Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
New evidence has shown how coronavirus has caused much damage to the brain. There is a new evidence that shows that COVID-19 assault on the brain I has the power to be multipronged. What this means is that it can attack on certain Brain cells such as reduce the amount of blood flow that the brain needs to the brain tissue.
Along with brain damage COVID-19 has also caused strokes and memory loss. A neurologist at yell University Serena Spudich says, “Can we intervene early to address these abnormalities so that people don’t have long-term problems?”
We’re on 80% of the people who have been hospitalized due to COVID-19 have showed brain symptoms which seem to be correlated to coronavirus.
At the start of the pandemic a group of researchers speculated that coronavirus they can damage the brain by infecting the neurons in the cells which are important in the process of transmitting information. After further studies they found out that coronavirus has a harder time getting past the brains defense system and the brain barrier and that it does not affect the neurons in anyway.
An expert in this study indicated that a way in which SARS-CoV-2 may be able to get to the brain is by going through the olfactory mucosa which is the lining of the nasal cavity. It is found that this virus can be found in the nasal cavity which is why we swab the nose one getting tested for COVID-19.
Spudich quotes, “there’s not a tonne of virus in the brain”.
Recent studies indicate that SARS-CoV-2 have ability to infect astrocytes which is a type of cell found in the brain. Astrocytes do quite a lot that supports normal brain function,” including providing nutrients to neurons to keep them working, says Arnold Kriegstein, a neurologist at the University of California, San Francisco.
Astrocytes are star-shaped cells in the central nervous system that perform many functions, including providing nutrients to neurons.
Kriegstein and his fellow colleagues have found that SARS-CoV-2 I mostly infects the astrocytes over any of the other brain cells present. In this research they expose brain organoids which is a miniature brain that are grown from stem cells into the virus.
As quoted in the article” a group including Daniel Martins-de-Souza, head of proteomics at the University of Campinas in Brazil, reported6 in a February preprint that it had analysed brain samples from 26 people who died with COVID-19. In the five whose brain cells showed evidence of SARS-CoV-2 infection, 66% of the affected cells were astrocytes.”
The infected astrocytes could indicate the reasoning behind some of the neurological symptoms that come with COVID-19. Specifically, depression, brain fog and fatigue. Kreigstein quotes, “Those kinds of symptoms may not be reflective of neuronal damage but could be reflective of dysfunctions of some sort. That could be consistent with astrocyte vulnerability.”
A study that was published on June 21 they compared eight different brands of deceased people who did have COVID-19 along with 14 brains as the control. The results of this research were that they found that there was no trace of coronavirus Brain infected but they found that the gene expression was affected in some of the astrocytes.
As a result of doing all this research and the findings the researchers want to know more about this topic and how many brain cells need to be infected for there to be neurological symptoms says Ricardo Costa.
Further evidence has also been done on how SARS-CoV-2 can affect the brain by reducing its blood flow which impairs the neurons’ function which ends up killing them.
Pericytes can be found on the small blood vessels which are called capillaries and are found all throughout the body and in the brain. In a February pre-print there was a report about how SARS-CoV-2 can infect the pericyte in the brain organoids.
David Atwell, a neuroscientist at the University College London, along with his other colleagues had published a pre-print which has evidence to show that SARS-CoV-2 odes In fact pericytes behavior. I researchers saw that in the different part of the hamsters brain SARS-CoV-2 blocks the function of receptors on the pericytes which ultimately causes the capillaries found inside the tissues to constrict.
As stated in the article, It’s a “really cool” study, says Spudich. “It could be something that is determining some of the permanent injury we see — some of these small- vessel strokes.”
Attwell brought to the attention that the drugs that are used to treat high blood pressure may in fact be used in some cases of COVID-19. Currently there are two clinical trials that are being done to further investigate this idea.
There is further evidence showing that the neurological symptoms and damage could in fact be happening because of the bodies on immune system reacting or misfiring after having COVID-19.
Over the past 15 years it has become evident that people’s immune system’s make auto antibodies which attack their own tissues says Harald Prüss in the article who has a Neuroimmunologist at the German Center for neurogenerative Diseases in Berlin. This may cause neuromyelitis optica which is when you can experience loss of vision or weakness in limbs. Harald Prüss summarized that the autoantibodies can pass through the blood brain barrier and ultimately impact neurological disorders such as psychosis.
Prüss and his colleagues published a study last year that focused on them isolating antibodies against SARS-CoV-2 from people. They found that one was able to protect hamsters from lung damage and other infections. The purpose of this was to come up with and create new treatments. During this research they found that some of the antibodies from people. They found that one was able to protect hamsters from lung damage and other infections. The purpose of this was to come up with and create new treatments. During this research they found that some of the antibodies can bind to the brain tissue which can ultimately damage it. Prüss states, “We’re currently trying to prove that clinically and experimentally,” says Prüss.
Was published online in December including Prüss sorry the blood and cerebrospinal fluid of 11 people who were extremely sick with COVID-19. These 11 people had neurological symptoms as well. All these people were able to produce auto antibodies which combined to neurons. There is evidence that when the patients were given intravenous immunoglobin which is a type of antibody it was successful.
Astrocytes, pericytes and autoantibodies we’re not the only pathways. However it is likely that people with COVID-19 experience article symptoms for many reasons. As stated, In the article, Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.
Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines
The pattern of electrical signals propagated through neuronal networks determines brain function. Adam Cohen examines the possibility of visualizing these signals inside an intact brain using fluorescent transmembrane proteins that are sensitive to voltage. Cohen discusses the barriers to this approach, something he predicts scientists from many disciplines will eventually overcome.
Adam Cohen is Professor in the Departments of Chemistry and Physics at Harvard University and Investigator of the Howard Hughes Medical Institute. He develops biological tools and analytical approaches to investigate the behaviors of molecules and cells in vitro and in vivo. His lab merges protein engineering, optics, and physics, among other disciplines, on a variety of projects. For example, they have developed a fluorescent transmembrane protein that detects membrane voltage, which is useful in visualizing electrical activity in cells, such as cultured neurons.
Evolution can be defined as a change in heritable characteristics. In her fist talk, Hale does a excellent job of explaining how these changes occur. She uses examples, such as the variable color of the pepper moth, to explain selection of characteristics and she describes how geographic isolation can lead to the evolution of new species. In her second lecture, Hale describes work from her lab on the startle response, a highly conserved behavior found in fish and other vertebrates. Comparisons of the neurons which control the startle response, across many species of fish, have allowed Hale and her colleagues to determine how this neuronal circuit, and this behavior, have evolved over hundreds of millions of years.
Part 1 is an outstanding video for high school or undergraduate educators looking for material to teach evolution.
This is an expression of all the genes of a neuron during the first hours after its birth. Each circle represents a development stage (6h, 12h, 24h), and the colored points within each circle represent the level of gene expression. (Credit: Jabaudon Lab/ UNIGE)
Our brain is home to different types of neurons, each with their own genetic signature that defines their function. These neurons are derived from progenitor cells, which are specialized stem cells that have the ability to divide to give rise to neurons. Neuroscientists from the Faculty of Medicine at the University of Geneva (UNIGE) shed light on the mechanisms that allow progenitors to generate neurons. By developing a novel technology called FlashTag that enables them to isolate and visualize neurons at the very moment they are born, they have deciphered the basic genetic code allowing the construction of a neuron. This discovery, which is published in Science, allows not only to understand how our brain develops, but also how to use this code to reconstruct neurons from stem cells. Researchers will now be able to better understand the mechanisms underlying neurological diseases such as autism and schizophrenia.
Directed by Denis Jabaudon, a neuroscientist and neuroscientist at the Department of Basic Neurosciences at UNIGE Faculty of Medicine and neurologist at the University Hospitals Geneva (HUG), the researchers developed a technology termed FlashTag, which visualizes neurons as they are being born. Using this approach, at the very moment where a progenitor divides, it is tagged with a fluorescent marker that persists in its progeny. Scientists can then visualize and isolate newborn neurons in order to dynamically observe which genes are expressed in the first few hours of their existence. Over time, they can then study their evolution and changes in gene expression. “Previously, we only had a few photos to reconstruct the history of neurons, which left a lot of room for speculation. Thanks to FlashTag, there is now a full genetic movie unfolding before our eyes. Every instant becomes visible from the very beginning, which allows us to understand the developmental scenario at play, identify the main characters, their interactions and their incentives”, notes Jabaudon. Working in the cerebral cortex of the mouse, the scientists have thus identified the key genesto neuronal development, and demonstrated that their expression dynamics is essential for the brain to develop normally.
A very precise primordial choreography
This discovery, by giving access to the primordial code of the formation of neurons, helps us to understand how neurons function in the adult brain. And it appears that several of these original genes are also involved in neurodevelopmental and neurodegenerative diseases, which can occur many years later. This suggests that a predisposition may be present from the very first moments in the existence of neurons, and that environmental factors can then impact on how diseases may develop later on. By understanding the genetic choreography of neurons, the researchers can therefore observe how these genes behave from the start, and identify potential anomalies predicting diseases.
After successfully reading this genetic code, the scientists we able to rewrite it in newborn neurons. By altering the expression of certain genes, they were able to accelerate neuronal growth, thus altering the developmental script. With FlashTag, it is now possible to isolate newborn neurons and recreate cerebral circuits in vitro, which enables scientists to test their function as well as to develop new treatments.
A website open to all
The UNIGE team posted a website where it is possible to enter the name of a gene and observe how it is expressed, and how it interacts with other genes. “Each research team can only focus on a handful of genes at a time, while our genome is made up of close to 20,000 genes. We therefore made our tool available for other researchers to use it, in a fully open way,” highlights Jabaudon.
A new study suggests that long-term stress can hurt short-term memory, in part due to inflammation brought on by an immune response.
Researchers from Ohio State University performed experiments where mice were exposed to repeated social defeat by exposure to an aggressive, larger, alpha mouse. The mice that were under chronic stress, had difficulty remembering where the escape hole was in a maze they had previously mastered before the stressful period.
The findings were published in The Journal of Neuroscience.
“The stressed mice didn’t recall it. The mice that weren’t stressed really remembered it,” lead researcher Johnathan Godbout, associate professor of neuroscience at Ohio State, said in statement.
The researchers noted that this kind of stress isn’t the once-in-a-while, acute stress someone might feel before a big meeting or presentation, but prolonged, continued stress.
The mice also displayed depressive-like behavior through social avoidance that continued after four weeks of observation.
Brain changes were also observed in the stressed mice, including inflammation associated with the presence of immune cells, known as macrophages, in the brain. The researchers also recorded shortfalls in the development of new neurons at 10 days and 28 days after the chronic stress ended.
John Sheridan, associate director of Ohio State’s Institute for Behavioral Medicine said in a statement that there might be ways to interrupt the inflammation that occurs in the brain.
When the mice were given a chemical that inhibited inflammation, both memory loss and the inflammatory macrophages disappeared, leading researchers to conclude that post-stress memory deficits is directly tied to inflammation and the immune system. The depressive symptoms and the brain-cell problem did not go away.
“Stress releases immune cells from the bone marrow and those cells can traffic to brain areas associated with neuronal activation in response to stress,” Sheridan said. “They’re being called to the brain, to the center of memory.”
The team aims to understand the underpinnings of stress and responses that could one day lead to treatments for people that suffer from anxiety, depression, or post-traumatic stress disorder.
New information from this study could lead to immune-based treatments, Godbout said.
Blood-brain barrier (BBB) models are often used to investigate BBB function and screen brain-penetrating therapeutics, but it has been difficult to construct a human model that possesses an optimal BBB phenotype and is readily scalable. To address this challenge, we developed a human in vitro BBB model comprising brain microvascular endothelial cells (BMECs), pericytes, astrocytes and neurons derived from renewable cell sources. First, retinoic acid (RA) was used to substantially enhance BBB phenotypes in human pluripotent stem cell (hPSC)-derived BMECs, particularly through adherens junction, tight junction, and multidrug resistance protein regulation. RA-treated hPSC-derived BMECs were subsequently co-cultured with primary human brain pericytes and human astrocytes and neurons derived from human neural progenitor cells (NPCs) to yield a fully human BBB model that possessed significant tightness as measured by transendothelial electrical resistance (~5,000 Ωxcm2). Overall, this scalable human BBB model may enable a wide range of neuroscience studies.
The blood-brain barrier (BBB) is composed of brain microvascular endothelial cells (BMECs) which line brain capillaries and control molecular and cellular trafficking between the bloodstream and neural tissue. These properties are tightly regulated by the surrounding neurovascular microenvironment throughout BBB development and into adulthood. While this barrier is essential for preserving healthy brain activity, its dysfunction has been implicated in a number of neurological diseases1. Moreover, an intact BBB serves as a major bottleneck for brain drug delivery2. Studies regarding BBB development and regulation can be difficult and time-consuming to conduct in vivo and testing brain penetration of therapeutics in vivo is a low throughput endeavor. As such, in vitro BBB models have been widely implemented to study interactions between BMECs and other cells of the neurovascular unit and to conduct screens for prospective BBB-permeant drugs.
In vitro BBB models are typically constructed using primary BMECs isolated from animal brain tissue, including bovine, porcine, rat, and mouse (reviewed extensively in ref. 3). These BMECs are then co-cultured with combinations of other cells of the neurovascular unit, such as neurons, pericytes, and astrocytes, to upregulate BBB properties4,5,6,7. Models derived from animal tissue have proven extremely useful in studying various aspects of the BBB, such as developmental and regulatory mechanisms8,9,10,11,12 and assaying drug permeability, but it is generally well-accepted that owing to species differences, a robust human BBB model is vital to achieve a detailed understanding of human developmental pathways and to conduct relevant drug discovery and design studies13. Human BMEC sources for BBB models have previously consisted of either primary biopsied brain tissue14,15 or immortalized cell lines16. Primary human BMECs typically possess moderate barrier properties but are of limited scale14,15, and immortalized BMECs are clonal and readily scalable but often suffer from suboptimal barrier properties16,17. From a co-culture perspective, human neurons, astrocytes, and pericytes can also be difficult to obtain from primary tissue sources in sufficient quantities for modeling purposes. These collective issues have hindered the development of in vitro human BBB models that are both high fidelity and scalable3.
We have recently demonstrated that stem cells may be attractive candidates to replace primary cells in human BBB models. Human pluripotent stem cells (hPSCs), including both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), can be differentiated into cells possessing both endothelial and BBB properties (coined hPSC-derived BMECs) via co-differentiation of neural and endothelial progenitors, followed by selection and subsequent culture of the endothelial cells18. The iPSC-derived BMECs co-cultured with rat astrocytes possessed reasonable barrier tightness as measured by TEER (860 ± 260 Ωxcm2)18, but the TEER remained below some primary bovine19 and porcine20,21 models (800–2,000 Ωxcm2) and substantially lower than in vivo TEER (measured up to 5,900 Ωxcm2)22. In searching for candidates to improve the BBB phenotype, we identified all-trans retinoic acid (RA). BMECs in vivo have been shown to express retinol-binding protein and its membrane receptor STRA623,STRA6 expression has been detected in brain endothelium but not peripheral endothelium in adult mice24, and STRA6 expression was increased during the differentiation of hPSC-derived BMECs in our previous work18. Moreover, RA has been shown to upregulate certain BBB properties in immortalized rodent25,26 and human27 BMEC lines. In this manuscript, we demonstrate maturation of hPSC-derived BMEC phenotypes following retinoic acid (RA) addition during the differentiation process, including enhanced adherens junction protein expression, barrier function, and multidrug resistance protein (MRP) efflux activity. We also demonstrated in previous work that primary human neural progenitor cells (NPCs) could be differentiated to a defined mixture of neurons and astrocytes capable of inducing BBB properties in rat BMECs in co-culture7. In this manuscript, it is shown that under optimized culture conditions, RA-treated hPSC-derived BMECs sequentially co-cultured with primary human brain pericytes and NPC-derived astrocytes and neurons can achieve physiologic TEER values, forming a scalable, fully human BBB model.
The purpose of this work was to construct a renewable, robust human BBB multicellular co-culture model employing hPSCs, NPCs, and pericytes. Using previous studies as guides25,26,31, RA was identified as a significant modulator of BMEC properties during hPSC differentiation that greatly enhanced physical barrier characteristics as demonstrated by elevated TEER in BMECs cultured alone or with neurovascular cell co-culture. In recent work, RA treatment on the hCMEC/D3 human brain endothelial cell line served to increase occludin and VE-cadherin expression, and the authors suggested that RA secreted by radial glia may be involved in BBB development27. In our study, when RA was added during the endothelial progenitor expansion phase of hPSC-derived BMEC differentiation, similar results were observed including an earlier onset of VE-cadherin expression and increased occludin expression. Moreover, the BMEC yield was increased 2-fold and the tightness of the hPSC-derived BMEC monolayers as measured by elevated TEER was significantly enhanced for three different hPSC lines. Somewhat unexpectedly, RA treatment resulted in decreased claudin-5 expression. However, the Western blotting analysis was conducted using whole-cell lysates and does not take into account the substantially improved intercellular claudin-5 junctional continuity upon RA treatment (Fig. 2C). We and others have previously observed a strong correlation between such junctional continuity and resultant barrier phenotype6,29,32. In addition, previous work has demonstrated claudin-5 expression is relatively constant across peripheral and BBB endothelium while occludin expression is increased at the BBB relative to other vascular beds31. Thus, a combination of claudin-5 localization and elevated occludin expression may be the key phenotypic indicators of increased barrier function31,33. RA treatment of hPSC-derived BMECs also selectively increased MRP efflux activity, which agrees with reports demonstrating that signaling via nuclear receptors can regulate efflux transporter expression and activity at the blood-brain barrier in vitro and in vivo34,35,36,37. RA influences many aspects of brain development, such as anterior/posterior axis patterning in the hindbrain and anterior spinal cord38,39,40 and regulation of neurogenesis41,42,43. During BMEC differentiation, RA could trigger several modes of action. RA may act directly on the developing endothelial cells to upregulate BBB properties, it could induce changes in the neural cells to indirectly promote BBB differentiation, or it could act by a combination of these mechanisms. Future work will be necessary to deconvolute the RA signaling mechanisms affecting the hPSC-derived BMEC differentiation scheme.
In Your Dreams
Understanding the sleeping brain may be the key to unlocking the secrets of the human mind.
Many scientists who study the mind live in fantasyland. They ought to move back to reality: neuroscientists, psychologists, computer scientists pursuing artificial intelligence, and the philosophers of mind who are, in many cases, the sharpest thinkers in the room.
The mind makes us rational. That mind is the one we choose to study. When we study sleep or dreaming, we isolate them first—as the specialized topics they are. But, as I argue in my new book The Tides of Mind, we will never reach a deep understanding of mind unless we start with an integrated view, stretching from rational, methodical thought to nightmares.
Integrating dreaming with the rest of mind is something like being asked to assemble a car from a large pile of metal, plastic, rubber, glass, and an ocelot. Dreaming is hallucination, centering on a radically different self from our waking selves, within unreal settings and stories. Dreams can please or scare us far more vividly than our ordinary thoughts. And they are so slippery, so hard to grasp, that we start losing them the moment we wake up.
But dreaming fits easily into the big picture of mind; and we will make no basic progress on understanding the mind until we see how. Dreaming is the endpoint of the spectrum of consciousness, the smooth progression from one type of consciousness to the next, that we each experience daily.
The simplest approach to the spectrum centers on mental focus. The quality of our attention goes from concentrated to diffuse over the course of a normal day; from a state in which we can concentrate—we can think and remember in a relatively disciplined way—to one in which, with our minds wandering and memory growing increasingly vibrant and distracting, we approach sleep. Then our thinking becomes hallucinatory (as we pass through “sleep-onset thought”); and finally, we are asleep and dreaming. Usually, we oscillate down and up more than once during the day. We move partway down, come partway back, then finally slide slowly to the bottom, when we sleep and dream.
We can also describe the spectrum as a steady shift from a mind dominated by action to one dominated by passive mental experience; from mental doing to mental being. In the upper spectrum, we tend to ignore emotion as we pursue some mental object by means of reasoning or analysis. But the daydreams and fantasies that occupy us as we move down-spectrum are often emotional. And in dreaming we encounter the most saturated emotions, good and bad, that the mind can generate.
The spectrum clarifies important aspects of the mind. “Intentionality,” the quality of aboutness (“I believe that bird is a sparrow” is about “that bird”), is sometimes called “the mark of the mental”—the distinguishing attribute of mental states. But intentionality belongs strictly to the upper spectrum, and disappears gradually as we descend. At the bottom, our minds are dominated by experience, pure being. Happiness or pain or “the experience of seeing purple” are states that have causes but are about nothing.
Software simulations of the upper spectrum, of thinking-about, have grown steadily stronger over the years. That trend will continue. Being, however, is not computable. Software can no more reproduce “being happy” than it can reproduce “being rusty.” Such states depend on physical properties of particular objects. A digital computer resembles only the upper-spectrum mind. Software will never come close to reproducing the mind as a whole.
Leaving sleep outside our investigation is a good way not to see any of this. Arbitrarily hacking off one end of any natural spectrum is an invitation to conceptual chaos. There has been plenty of that in the science of mind. We must start by understanding sleep and dreaming, and go from there.
N.M. Murray et al., “Insomnia caused by serotonin depletion is due to hypothermia,” Sleep, 38:1985-93, 2015.
Sleepless nights
Early research into serotonin’s functions suggested that the neurotransmitter promotes sleep: lab animals deprived of the chemical often developed insomnia. More recent evidence indicated that serotonin plays a part in wakefulness instead, a theory that has gained significant traction. But explanations of the initial experimental data were scarce—so Nick Murray, then a research fellow at the University of Iowa Carver College of Medicine, started digging.
Faulty furnace?
“Over the past 5 or 10 years, we’ve found that serotonin is a key neurotransmitter for generating body heat,” says Murray. To investigate whether this role was related to serotonin’s impact on sleep, he and his colleagues injected para-chlorophenylalanine into mice to inhibit serotonin synthesis.
On ice
When kept at room temperature (20 °C), the mice with depleted serotonin slept less and developed a lower body temperature compared with their control counterparts. However, when housed at 33 °C—a thermoneutral temperature for mice—the sleep and body temperature of the treated mice stayed normal. “Serotonin isn’t a sleep-promoting neurotransmitter,” concludes Murray, now a resident at California Pacific Medical Center. He suggests that mice lacking serotonin had a tough time sleeping under early experimental conditions simply because the animals were cold, and that at higher temperatures other neurotransmitter systems in the brain would function to allow them a normal sleep-wake cycle.
Case closed
The study “solves a long-standing mystery” in the field, says Clifford Saper of Harvard University. “Not very many labs measure sleep and body temperature at the same time,” he adds. “It just basically escaped everybody’s notice for all these years.”
Computer scientists at Columbia Engineering, Harvard, and MIT have demonstrated that acoustic properties — both sound and vibration — can be controlled by 3D-printing specific shapes.
They designed an optimization algorithm and used computational methods and digital fabrication to alter the shape of 2D and 3D objects, creating what looks to be a simple children’s musical instrument — a xylophone with keys in the shape of zoo animals.
Practical uses
“Our discovery could lead to a wealth of possibilities that go well beyond musical instruments,” says Changxi Zheng, assistant professor of computer science at Columbia Engineering, who led the research team.
“Our algorithm could lead to ways to build less noisy computer fans and bridges that don’t amplify vibrations under stress, and advance the construction of micro-electro-mechanical resonators whose vibration modes are of great importance.”
Zheng, who works in the area of dynamic, physics-based computational sound for immersive environments, wanted to see if he could use computation and digital fabrication to actively control the acoustical property, or vibration, of an object.
Zheng’s team decided to focus on simplifying the slow, complicated, manual process of designing “idiophones” — musical instruments that produce sounds through vibrations in the instrument itself, not through strings or reeds.
The surface vibration and resulting sounds depend on the idiophone’s shape in a complex way, so designing the shapes to obtain desired sound characteristics is not straightforward, and their forms have so far been limited to well-understood designs such as bars that are tuned by careful drilling of dimples on the underside of the instrument.
Optimizing sound properties
To demonstrate their new technique, the team settled on building a “zoolophone,” a metallophone with playful animal shapes (a metallophone is an idiophone made of tuned metal bars that can be struck to make sound, such as a glockenspiel).
Findings could enhance teaching methods and lead to treatments for cognitive problems
October 28, 2015
A Johns Hopkins University-led research team has proven a working theory that explains what happens in the brain when we learn, as described in the current issue of the journal Neuron.
More than a century ago, Pavlov figured out that dogs fed after hearing a bell eventually began to salivate when they heard the bell ring. The team looked into the question of how Pavlov’s dogs (in “classical conditioning”) managed to associate an action with a delayed reward to create knowledge. For decades, scientists had a working theory of how it happened, but the team is now the first to prove it.
“If you’re trying to train a dog to sit, the initial neural stimuli, the command, is gone almost instantly — it lasts as long as the word sit,” said neuroscientist Alfredo Kirkwood, a professor with the university’s Zanvyl Krieger Mind/Brain Institute. “Before the reward comes, the dog’s brain has already turned to other things. The mystery was, ‘How does the brain link an action that’s over in a fraction of a second with a reward that doesn’t come until much later?’ ”
Eligibility traces
The working theory — which Kirkwood’s team has now validated experimentally — is that invisible “synaptic eligibility traces” effectively tag the synapses activated by the stimuli so that the learning can be cemented with the arrival of a reward. The reward is a neuromodulator* (neurochemical) that floods the dog’s brain with “good feelings.” Though the brain has long since processed the “sit” command, eligibility traces in the synapse respond to the neuromodulators, prompting a lasting synaptic change, a.k.a. “learning.”
The team was able to prove the eligibility-traces theory by isolating cells in the visual cortex of a mouse. When they stimulated the axon of one cell with an electrical impulse, they sparked a response in another cell. By doing this repeatedly, they mimicked the synaptic response between two cells as they process a stimulus and create an eligibility trace.
When the researchers later flooded the cells with neuromodulators, simulating the arrival of a delayed reward, the response between the cells strengthened (“long-term potentiation”) or weakened (“long-term depression”), showing that the cells had “learned” and were able to do so because of the eligibility trace.
“This is the basis of how we learn things through reward,” Kirkwood said, “a fundamental aspect of learning.”
In addition to a greater understanding of the mechanics of learning, these findings could enhance teaching methods and lead to treatments for cognitive problems, the researchers suggest.
Scientists at the University of Texas at Houston and the University of California, Davis were also involved in the research, which was supported by grants from JHU’s Science of Learning Institute and National Institutes of Health.
* The neuromodulators tested were norepinephrine, serotonin, dopamine, and acetylcholine, all of which have been implicated in cortical plasticity (ability to grow and form new connections to other neurons).
Abstract of Distinct Eligibility Traces for LTP and LTD in Cortical Synapses
In reward-based learning, synaptic modifications depend on a brief stimulus and a temporally delayed reward, which poses the question of how synaptic activity patterns associate with a delayed reward. A theoretical solution to this so-called distal reward problem has been the notion of activity-generated “synaptic eligibility traces,” silent and transient synaptic tags that can be converted into long-term changes in synaptic strength by reward-linked neuromodulators. Here we report the first experimental demonstration of eligibility traces in cortical synapses. We demonstrate the Hebbian induction of distinct traces for LTP and LTD and their subsequent timing-dependent transformation into lasting changes by specific monoaminergic receptors anchored to postsynaptic proteins. Notably, the temporal properties of these transient traces allow stable learning in a recurrent neural network that accurately predicts the timing of the reward, further validating the induction and transformation of eligibility traces for LTP and LTD as a plausible synaptic substrate for reward-based learning.
Holographic sonic tractor beam lifts and moves objects using soundwaves
Another science-fiction idea realized
October 27, 2015
British researchers have built a working Star-Trek-style “tractor beam” — a device that can attract or repel one object to another from a distance. It uses high-amplitude soundwaves to generate an acoustic hologram that can grasp and move small objects.
The technique, published in an open-access paper in Nature Communications October 27, has a wide range of potential applications, the researchers say. A sonic production line could transport delicate objects and assemble them, all without physical contact. Or a miniature version could grip and transport drug capsules or microsurgical instruments through living tissue.
The researchers used an array of 64 miniature loudspeakers. The whole system consumes just 9 Watts of power, used to create high-pitched (40Khz), high-intensity sound waves to levitate a spherical bead 4mm in diameter made of expanded polystyrene.
The tractor beam works by surrounding the object with high-intensity sound to create a force field that keeps the objects in place. By carefully controlling the output of the loudspeakers, the object can be held in place, moved, or rotated.
Three different shapes of acoustic force fields work as tractor beams: an acoustic force field that resembles a pair of fingers or tweezers; an acoustic vortex, the objects becoming trapped at the core; and a high-intensity “cage” that surrounds the objects and holds them in place from all directions.
Previous attempts surrounded the object with loudspeakers, which limits the extent of movement and restricts many applications. Last year, the University of Dundee presented the concept of a tractor beam, but no objects were held in the ray.
The team is now designing different variations of this system. A bigger version aims at levitating a soccer ball from 10 meters away and a smaller version aims at manipulating particles inside the human body.
https://youtu.be/g_EM1y4MKSc Asier Marzo, Matt Sutton, Bruce Drinkwater and Sriram Subramanian | Acoustic holograms are projected from a flat surface and contrary to traditional holograms, they exert considerable forces on the objects contained within. The acoustic holograms can be updated in real time to translate, rotate and combine levitated particles enabling unprecedented contactless manipulators such as tractor beams.
Abstract of Holographic acoustic elements for manipulation of levitated objects
Sound can levitate objects of different sizes and materials through air, water and tissue. This allows us to manipulate cells, liquids, compounds or living things without touching or contaminating them. However, acoustic levitation has required the targets to be enclosed with acoustic elements or had limited maneuverability. Here we optimize the phases used to drive an ultrasonic phased array and show that acoustic levitation can be employed to translate, rotate and manipulate particles using even a single-sided emitter. Furthermore, we introduce the holographic acoustic elements framework that permits the rapid generation of traps and provides a bridge between optical and acoustical trapping. Acoustic structures shaped as tweezers, twisters or bottles emerge as the optimum mechanisms for tractor beams or containerless transportation. Single-beam levitation could manipulate particles inside our body for applications in targeted drug delivery or acoustically controlled micro-machines that do not interfere with magnetic resonance imaging.
Could benefit a large population of patients with neurodegenerative disorders
October 26, 2015
Researchers at Massachusetts Eye and Ear/Harvard Medical School and Boston University have developed a new technique to deliver drugs across the blood-brain barrier and have successfully tested it in a Parkinson’s mouse model (a line of mice that has been genetically modified to express the symptoms and pathological features of Parkinson’s to various extents).
Their findings, published in the journal Neurosurgery, lend hope to patients with neurological conditions that are difficult to treat due to a barrier mechanism that prevents approximately 98 percent of drugs from reaching the brain and central nervous system.
“Although we are currently looking at neurodegenerative disease, there is potential for the technology to be expanded to psychiatric diseases, chronic pain, seizure disorders, and many other conditions affecting the brain and nervous system down the road,” said senior author Benjamin S. Bleier, M.D., of the department of otolaryngology at Mass. Eye and Ear/Harvard Medical School.
The nasal mucosal grafting solution
Researchers delivered glial derived neurotrophic factor (GDNF), a therapeutic protein in testing for treating Parkinson’s disease, to the brains of mice. They showed that their delivery method was equivalent to direct injection of GDNF, which has been shown to delay and even reverse disease progression of Parkinson’s disease in pre-clinical models.
Once they have finished the treatment, they use adjacent nasal lining to rebuild the hole in a permanent and safe way. Nasal mucosal grafting is a technique regularly used in the ENT (ear, nose, and throat) field to reconstruct the barrier around the brain after surgery to the skull base. ENT surgeons commonly use endoscopic approaches to remove brain tumors through the nose by making a window through the blood-brain barrier to access the brain.
The safety and efficacy of these methods have been well established through long-term clinical outcomes studies in the field, with the nasal lining protecting the brain from infection just as the blood brain barrier has done.
By functionally replacing a section of the blood-brain barrier with nasal mucosa, which is more than 1,000 times more permeable than the native barrier, surgeons could create a “screen door” to allow for drug delivery to the brain and central nervous system.
The technique has the potential to benefit a large population of patients with neurodegenerative disorders, where there is still a specific unmet need for blood-brain-penetrating therapeutic delivery strategies.
Abstract of Heterotopic Mucosal Grafting Enables the Delivery of Therapeutic Neuropeptides Across the Blood Brain Barrier
BACKGROUND: The blood-brain barrier represents a fundamental limitation in treating neurological disease because it prevents all neuropeptides from reaching the central nervous system (CNS). Currently, there is no efficient method to permanently bypass the blood-brain barrier.
OBJECTIVE: To test the feasibility of using nasal mucosal graft reconstruction of arachnoid defects to deliver glial-derived neurotrophic factor (GDNF) for the treatment of Parkinson disease in a mouse model.
METHODS: The Institutional Animal Care and Use Committee approved this study in an established murine 6-hydroxydopamine Parkinson disease model. A parietal craniotomy and arachnoid defect was repaired with a heterotopic donor mucosal graft. The therapeutic efficacy of GDNF (2 [mu]g/mL) delivered through the mucosal graft was compared with direct intrastriatal GDNF injection (2 [mu]g/mL) and saline control through the use of 2 behavioral assays (rotarod and apomorphine rotation). An immunohistological analysis was further used to compare the relative preservation of substantia nigra cell bodies between treatment groups.
RESULTS: Transmucosal GDNF was equivalent to direct intrastriatal injection at preserving motor function at week 7 in both the rotarod and apomorphine rotation behavioral assays. Similarly, both transmucosal and intrastriatal GDNF demonstrated an equivalent ratio of preserved substantia nigra cell bodies (0.79 +/- 0.14 and 0.78 +/- 0.09, respectively, P = NS) compared with the contralateral control side, and both were significantly greater than saline control (0.53 +/- 0.21; P = .01 and P = .03, respectively).
CONCLUSION: Transmucosal delivery of GDNF is equivalent to direct intrastriatal injection at ameliorating the behavioral and immunohistological features of Parkinson disease in a murine model. Mucosal grafting of arachnoid defects is a technique commonly used for endoscopic skull base reconstruction and may represent a novel method to permanently bypass the blood-brain barrier.
DARPA-funded study may lead to building prosthetic limbs for humans using a direct brain-electrode interface to recreate the sense of touch
October 26, 2015
Neuroscientists in a project headed by the University of Chicago have determined some of the specific characteristics of electrical stimuli that should be applied to the brain to produce different sensations in an artificial upper limb intended to restore natural motor control and sensation in amputees.
For this study, the researchers used monkeys, whose sensory systems closely resemble those of humans. They implanted electrodes into the primary somatosensory cortex, the area of the brain that processes touch information from the hand. The animals were trained to perform two perceptual tasks: one in which they detected the presence of an electrical stimulus, and a second task in which they indicated which of two successive stimuli was more intense.
The sense of touch is made up of a complex and nuanced set of sensations, from contact and pressure to texture, vibration and movement. The goal of the research is to document the range, composition and specific increments of signals that create sensations that feel different from each other.
To achieve that, the researchers manipulated various features of the electrical pulse train, such as its amplitude, frequency, and duration, and noted how the interaction of each of these factors affected the animals’ ability to detect the signal.
Of specific interest were the “just-noticeable differences” (JND),” — the incremental changes needed to produce a sensation that felt different. For instance, at a certain frequency, the signal may be detectable first at a strength of 20 microamps of electricity. If the signal has to be increased to 50 microamps to notice a difference, the JND in that case is 30 microamps.*
“When you grasp an object, for example, you can hold it with different grades of pressure. To recreate a realistic sense of touch, you need to know how many grades of pressure you can convey through electrical stimulation,” said Sliman Bensmaia, PhD, Associate Professor in the Department of Organismal Biology and Anatomy at the University of Chicago and senior author of the study, which was published today (Oct. 26) in the Proceedings of the National Academy of Sciences. “Ideally, you can have the same dynamic range for artificial touch as you do for natural touch.”
“This study gets us to the point where we can actually create real algorithms that work. It gives us the parameters as to what we can achieve with artificial touch, and brings us one step closer to having human-ready algorithms.”
Researchers from the University of Pittsburgh and Johns Hopkins University were also involved in the DARPA-supported study.
* The study also has important scientific implications beyond neuroprosthetics. In natural perception, a principle known as Weber’s Law states that the just-noticeable difference between two stimuli is proportional to the size of the stimulus. For example, with a 100-watt light bulb, you might be able to detect a difference in brightness by increasing its power to 110 watts. The JND in that case is 10 watts. According to Weber’s Law, if you double the power of the light bulb to 200 watts, the JND would also be doubled to 20 watts.
However, Bensmaia’s research shows that with electrical stimulation of the brain, Weber’s Law does not apply — the JND remains nearly constant, no matter the size of the stimulus. This means that the brain responds to electrical stimulation in a much more repeatable, consistent way than through natural stimulation.
“It shows that there is something fundamentally different about the way the brain responds to electrical stimulation than it does to natural stimulation,” Bensmaia said.
Abstract of Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex
Intracortical microstimulation (ICMS) is a powerful tool to investigate the functional role of neural circuits and may provide a means to restore sensation for patients for whom peripheral stimulation is not an option. In a series of psychophysical experiments with nonhuman primates, we investigate how stimulation parameters affect behavioral sensitivity to ICMS. Specifically, we deliver ICMS to primary somatosensory cortex through chronically implanted electrode arrays across a wide range of stimulation regimes. First, we investigate how the detectability of ICMS depends on stimulation parameters, including pulse width, frequency, amplitude, and pulse train duration. Then, we characterize the degree to which ICMS pulse trains that differ in amplitude lead to discriminable percepts across the range of perceptible and safe amplitudes. We also investigate how discriminability of pulse amplitude is modulated by other stimulation parameters—namely, frequency and duration. Perceptual judgments obtained across these various conditions will inform the design of stimulation regimes for neuroscience and neuroengineering applications.
references:
Sungshin Kim, Thierri Callier, Gregg A. Tabot, Robert A. Gaunt, Francesco V. Tenore, and Sliman J. Bensmaia. Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex. PNAS 2015; doi:10.1073/pnas.1509265112
This article is concerned only with updating the importance of key nutrients for maintenance of health. Nutritional losses are associated with memory loss, impaired immunity, and loss of lean body mass.
Low levels of omega-3 fatty acids may cause memory problems
ST. PAUL, Minn. – A diet lacking in omega-3 fatty acids, nutrients commonly found in fish, may cause your brain to age faster and lose some of its memory and thinking abilities, according to a study published in the February 28, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology. Omega-3 fatty acids include the nutrients called docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
salmon dinner
“People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging,” said study author Zaldy S. Tan, MD, MPH, of the Easton Center for Alzheimer’s Disease Research and the Division of Geriatrics, University of California at Los Angeles.
For the study, 1,575 people with an average age of 67 and free of dementia underwent MRI brain scans. They were also given tests that measured mental function, body mass and the omega-3 fatty acid levels in their red blood cells.
The researchers found that people whose DHA levels were among the bottom 25 percent of the participants had lower brain volume compared to people who had higher DHA levels. Similarly, participants with levels of all omega-3 fatty acids in the bottom 25 percent also scored lower on tests of visual memory and executive function, such as problem solving and multi-tasking and abstract thinking.
ABSTRACT In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin-proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications.
We’re Fishing the Oceans Dry. It’s Time to Reconsider Fish Farms.
Food and Agriculture Organization of the United Nations -State of World Fisheries and Aquaculture 2014
Aquaculture has gotten much greener, with American innovators leading the way.
When I meet Kenny Belov mid-morning at San Francisco’s Fisherman’s Wharf, the boats that would normally be out at sea chasing salmon sit tethered to their docks. The steady breeze coursing through the bay belies choppier conditions farther out—so rough that the local fishermen threw in the towel for the fifth morning in a row. Belov scans the horizon as he explains this, feet away from the warehouse of his sustainable seafood company, TwoXSea. Because his business hinges on what local fishermen can bring in, he’s used to coping with wild fish shortages.
If we continue to fish at the current pace, some scientists predict we’ll be facing oceans devoid of edible marine creatures by 2050.
But unlike these fishermen, Belov has a stash of treasure in his warehouse, as he soon shows me: a golf-cart-size container of plump trout, their glossy bodies still taut from rigor mortis. The night before, Belov drove north to Humboldt to help “chill kill” the fish by submerging them live into barrels of slushy ice water. Belov can count on shipments of these McFarland Springs trout every week—because he helped grow them himself on a farm.
For many consumers, aquaculture lost its appeal after unappetizing news spread about commercial fish farms—like fish feed’s pressure on wild resources, overflowing waste, toxic buildup in the water, and displacement of natural species. But consider this: Our appetite for seafood continues to rise. Globally, we’ve hungered for 3.2 percent more seafood every year for the last five decades, double the rate of our population. Yet more than four-fifths of the world’s wild fisheries are overexploited or fully exploited (yielding the most fish possible with no expected room for growth). Only 3 percent of stocks are considered underexploited—meaning they have any significant room for expansion. If we continue to fish at the current pace, some scientists predict we’ll be facing oceans devoid of edible marine creatures by 2050.
Aquaculture could come to the rescue. The Food and Agriculture Organization of the United Nations predicts that farmed fish will soon surpass wild-caught; by 2030, aquaculture may produce more than 60 percent of fish we consume as food.
Food and Agriculture Organization of the United Nations “State of World Fisheries and Aquaculture” 2014 report
One of the most pressing concerns about aquaculture, though, is that many farmed fish are raised on a diet of 15 million tons a year of smaller bait fish—species like anchovies and menhaden. These bait—also known as forage fish—are ground up and converted into a substance called fishmeal. It takes roughly five pounds of them to produce one pound of farmed salmon. Bait fish are also used for nonfood products like pet food, makeup, farm animal feed, and fish oil supplements.
Forage fish are a “finite resource that’s been fully utilized.”
It may appear as though the ocean enjoys endless schools of these tiny fish, but they too have been mismanaged, and their populations are prone to collapse. They’re a “finite resource that’s been fully utilized,” says Mike Rust of NOAA’s fisheries arm. Which is disturbing, considering that researchers like those at Oceana argue that forage fish may play an outsize role in maintaining the ocean’s ecological balance, including by contributing to the abundance of bigger predatory fish.
And that’s where Belov’s trout come in: Though he swears no one can taste the difference, his fish are vegetarians. That means those five pounds of forage fish can rest easy at sea. It also means that the trout don’t consume some of the other rendered animal proteins in normal fishmeal pellets: bone meal, feather meal, blood meal, and chicken byproducts.
Belov and McFarland Springs’ owner David McFarland were inspired to switch to vegetarian feed in part by Rick Barrows, a USDA researcher. About six years ago, recounts Barrows, several USDA studies confirmed that fish rely on nutrients—vitamins, minerals, fatty acids, and protein—rather than fishmeal or fish oil, to thrive. If those nutrients could be found in other products, including purely plant-based substances, then aquaculture might not be so dependent on feeding fish other smaller fish.
Barrows and team began to test about 50 potential materials a year, and now have a database of 140 that anyone can browse through online. Belov was one of their first commercial partners. The plant-based food fed to McFarland Springs’ trout consists of a hearty blend of marine algae, freshwater micro algae, vitamins, minerals, flax, flax oil, corn, and nut waste. The resulting complete protein means the trout’s omega 3s are high and their omega 6s are low—a ratio that’s said to enhance anti-inflammatory properties. And “they don’t have the concentration of heavy metals that come from the bait fish,” Belov says. I took one of his rosy fillets home and turned it into trout lox; find the recipe here.
McFarland Springs manages the trout’s waste by funneling it out into a natural sagebrush pasture where it composts the soil.
Belov’s fish feed includes California nuts that are too broken or disfigured to be sold.
Barrows thinks region-specific material for this type of feed offers the most potential. For instance, his team learned that around 5 percent of California nuts can’t be sold because they’re broken or disfigured. They realized they could repurpose excess nut parts for the trout feed; the nut bits helped round out the complete protein. Lately, Barrows has become especially excited about turning barley surplus from the beer industry—which comes at a cheap price in Montana, where he’s based—into a feed-grade concentrate for trout feed.
“You can get just as much growth rate out of fishmeal-free feeds as fishmeal,” says Barrows. And his lab has proven as much with eight different fish species: cobia, Florida pompano, coho salmon, Atlantic salmon, walleye, yellowtail, and White seabass.
But the price difference still stands in the way for many fish farmers. Belov pays slightly more than $1/pound for his plant-based feed, whereas fishmeal pellets average around $0.71/pound. He sells his trout for $6.95/pound, about a dollar more than conventional. But he’s well positioned in the affluent Bay Area, and he usually sells out of his McFarland Springs trout well before the end of each week. As innovation continues in the realm of plant-based feeds, he’s hopeful, along with Barrows, that the price of the pellets will continue to drop.
Here in the United States, we consume plenty of farmed fish already, but only 5 percent of it is sourced domestically. “If we didn’t import so much farmed seafood,” implored Four Fish author Paul Greenberg in a recent New York Times op-ed, “we might develop a viable, sustainable aquaculture sector of our own.” It doesn’t just boil down to economics: The locations we generally export from, like China and South Asia, don’t have near the stringent environmental and health regulations as the US. “Growing more seafood at home would help with trade deficit, but also we could control the safety more,” says Barrows.
Though our current aquaculture sector is relatively tiny, US farmers are in a better position to innovate, because we have a sophisticated animal nutrition research center and feed sector, says NOAA’s Rust. “We’re the leading technical country in the world on feed.”
Belov wasn’t always open to aquaculture, and he still feels that fish—such as some salmon—with healthy wild fisheries attached to them should never be farmed. That way, environmentally responsible fishermen can stay in business. His long-term strategy for sustainable seafood? Draw from the “amazing [wild] fisheries that exist, and then you backfill with intelligent aquaculture, and yes, you can feed the planet with sustainable marine products.” Which may take more work, but as he puts it, “We depleted the ocean. It wasn’t anybody else’s fault. So it’s our job to fix it.”
http://www.ibiology.org/ibiomagazine/adam-cohen-visualizing-activity-brain.html
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
vaishnavee24
zraviv06
zs22