to do so)

Of course it would be okay! I think it would be very unique for a character to do so. Synesthesia is not a disorder that does damage, as far as I know, but simply over-working nerve cells, so there really is know reason to be scared to write about it :) it’s kinda cool. (Rather unfortunate during concerts tho…lol) also, if you’d want I could explain more about my grandfathers type of synesthesia if you’d like. Message me! Also, tag me in the fic hehe xx

New role for immature brain neurons in the dentate gyrus identified

University of Alabama at Birmingham researchers have proposed a model that resolves a seeming paradox in one of the most intriguing areas of the brain — the dentate gyrus.

This region helps form memories such as where you parked your car, and it also is one of only two areas of the brain that continuously produces new nerve cells throughout life.

“So the big question,” said Linda Overstreet-Wadiche, Ph.D., associate professor in the UAB Department of Neurobiology, “is why does this happen in this brain region? Entirely new neurons are being made. What is their role?”

In a paper published in Nature Communications on April 20, Overstreet-Wadiche and colleagues at UAB; the University of Perugia, Italy; Sandia National Laboratories, Albuquerque, New Mexico; and Duke University School of Medicine; present data and a simple statistical network model that describe an unanticipated property of newly formed, immature neurons in the dentate gyrus.

These immature granule cell neurons are thought to increase pattern discrimination, even though they are a small proportion of the granule cells in the dentate gyrus. But it is not clear how they contribute.

This work is one small step — along with other steps taken in a multitude of labs worldwide — towards cracking the neural code, one of the great biological challenges in research. As Eric Kandel and co-authors write in Principles of Neural Science, “The ultimate goal of neural science is to understand how the flow of electrical signals through neural circuits gives rise to the mind — to how we perceive, act, think, learn and remember.”

Newly formed granule cells can take six-to-eight weeks to mature in adult mice. Researchers wondered if the immature cells had properties that made them different. More than 10 years ago, researchers found one difference — the cells showed high excitability, meaning that even small electrical pulses made the immature cells fire their own electrical spikes. Thus they were seen as “highly excitable young neurons,” as described by Alejandro Schinder and others in the field.

But this created a paradox. Under the neural coding hypothesis, high excitability should degrade the ability of the dentate gyrus — an important processing center in the brain — to perceive the small differences in input patterns that are crucial in memory, to know your spatial location or the location of your car.

“The dentate gyrus is very sensitive to pattern differences,” Overstreet-Wadiche said. “It takes an input and accentuates the differences. This is called pattern separation.”

The dentate gyrus receives input from the entorhinal cortex, a part of the brain that processes sensory and spatial input from other regions of the brain. The dentate gyrus then sends output to the hippocampus, which helps form short- and long-term memories and helps you navigate your environment.

In their mouse brain slice experiments, Overstreet-Wadiche and colleagues did not directly stimulate the immature granule cells. They instead stimulated neurons of the entorhinal cortex.

“We tried to mimic a more physiological situation by stimulating the upstream neurons far away from the granule cells,” she said.

Use of this weaker and more diffuse stimulation revealed a new, previously underappreciated role for the immature dentate gyrus granule cells. Since these cells have fewer synaptic connections with the entorhinal cortex cells, as compared with mature granule cells, this lower connectivity meant that a lower signaling drive reached the immature granule cells when stimulation was applied at the entorhinal cortex.

The experiments by Overstreet-Wadiche and colleagues show that this low excitatory drive make the immature granule cells less — not more — likely to fire than mature granule cells. Less firing is known in computational neuroscience as sparse coding, which allows finer discrimination among many different patterns.

“This is potentially a way that immature granule cells can enhance pattern separation,” Overstreet-Wadiche said. “Because the immature cells have fewer synapses, they can be more selective.”

Seven years ago, paper co-author James Aimone, Ph.D., of Sandia National Laboratories, had developed a realistic network model for the immature granule cells, a model that incorporated their high intrinsic excitability. When he ran that model, the immature cells degraded, rather than improved, overall dentate gyrus pattern separation. For the current Overstreet-Wadiche paper, Aimone revised a simpler model incorporating the new findings of his colleagues. This time, the statistical network model showed a more complex result — immature granule cells with high excitability and low connectivity were able to broaden the range of input levels from the entorhinal cortex that could still create well-separated output representations.

In other words, the balance between low synaptic connectivity and high intrinsic excitability could enhance the capabilities of the network even with very few immature cells.

“The main idea is that as the cells develop, they have a different function,” Overstreet-Wadiche said. “It’s almost like they are a different neuron for a little while that is more excitable but also potentially more selective.”

The proposed role of the immature granule cells by Overstreet-Wadiche and colleagues meshes with prior experiments by other researchers who found that precise removal of immature granule cells of a rodent, using genetic manipulations, creates difficulty in distinguishing small differences in contexts of sensory cues. Thus, removal of this small number of cells degrades pattern separation.

Study Sheds New Light on Brain’s Source of Power

New research published in the journal Nature Communications represents a potentially fundamental shift in our understanding of how nerve cells in the brain generate the energy needed to function. The study shows neurons are more independent than previously believed and this research has implications for a range of neurological disorders. 

“These findings suggest that we need to rethink the way we look at brain metabolism,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Center for Translational Neuromedicine and lead author of the study. “Neurons, and not the brain’s support cells, are the primary consumers of glucose and this consumption appears to correlate with brain activity.”

The brain requires a tremendous amount of energy to do its job. While it only represents 2 percent of the body mass of the average adult human, the brain consumes an estimated 20 percent of body’s energy supply. Consequently, unravelling precisely how the brain’s cells – specifically, neurons – generate energy has significant implications for not only the understanding of basic biology, but also for neurological diseases which may be linked to too little, or too much, metabolism in the brain.

Our digestive system converts carbohydrates found in food into glucose, a sugar molecule that is the body’s main source of energy, which is then transported throughout the body via the blood system. Once inside cells, the mitochondria, which serve as tiny cellular power plants, combine these sugars with oxygen to generate energy.

Unlike the rest of the body, the brain maintains its own unique ecosystem. Scientists have long believed that a support cell found in the brain, called the astrocyte, played an intermediary role in the supplying neurons with energy. This theory is called the lactate shuttle hypothesis.

Scientists have speculated that the astrocytes are the brain’s primary consumer of glucose and, like a mother bird that helps its chicks digest food, these cells convert the molecules to another derivative (lactate) before it is passed along to the neurons. Lactate is a form of sugar molecule that is used by mitochondria for fuel.

“The problem with the lactate shuttle hypothesis is that by outsourcing lactate production to astrocytes, it places the neuron in a dangerous position,” said Nedergaard. “Why would neurons, the cell type that is most critical for our survival, be dependent upon another cell for its energy supply?”

The new research, which was conducted in both mice and human brain cells, was possible due to new imaging technologies called 2-photon microscopy that enable scientists to observe activity in the brain in real time.

Using a glucose analogue, the researchers found that it was the neurons, and not the astrocytes, that directly take up more glucose in the brain. They also found that when stimulated and more active, the neurons increase consumption of glucose, and when the mice where anesthetized, there was less neuronal uptake of glucose. On the other hand, the uptake of glucose by astrocytes remained relatively constant regardless of brain activity.

On the cellular level, the researchers observed that the neurons were doing their own job of converting glucose to lactate and that an enzyme that plays a key role in the creation lactate, called hexokinase, was present in greater amounts in neurons compared to astrocytes.

These findings have significant implications for understanding a host of diseases. The overproduction of lactate can result in lactic acidosis, which can damage nerve cells and cause confusion, delirium, and seizures. In stroke, lactate accumulation contributes to the loss of brain tissue and can impact recovery. Neuronal metabolism also plays an important role in conditions such as Alzheimer’s and other neurodegenerative diseases.  

Recent research has shown that inhibiting the transport of lactate between cells can reduce seizure activity in mice. However, much of this prior work has assumed that lactate was produced by astrocytes and that neurons were passive bystanders. The new study brings into question these assumptions by showing that neurons consume glucose directly and do not depend on astrocytic production and delivery of lactate.  

“Understanding the precise and complex biological mechanisms of the brain is a critical first step in disease-based research,” said Nedergaard. “Any misconception about biological functions – such as metabolism – will ultimately impact how scientists form hypothesize and analyze their findings. If we are looking in the wrong place, we won’t be able to find the right answers.”

Migrating immune cells promote nerve cell demise in the brain

The slow death of dopamine-producing nerve cells in a certain region of the brain is the principal cause underlying Parkinson’s disease. In mice, it is possible to simulate the symptoms of this disease using a substance that selectively kills dopamine-producing neurons. Scientists from the German Cancer Research Center (DKFZ) have now shown for the first time in mouse experiments that after this treatment, cells of the peripheral immune system migrate from the bloodstream into the brain, where they play a major role in the death of neurons. The investigators were able to reduce the level of neurodegeneration using a substance that blocks a specific surface molecule on these inflammatory cells.

A small area in the midbrain known as the substantia nigra is the control center for all bodily movement. Increasing loss of dopamine-generating neurons in this part of the brain therefore leads to the main symptoms of Parkinson’s disease – slowness of movement, rigidity and shaking.

In recent years, there has been increasing scientific evidence suggesting that inflammatory changes in the brain play a major role in Parkinson’s. So far, it has been largely unclear whether this inflammation arises inside the brain itself or whether cells of the innate immune system that enter the brain from the bloodstream are also involved.

At the DKFZ, a team led by Prof. Dr. Ana Martin-Villalba is investigating causes of cell death in the central nervous system. Neuroscientist Martin-Villalba has suspected that a specific pair of molecules, the CD95 system, is involved in neuronal death in Parkinson’s. This pair consists of the CD95 ligand and its corresponding receptor, CD95, also known as the “death receptor”.

Martin-Villalba recently showed that after spinal cord injury, inflammatory cells use these molecules to migrate to the injury site, where they cause damage to the tissue. Martin-Villalba then wanted to investigate whether peripheral inflammatory cells also play a role in chronic neurodegenerative processes such as Parkinson’s disease.

To investigate the process of neurodegeneration in mice, the scientists utilized a model system using the substance MPTP, which causes the selective death of dopamine-generating neurons in the human brain. In mice, MPTP typically causes Parkinson-like symptoms.

However, in mice whose inflammatory cells (monocytes, microglia) were unable to produce CD95L, MPTP treatment resulted in almost no neurodegeneration. This suggested that CD95L-bearing inflammatory cells are involved in the destruction of neurons. However, it remained unclear whether the true culprits are specific macrophages in the brain called microglia, or rather monocytes in the bloodstream that infiltrate the brain.

In order to make this distinction, the investigators used a chemical that blocks CD95L without being able to pass the blood-brain barrier. This substance therefore reaches only the inflammatory cells that circulate in the bloodstream and not the microglia that reside in the brain. Mice that had received this substance were also protected from MPTP-induced neurodegeneration.

“Thus, we have shown for the first time that peripheral inflammatory cells of the innate immune system also play a role in neurodegeneration,” say Liang Gao and David Brenner, first authors of the publication. “A key role in this process is played by CD95L, which enhances the mobility of these cells.”

Project leader Martin-Villalba speculates that a self-reinforcing vicious cycle arises in the brain: The breakdown of a few neurons that die from various causes attracts inflammatory cells that, in turn, further fuel the death of more neurons through inflammation-promoting signaling molecules.

At present, the researchers can only indirectly conclude that the results obtained in the artificial animal model are also relevant in human Parkinson’s disease. In collaboration with colleagues from Ulm, Martin-Villalba’s team recently found elevated quantities of inflammatory monocytes that were hyperactive in blood samples from Parkinson’s patients. Monocyte number correlated with the severity of disease symptoms. However, the researchers do not yet know whether these inflammatory cells also migrate into the brains of patients and contribute to the demise of neurons there, like they do in the mice with Parkinson’s.

“If this is the case, drugs that inhibit CD95L might mitigate Parkinson’s symptoms if administered early on – similar to what we observed in our experimental mice,” says Martin-Villalba. The substance required for this has already been investigated in clinical Phase II trials. Martin-Villalba also suspects that activated cells of the peripheral immune system might drive neurodegeneration not only in Parkinson’s disease but also in other neurodegenerative disorders such as Alzheimer’s.

Researchers control transport in neurons using light
Cell biologists at Utrecht University have successfully moved selected parts of a neuron to another specific location within the cell. This allows them to accurately study which role the position of a cell component performs in the cell’s function. This is vital in order to understand the origins of neurodegenerative diseases such as Alzheimer’s disease and ALS. The researchers’ research will be published in the 7 January 2015 issue of Nature.

The technique they have developed is interesting for research into all cells, but especially for the hundred billion nerve cells that we use to think, feel, move and observe the world around us. Unlike other cells, damaged nerve cells, or neurons, are seldom replaced by new cells. This means that the growth and repair of damaged cells is crucial for a healthy nervous system. Diseases such as Alzheimer’s and ALS result from malfunctions in this process, which can be caused by defects in the proper transport of cellular components.

“With our technique, we can now study whether improving this transport process can contribute to the rehabilitation of neural damage. Five years ago, I wouldn’t have dreamt that we would be able to study this process in such detail”, according to Utrecht University research leader Dr. Lukas Kapitein.

Selective and local control

The proper function of cells requires specialised components, such as mitochondria, which provide the energy the cell needs. “We have evidence that the proper position of these components is essential for the proper functioning of the cell”, explains Kapitein. “Unfortunately, until now it has been impossible to move a specific cell component to a specific location or remove it entirely. With our technique, we can finally selectively and locally control the cell’s transportation system.”

Blue laser light

The cell biologists from Utrecht control the components that they wish to study using blue laser light. In the part of the cell that is illuminated using laser light, the selected components bind to ‘motor proteins’. These molecular motors can travel throughout the cell’s structure in order to transport components. Each type of motor protein has its own destination. By linking and unlinking to the proper motor protein, the researchers can steer the components they wish to study to the desired location in the cell.

Controlled outgrowth

In the publication in Nature, the cell biologists from Utrecht show the effect that the position of a specific type of transport vesicle has on the growth of the axon. An axon is an appendage of a neuron that sends signals to other neurons, and can reach lengths of up to a meter. The tip of the axon has a feature called a growth cone. “By varying the position of the vesicles, we were able to prove that their presence in the growth cone contributes to the growth of the axon. If they are in a different location, then they do not support cell growth”, explains Kapitein.

Drug Shows Early Promise in Treating Liver Failure-Related Seizures

A study out today in the journal Nature Medicine suggests a potential new treatment for the seizures that often plague children with genetic metabolic disorders and individuals undergoing liver failure. The discovery hinges on a new understanding of the complex molecular chain reaction that occurs when the brain is exposed to too much ammonia. 

The study shows that elevated levels of ammonia in the blood overwhelm the brain’s defenses, ultimately causing nerve cells to become overexcited. The researchers have also discovered that bumetanide – a diuretic drug used to treat high blood pressure – can restore normal electrical activity in the brains of mice with the condition and prevent seizures. 

 “Ammonia is a ubiquitous waste product of regular protein metabolism, but it can accumulate in toxic levels in individuals with metabolic disorders,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and lead author of the article. “It appears that the key to preventing the debilitating neurological effects of ammonia toxicity is to correct a molecular malfunction which causes nerve cells in the brain to become chemically unbalanced.”

In healthy people, ammonia is processed in the liver, converted to urea, and expelled from the body in urine. Because it is a gas, ammonia can slip through the blood-brain-barrier and make its way into brain tissue. Under normal circumstances, the brain’s housekeeping cells – called astrocytes – sweep up this unwanted ammonia and convert it into a compound called glutamine which can be more easily expelled from the brain. 

However, individuals with certain genetic metabolic disorders and people with impaired liver function because of chronic hepatitis, alcoholism, acetaminophen overdose, and other toxic liver conditions cannot remove ammonia from their bodies quickly enough. The result is a larger than normal concentration of ammonia in the blood, a condition called hyperammonemia. 

When too much ammonia makes its way into the central nervous system, it can lead to tremors, seizures and, in extreme cases, can cause comas and even lead to death. In children with metabolic disorders the frequent seizures can lead to long-term neurological impairment. 

While ammonia has long been assumed to be the culprit behind the neurological problems associated with inherited metabolic disorders and liver failure, the precise mechanisms by which it triggers seizures and comas have not been fully understood. The new study reveals that ammonia causes a chain of events that alters the chemistry and electrical activity of the brain’s nerve cells, causing them to fire in uncontrolled bursts.

One of the keys to unraveling the effects of ammonia on the brain has been new imagining technologies such as two-photon microscopy which allow researchers to watch this phenomenon in real time in the living brains of mice. As suspected, they observed that when high levels of ammonia enter the brain, astrocytes become quickly overwhelmed and cannot remove it fast enough. 

The abundant ammonia in the brain mimics the function of potassium, an important player in neurotransmission, and tricks neurons into becoming depolarized. This makes it more likely that electrical activity in the brain will exceed the threshold necessary to trigger seizures.

Furthermore, the researchers observed that one of the neuron’s key molecular gatekeepers – a transporter known as NKCC1 – was also fooled into thinking that the ammonia was potassium. As a result, it went into overdrive, loading neurons with too much chloride. This in turn prevents the cells from stabilizing itself after spikes in activity, keeping the cells in a heightened level of electrical “excitability.” 

The team found that the drug bumetanide, a known NKCC1 inhibitor, blocked this process and prevented the cells from overloading with chloride. By knocking down this “secondary” cellular effect of ammonia, the researchers were able to control the seizures in the mice and prolong their survival.

“The neurologic impact of hyperammonemia is a tremendous clinical problem without an effective medical solution,” said Nedergaard.   “The fact that bumetanide is already approved for use gives us a tremendous head start in terms of developing a potential treatment for this condition. This study provides a framework to further explore the therapeutic potential of this and other NKCC1 inhibitors.”