We Might Think We Know The Human Body Pretty Well By Now, But Scientists Are Still Discovering Incredible

This Week in Chemistry: Preventing marble statue weathering, further progress towards hydrogen fusion, and more! Links: http://goo.gl/WeJRV5

(Image caption: An fMRI scan shows regions of the brain that become active when devoutly religious study participants have a spiritual experience, including a reward center in the brain, the nucleus accumbens. Credit: Jeffrey Anderson)

This is your brain on God

Religious and spiritual experiences activate the brain reward circuits in much the same way as love, sex, gambling, drugs and music, report researchers at the University of Utah School of Medicine. The findings were published in the journal Social Neuroscience.

“We’re just beginning to understand how the brain participates in experiences that believers interpret as spiritual, divine or transcendent,” says senior author and neuroradiologist Jeff Anderson. “In the last few years, brain imaging technologies have matured in ways that are letting us approach questions that have been around for millennia.”

Specifically, the investigators set out to determine which brain networks are involved in representing spiritual feelings in one group, devout Mormons, by creating an environment that triggered participants to “feel the Spirit.” Identifying this feeling of peace and closeness with God in oneself and others is a critically important part of Mormons’ lives — they make decisions based on these feelings; treat them as confirmation of doctrinal principles; and view them as a primary means of communication with the divine.

During fMRI scans, 19 young-adult church members — including seven females and 12 males — performed four tasks in response to content meant to evoke spiritual feelings. The hour-long exam included six minutes of rest; six minutes of audiovisual control (a video detailing their church’s membership statistics); eight minutes of quotations by Mormon and world religious leaders; eight minutes of reading familiar passages from the Book of Mormon; 12 minutes of audiovisual stimuli (church-produced video of family and Biblical scenes, and other religiously evocative content); and another eight minutes of quotations.

During the initial quotations portion of the exam, participants — each a former full-time missionary — were shown a series of quotes, each followed by the question “Are you feeling the spirit?” Participants responded with answers ranging from “not feeling” to “very strongly feeling.”

Researchers collected detailed assessments of the feelings of participants, who, almost universally, reported experiencing the kinds of feelings typical of an intense worship service. They described feelings of peace and physical sensations of warmth. Many were in tears by the end of the scan. In one experiment, participants pushed a button when they felt a peak spiritual feeling while watching church-produced stimuli.

“When our study participants were instructed to think about a savior, about being with their families for eternity, about their heavenly rewards, their brains and bodies physically responded,” says lead author Michael Ferguson, who carried out the study as a bioengineering graduate student at the University of Utah.

Based on fMRI scans, the researchers found that powerful spiritual feelings were reproducibly associated with activation in the nucleus accumbens, a critical brain region for processing reward. Peak activity occurred about 1-3 seconds before participants pushed the button and was replicated in each of the four tasks. As participants were experiencing peak feelings, their hearts beat faster and their breathing deepened.

In addition to the brain’s reward circuits, the researchers found that spiritual feelings were associated with the medial prefrontal cortex, which is a complex brain region that is activated by tasks involving valuation, judgment and moral reasoning. Spiritual feelings also activated brain regions associated with focused attention.

“Religious experience is perhaps the most influential part of how people make decisions that affect all of us, for good and for ill. Understanding what happens in the brain to contribute to those decisions is really important,” says Anderson, noting that we don’t yet know if believers of other religions would respond the same way. Work by others suggests that the brain responds quite differently to meditative and contemplative practices characteristic of some eastern religions, but so far little is known about the neuroscience of western spiritual practices.

The study is the first initiative of the Religious Brain Project, launched by a group of University of Utah researchers in 2014, which aims to understand how the brain operates in people with deep spiritual and religious beliefs.

Gertrude B. Elion: Women who changed science

With the drugs that she created, Gertrude Elion fulfilled her life’s mission: to alleviate human suffering. Beyond the individual drugs she discovered, she pioneered a new, more scientific approach to drug development that forever altered – and accelerated – medical research. 

Discover her story at 

https://www.nobelprize.org/womenwhochangedscience/stories

(Image caption: A new technique called magnified analysis of proteome (MAP), developed at MIT, allows researchers to peer at molecules within cells or take a wider view of the long-range connections between neurons. Credit: Courtesy of the researchers)

Imaging the brain at multiple size scales

MIT researchers have developed a new technique for imaging brain tissue at multiple scales, allowing them to peer at molecules within cells or take a wider view of the long-range connections between neurons.

This technique, known as magnified analysis of proteome (MAP), should help scientists in their ongoing efforts to chart the connectivity and functions of neurons in the human brain, says Kwanghun Chung, the Samuel A. Goldblith Assistant Professor in the Departments of Chemical Engineering and Brain and Cognitive Sciences, and a member of MIT’s Institute for Medical Engineering and Science (IMES) and Picower Institute for Learning and Memory.

“We use a chemical process to make the whole brain size-adjustable, while preserving pretty much everything. We preserve the proteome (the collection of proteins found in a biological sample), we preserve nanoscopic details, and we also preserve brain-wide connectivity,” says Chung, the senior author of a paper describing the method in the July 25 issue of Nature Biotechnology.

The researchers also showed that the technique is applicable to other organs such as the heart, lungs, liver, and kidneys.

The paper’s lead authors are postdoc Taeyun Ku, graduate student Justin Swaney, and visiting scholar Jeong-Yoon Park.

Multiscale imaging

The new MAP technique builds on a tissue transformation method known as CLARITY, which Chung developed as a postdoc at Stanford University. CLARITY preserves cells and molecules in brain tissue and makes them transparent so the molecules inside the cell can be imaged in 3-D. In the new study, Chung sought a way to image the brain at multiple scales, within the same tissue sample.

“There is no effective technology that allows you to obtain this multilevel detail, from brain region connectivity all the way down to subcellular details, plus molecular information,” he says.

To achieve that, the researchers developed a method to reversibly expand tissue samples in a way that preserves nearly all of the proteins within the cells. Those proteins can then be labeled with fluorescent molecules and imaged.

The technique relies on flooding the brain tissue with acrylamide polymers, which can form a dense gel. In this case, the gel is 10 times denser than the one used for the CLARITY technique, which gives the sample much more stability. This stability allows the researchers to denature and dissociate the proteins inside the cells without destroying the structural integrity of the tissue sample.

Before denaturing the proteins, the researchers attach them to the gel using formaldehyde, as Chung did in the CLARITY method. Once the proteins are attached and denatured, the gel expands the tissue sample to four or five times its original size.

“It is reversible and you can do it many times,” Chung says. “You can then use off-the-shelf molecular markers like antibodies to label and visualize the distribution of all these preserved biomolecules.”

There are hundreds of thousands of commercially available antibodies that can be used to fluorescently tag specific proteins. In this study, the researchers imaged neuronal structures such as axons and synapses by labeling proteins found in those structures, and they also labeled proteins that allow them to distinguish neurons from glial cells.

“We can use these antibodies to visualize any target structures or molecules,” Chung says. “We can visualize different neuron types and their projections to see their connectivity. We can also visualize signaling molecules or functionally important proteins.”

High resolution

Once the tissue is expanded, the researchers can use any of several common microscopes to obtain images with a resolution as high as 60 nanometers — much better than the usual 200 to 250-nanometer limit of light microscopes, which are constrained by the wavelength of visible light. The researchers also demonstrated that this approach works with relatively large tissue samples, up to 2 millimeters thick.

“This is, as far as I know, the first demonstration of super-resolution proteomic imaging of millimeter-scale samples,” Chung says.

“This is an exciting advance for brain mapping, a technique that reveals the molecular and connectional architecture of the brain with unprecedented detail,” says Sebastian Seung, a professor of computer science at the Princeton Neuroscience Institute, who was not involved in the research.

Currently, efforts to map the connections of the human brain rely on electron microscopy, but Chung and colleagues demonstrated that the higher-resolution MAP imaging technique can trace those connections more accurately.

Chung’s lab is now working on speeding up the imaging and the image processing, which is challenging because there is so much data generated from imaging the expanded tissue samples.

“It’s already easier than other techniques because the process is really simple and you can use off-the-shelf molecular markers, but we are trying to make it even simpler,” Chung says.

How Do Antidepressants Work? (Video)

Your brain is a network of billions of neurones, all somehow connected to each other. At this very second, millions of impulses are being transmitted through these connections carrying information about what you can see and hear, as well as your emotional state. It’s an incredibly complex system but sometimes things go wrong. Despite extensive research, we are still not certain on the biology that underlies mental illnesses- including depression. However, we have come pretty far in developing effective treatments. 

WATCH: Crystal Birth, a Beautiful Timelapse of Metallic Crystals Forming in Chemical Solutions [video]

Estrogen Alters Memory Circuit Function in Women with Gene Variant

Fluctuations in estrogen can trigger atypical functioning in a key brain memory circuit in women with a common version of a gene, NIMH scientists have discovered. Brain scans revealed altered circuit activity linked to changes in the sex hormone in women with the gene variant while they performed a working memory task.

(Image caption: Both PET scans (left) and fMRI scans (right) showed the same atypical activation (yellow) in the brain’s memory hub, or hippocampus, in response to estrogen in women performing a working memory task – if they carried a uniquely human version of the BDNF gene. Activity in this area is typically suppressed during working memory. Picture shows PET and fMRI data superimposed over anatomical MRI image)

The findings may help to explain individual differences in menstrual cycle and reproductive-related mental disorders linked to fluctuations in the hormone. They may also shed light on mechanisms underlying sex-related differences in onset, severity, and course of mood and anxiety disorders and schizophrenia. The gene-by-hormone interaction’s effect on circuit function was found only with one of two versions of the gene that occurs in about a fourth of white women.

Drs. Karen Berman, Peter Schmidt, Shau-Ming Wei, and colleagues, of the NIMH Intramural Research Program, report on this first such demonstration in women April 18, 2017 in the journal Molecular Psychiatry.

Prior to the study, there was little evidence from research on the human brain that might account for individual differences in cognitive and behavioral effects of sex hormones. For example, why do some women develop postpartum depression and others do not – in response to the same hormone changes? Why do some women report that estrogen replacement improved their memory, whereas large studies of postmenopausal estrogen therapy show no overall improvement in memory performance?

Evidence from humans has also been lacking for the neural basis of stark sex differences in prevalence and course of mental disorders that are likely related to sex hormones. For example, why are there higher rates of mood disorders in females and higher rates of ADHD in males – or later onset of schizophrenia in females?

In seeking answers to these questions, the researchers focused on working memory, a well-researched brain function often disturbed in many of these disorders. It was known that working memory is mediated by a circuit from the brain’s executive hub, the prefrontal cortex, to its memory hub, the hippocampus. Notably, hippocampus activity is typically suppressed during working memory processing.

Following-up on a clue from experiments in mice, the NIMH team hypothesized that estrogen tweaks circuit function by interacting with a uniquely human version of the gene that codes for brain derived neurotrophic factor (BDNF), a pivotal chemical messenger operating in this circuit. To find out, the researchers experimentally manipulated estrogen levels in healthy women with one or the other version of the BDNF gene over a period of months. Researchers periodically scanned the women’s brain activity while they performed a working memory task to see any effects of the gene-hormone interaction on circuit function.

The researchers first scanned 39 women using PET (positron emission tomography) and later confirmed the results in 27 women using fMRI (functional magnetic resonance imaging). Both pegged atypical activity in the hippocampus to the interaction. Turning up the same findings using two types of neuroimaging strengthens the case for the accuracy of their observations, say the researchers. Such gene-hormone interactions affecting thinking and behavior are consistent with findings from animal studies and are suspect mechanisms conferring risk for mental illness, they add.

A New Way to Cross the Blood–Brain Barrier -  A Mental Unblock

The brain presents a unique challenge for medical treatment: it is locked away behind an impenetrable layer of tightly packed cells. Although the blood-brain barrier prevents harmful chemicals and bacteria from reaching our control center, it also blocks roughly 95 percent of medicine delivered orally or intravenously. As a result, doctors who treat patients with neurodegenerative diseases, such as Parkinson’s, often have to inject drugs directly into the brain, an invasive approach that requires drilling into the skull.

Some scientists have had minor successes getting intravenous drugs past the barrier with the help of ultrasound or in the form of nanoparticles, but those methods can target only small areas. Now neuroscientist Viviana Gradinaru and her colleagues at the California Institute of Technology show that a harmless virus can pass through the barricade and deliver treatment throughout the brain.

Gradinaru’s team turned to viruses because the infective agents are small and adept at entering cells and hijacking the DNA within. They also have protein shells that can hold beneficial deliveries, such as drugs or genetic therapies. To find a suitable virus to enter the brain, the researchers engineered a strain of an adeno-associated virus into millions of variants with slightly different shell structures. They then injected these variants into a mouse and, after a week, recovered the strains that made it into the brain. A virus named AAV-PHP.B most reliably crossed the barrier.

Next the team tested to see if AAV-PHP.B could work as a potential vector for gene therapy, a technique that treats diseases by introducing new genes into cells or by replacing or inactivating genes already there. The scientists injected the virus into the bloodstream of a mouse. In this case, the virus was carrying genes that encoded green fluorescent proteins. So if the virus made it to the brain and the new DNA was incorporated in neurons, the success rate could be tracked via a green glow on dissection. Indeed, the researchers observed that the virus infiltrated most brain cells and that the glowing effects lasted as long as one year. The results were recently published in Nature Biotechnology.

In the future, this approach could be used to treat a range of neurological diseases. “The ability to deliver genes to the brain without invasive methods will be extremely useful as a research tool. It has tremendous potential in the clinic as well,” says Anthony Zador, a neuroscientist who studies brain wiring at Cold Spring Harbor Laboratory. Gradinaru also thinks the method is a good candidate for targeting areas other than the brain, such as the peripheral nervous system. The sheer number of peripheral nerves has made pain treatment for neuropathy difficult, and a virus could infiltrate them all.

Image Credit: Thomas Fuchs

Source: Scientific American (By Monique Brouillette)

“Sixth sense” may be more than just a feeling

With the help of two young patients with a unique neurological disorder, an initial study by scientists at the National Institutes of Health suggests that a gene called PIEZO2 controls specific aspects of human touch and proprioception, a “sixth sense” describing awareness of one’s body in space. Mutations in the gene caused the two to have movement and balance problems and the loss of some forms of touch. Despite their difficulties, they both appeared to cope with these challenges by relying heavily on vision and other senses.

“Our study highlights the critical importance of PIEZO2 and the senses it controls in our daily lives,” said Carsten G. Bönnemann, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a co-leader of the study published in the New England Journal of Medicine. “The results establish that PIEZO2 is a touch and proprioception gene in humans. Understanding its role in these senses may provide clues to a variety of neurological disorders.”

Dr. Bönnemann’s team uses cutting edge genetic techniques to help diagnose children around the world who have disorders that are difficult to characterize. The two patients in this study are unrelated, one nine and the other 19 years old. They have difficulties walking; hip, finger and foot deformities; and abnormally curved spines diagnosed as progressive scoliosis.

Working with the laboratory of Alexander T. Chesler, Ph.D., investigator at NIH’s National Center for Complementary and Integrative Health (NCCIH), the researchers discovered that the patients have mutations in the PIEZO2 gene that appear to block the normal production or activity of Piezo2 proteins in their cells. Piezo2 is what scientists call a mechanosensitive protein because it generates electrical nerve signals in response to changes in cell shape, such as when skin cells and neurons of the hand are pressed against a table. Studies in mice suggest that Piezo2 is found in the neurons that control touch and proprioception.

“As someone who studies Piezo2 in mice, working with these patients was humbling,” said Dr. Chesler. “Our results suggest they are touch-blind. The patient’s version of Piezo2 may not work, so their neurons cannot detect touch or limb movements.”

Further examinations at the NIH Clinical Center suggested the young patients lack body awareness. Blindfolding them made walking extremely difficult, causing them to stagger and stumble from side to side while assistants prevented them from falling. When the researchers compared the two patients with unaffected volunteers, they found that blindfolding the young patients made it harder for them to reliably reach for an object in front of their faces than it was for the volunteers. Without looking, the patients could not guess the direction their joints were being moved as well as the control subjects could.

The patients were also less sensitive to certain forms of touch. They could not feel vibrations from a buzzing tuning fork as well as the control subjects could. Nor could they tell the difference between one or two small ends of a caliper pressed firmly against their palms. Brain scans of one patient showed no response when the palm of her hand was brushed.

Nevertheless, the patients could feel other forms of touch. Stroking or brushing hairy skin is normally perceived as pleasant. Although they both felt the brushing of hairy skin, one claimed it felt prickly instead of the pleasant sensation reported by unaffected volunteers. Brain scans showed different activity patterns in response to brushing between unaffected volunteers and the patient who felt prickliness.

Despite these differences, the patients’ nervous systems appeared to be developing normally. They were able to feel pain, itch, and temperature normally; the nerves in their limbs conducted electricity rapidly; and their brains and cognitive abilities were similar to the control subjects of their age.

“What’s remarkable about these patients is how much their nervous systems compensate for their lack of touch and body awareness,” said Dr. Bönnemann. “It suggests the nervous system may have several alternate pathways that we can tap into when designing new therapies.”

Previous studies found that mutations in PIEZO2 may have various effects on the Piezo2 protein that may result in genetic musculoskeletal disorders, including distal arthrogryposis type 5, Gordon Syndrome, and Marden-Walker Syndrome. Drs. Bönnemann and Chesler concluded that the scoliosis and joint problems of the patients in this study suggest that Piezo2 is either directly required for the normal growth and alignment of the skeletal system or that touch and proprioception indirectly guide skeletal development.

“Our study demonstrates that bench and bedside research are connected by a two-way street,” said Dr. Chesler. “Results from basic laboratory research guided our examination of the children. Now we can take that knowledge back to the lab and use it to design future experiments investigating the role of PIEZO2 in nervous system and musculoskeletal development.”

Heart Regeneration

If a person suffers a heart attack and survives, chances are their heart muscle will never be quite the same. Indeed, the associated scarring often results in permanent damage that can lead to heart failure and eventual death. Scientists are therefore searching for possible ways to promote regeneration of damaged hearts, and it’s possible that newborn mice may hold the answer. For a few weeks after birth, these animals can almost entirely regenerate their heart tissue after an injury. And new research suggests a key process that may be critical for this regenerative ability: regrowth of nerves. Blocking nerve growth specifically in experimental animals completely prevented the regrowth of damaged heart tissue. In control animals, the nerves regrew into their normal branching patterns—like those pictured. Thus if researchers are to have any hope of regenerating adult hearts after injury, their best bet might be to boost accompanying nerve growth.

Written by Ruth Williams

Image from work by Ian A. White and colleagues

Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, USA

Image copyright held by the American Heart Association

Published in Circulation Research, December 2015

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