Neuroscience

(Credit: Oleg Zabielin / Shutterstock)

A new study in animals shows that chronic stress during pregnancy prevents brain benefits of motherhood, a finding that researchers suggest could increase understanding of postpartum depression.

Rat mothers showed an increase in brain cell connections in regions associated with learning, memory and mood. In contrast, the brains of mother rats that were stressed twice a day throughout pregnancy did not show this increase.

The researchers were specifically interested in dendritic spines – hair-like growths on brain cells that are used to exchange information with other neurons.

Previous animal studies conducted by lead author Benedetta Leuner of Ohio State University showed that an increase of dendritic spines in new mothers’ brains was associated with improved cognitive function on a task that requires behavioral flexibility – in essence, enabling more effective multitasking. The dendritic spines increased by about 20 percent in these brain regions in new mothers, according to her findings.

The stress in this new study negated those brain benefits of motherhood, causing the stressed rats’ brains to match brain characteristics of animals that had no reproductive or maternal experience.

The stressed rats also had less physical interaction with their babies than did unstressed rats, a behavior observed in human mothers who experience postpartum depression.

“Animal mothers in our research that are unstressed show an increase in the number of connections between neurons. Stressed mothers don’t,” said Leuner, assistant professor of psychology and neuroscience at Ohio State and lead author of the study. “We think that makes the stressed mothers more vulnerable. They don’t have the capacity for brain plasticity that the unstressed mothers do, and somehow that’s contributing to their susceptibility to depression.”

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A new finding could lead to strategies for treating speech loss after a stroke and helping children with dyslexia.

New research links motor skills and perception, specifically as it relates to a second finding—a new understanding of what the left and right brain hemispheres “hear.” Georgetown University Medical Center researchers say these findings may eventually point to strategies to help stroke patients recover their language abilities, and to improve speech recognition in children with dyslexia.

The study, presented at Neuroscience 2012, the annual meeting of the Society for Neuroscience, is the first to match human behavior with left brain/right brain auditory processing tasks. Before this research, neuroimaging tests had hinted at differences in such processing.

“Language is processed mainly in the left hemisphere, and some have suggested that this is because the left hemisphere specializes in analyzing very rapidly changing sounds,” says the study’s senior investigator, Peter E. Turkeltaub, M.D., Ph.D., a neurologist in the Center for Brain Plasticity and Recovery. This newly created center is a joint program of Georgetown University and MedStar National Rehabilitation Network.

Turkeltaub and his team hid rapidly and slowly changing sounds in background noise and asked 24 volunteers to simply indicate whether they heard the sounds by pressing a button.

“We asked the subjects to respond to sounds hidden in background noise,” Turkeltaub explained. “Each subject was told to use his or her right hand to respond during the first 20 sounds, then the left hand for the next 20 second, then right, then left, and so on.”

He says when a subject was using their right hand, they heard the rapidly changing sounds more often than when they used their left hand, and vice versa for the slowly changing sounds.

“Since the left hemisphere controls the right hand and vice versa, these results demonstrate that the two hemispheres specialize in different kinds of sounds—the left hemisphere likes rapidly changing sounds, such as consonants, and the right hemisphere likes slowly changing sounds, such as syllables or intonation,” Turkeltaub explains.

“These results also demonstrate the interaction between motor systems and perception. It’s really pretty amazing. Imagine you’re waving an American flag while listening to one of the presidential candidates. The speech will actually sound slightly different to you depending on whether the flag is in your left hand or your right hand.”

Ultimately, Turkeltaub hopes that understanding the basic organization of auditory systems and how they interact with motor systems will help explain why language resides in the left hemisphere of the brain, and will lead to new treatments for language disorders, like aphasia (language difficulties after stroke or brain injury) or dyslexia.

“If we can understand the basic brain organization for audition, this might ultimately lead to new treatments for people who have speech recognition problems due to stroke or other brain injury. Understanding better the specific roles of the two hemispheres in auditory processing will be a big step in that direction. If we find that people with aphasia, who typically have injuries to the left hemisphere, have difficulty recognizing speech because of problems with low-level auditory perception of rapidly changing sounds, maybe training the specific auditory processing deficits will improve their ability to recognize speech,” Turkeltaub concludes.

Scientists at Wake Forest Baptist Medical Center have taken the first steps to create neural-like stem cells from muscle tissue in animals. Details of the work are published in two complementary studies published in the September online issues of the journals Experimental Cell Research and Stem Cell Research.

“Reversing brain degeneration and trauma lesions will depend on cell therapy, but we can’t harvest neural stem cells from the brain or spinal cord without harming the donor,” said Osvaldo Delbono, M.D., Ph.D., professor of internal medicine at Wake Forest Baptist and lead author of the studies.

“Skeletal muscle tissue, which makes up 50 percent of the body, is easily accessible and biopsies of muscle are relatively harmless to the donor, so we think it may be an alternative source of neural-like cells that potentially could be used to treat brain or spinal cord injury, neurodegenerative disorders, brain tumors and other diseases, although more studies are needed.”

In an earlier study, the Wake Forest Baptist team isolated neural precursor cells derived from skeletal muscle of adult transgenic mice (PLOS One, Feb.3, 2011).

In the current research, the team isolated neural precursor cells from in vitro adult skeletal muscle of various species including non-human primates and aging mice, and showed that these cells not only survived in the brain, but also migrated to the area of the brain where neural stem cells originate.

Another issue the researchers investigated was whether these neural-like cells would form tumors, a characteristic of many types of stem cells. To test this, the team injected the cells below the skin and in the brains of mice, and after one month, no tumors were found.

“Right now, patients with glioblastomas or other brain tumors have very poor outcomes and relatively few treatment options,” said Alexander Birbrair, a doctoral student in Delbono’s lab and first author of these studies. “Because our cells survived and migrated in the brain, we may be able to use them as drug-delivery vehicles in the future, not only for brain tumors but also for other central nervous system diseases.”

In addition, the Wake Forest Baptist team is now conducting research to determine if these neural-like cells also have the capability to become functioning neurons in the central nervous system.

A paper by Shizhong Han and colleagues in the current issue of Biological Psychiatry implicates a new gene in the risk for cannabis dependence. This gene, NRG1, codes for the ErbB4 receptor, a protein implicated in synaptic development and function.

The researchers set out to investigate susceptibility genes for cannabis dependence, as research has already shown that it has a strong genetic component.

To do this, they employed a multi-stage design using genetic data from African American and European American families. In the first stage, a linkage analysis, the strongest signal was identified in African Americans on chromosome 8p21. Then using a genome-wide association study dataset, they identified one genetic variant at NRG1 that showed consistent evidence for association in both African Americans and European Americans. Finally, they replicated the association of that same variant in an independent sample of African-Americans.

All together, the findings suggest that NRG1 may be a susceptibility gene for cannabis dependence.

An interesting feature of this paper is that these findings may also suggest a link between the genetics of schizophrenia and the genetics of cannabis dependence. NRG1 emerged into public awareness after a series of genetic studies implicated it in the heritable risk for schizophrenia. Subsequent studies in post-mortem brain tissue also suggested that the regulation of NRG1 was altered in the brains of individuals diagnosed with schizophrenia.

Thus, the current findings may help to explain the already established link between cannabis use and the risk for developing schizophrenia. A number of epidemiologic studies have attributed the association of cannabis use and schizophrenia to the effects of cannabis on the brain rather than a common genetic link between these two conditions.

"The current data provide a potentially important insight into the heritable risk for schizophrenia and raise the possibility that there are some common genetic contributions to these two disorders," commented Dr. John Krystal, Editor of Biological Psychiatry.

However, further research will be necessary to further confirm the role that NRG1 plays in cannabis dependence and the potential link between cannabis use and psychosis.

Scientists have proved a 60-year-old theory about how nerve signals are sent around the body at varying speeds as electrical impulses.

Researchers tested how these signals are transmitted through nerve fibres, which enables us to move and recognise sensations such as touch and smell.

The findings from the University of Edinburgh have validated an idea first proposed by Nobel laureate Sir Andrew Huxley.

It has been known for many years that an insulating layer – known as myelin – which surrounds nerve fibres is crucial in determining how quickly these signals are sent.

This insulating myelin is interrupted at regular intervals along the nerve by gaps called nodes.

Scientists, whose work was funded by the Wellcome Trust, have now proved that the longer the distance between nodes, the quicker the nerve fibres send signals down the nerves.

The theory that the distance between these gaps might affect the speed of electrical signals was first proposed by Sir Andrew Huxley, who won the Nobel Prize in 1963 for his work on electrical signalling in the nervous system, and who died earlier this year.

The study, published in the journal Current Biology, will help provide insight into what happens in people with nerve damage. It will also shed light on how nerves develop before and after birth.

Professor Peter Brophy, Director of the University of Edinburgh’s Centre for Neuroregeneration, said: “The study gives us greater insight into how the central and peripheral nervous systems work and what happens after nerves become injured. We know that peripheral nerves have the capacity to repair, but shorter lengths of insulation around the nerve fibres after repair affect the speed with which impulses are sent around the body.”

The researchers found that when the myelin reached a certain length, the speed with which nerves impulses were conducted reached a peak.

The study, carried out in mice, also confirmed that a protein – periaxin – plays a key role in regulating the length of myelin layers around nerve fibres.

Washington State University researchers have developed a new drug candidate that dramatically improves the cognitive function of rats with Alzheimer’s-like mental impairment.

Their compound, which is intended to repair brain damage that has already occurred, is a significant departure from current Alzheimer’s treatments, which either slow the process of cell death or inhibit cholinesterase, an enzyme believed to break down a key neurotransmitter involved in learning and memory development.

Such drugs, says Joe Harding, a professor in WSU’s College of Veterinary Medicine, are not designed to restore lost brain function, which can be done by rebuilding connections between nerve cells.

"This is about recovering function,” he says. "That’s what makes these things totally unique. They’re not designed necessarily to stop anything. They’re designed to fix what’s broken. As far as we can see, they work.”

Harding, College of Arts and Sciences Professor Jay Wright and other WSU colleagues report their findings in the online “Fast Forward” section of the Journal of Pharmacology and Experimental Therapeutics.

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Three studies conducted as part of Wayne State University’s Systems Biology of Epilepsy Project (SBEP) could result in new types of treatment for the disease and, as a bonus, for behavioral disorders as well.

The SBEP started out with funds from the President’s Research Enhancement Fund and spanned neurology, neuroscience, genetics and computational biology. It since has been supported by multiple National Institutes of Health-funded grants aimed at identifying the underlying causes of epilepsy, and it is uniquely integrated within the Comprehensive Epilepsy Program at the Wayne State School of Medicine and the Detroit Medical Center.

Under the guidance of Jeffrey Loeb, M.D., Ph.D., associate director of the Center for Molecular Medicine and Genetics (CMMG) and professor of neurology, the project brings together researchers from different fields to create an interdisciplinary research program that targets the complex disease. The multifaceted program at Wayne State is like no other in the world, officials say, with two primary goals: improving clinical care and creating novel strategies for diagnosis and treatment of patients with epilepsy.

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Scientists at the University of Bath are one step further to understanding the role of one of the proteins that causes the neurodegenerative disorder, Amyotrophic Lateral Sclerosis (ALS), also known as Motor Neurone Disease (MND).

The scientists studied a protein called angiogenin, which is present in the spinal cord and brain that protects neurones from cell death. Mutations in this protein have been found in sufferers of MND and are thought to play a key role in the progression of the condition.

MND triggers progressive weakness, muscle atrophy and muscle twitches and spasms. The disease affects around 5000 people in the UK.

The team of cell biologists and structural biologists have, for the first time, produced images of the 3D structures of 11 mutant versions of angiogenin to see how the mutations changed the structure of the active part of the molecule, damaging its function.

The study, published in the prestigious journal Nature Communications, provides insights into the causes of this disease and related conditions such as Parkinson’s Disease.

The team also looked at the effects of the malfunctioning proteins on neurones grown from embryonic stem cells in the laboratory.

They found that some of the mutations stopped the protein being transported to the cell nucleus, a process that is critical for the protein to function correctly.

The mutations also prevented the cells from producing stress granules, the neurone’s natural defence from stress caused by low oxygen levels.

Dr Vasanta Subramanian, Reader in Biology & Biochemistry at the University, said:

“This study is exciting because it’s the first time we’ve directly linked the structure of these faulty proteins with their effects in the cell.

“We’ve worked alongside Professor Ravi Acharya’s group to combine structural knowledge with cell biology to gain new insights into the causes of this devastating disease.

“We hope that the scientific community can use this new knowledge to help design new drugs that will bind selectively to the defective protein to protect the body from its damaging effects.”

The findings were welcomed by medical research charity, the Motor Neurone Disease (MND) Association, the only national charity in England, Wales and Northern Ireland dedicated to supporting people living with MND while funding and promoting cutting-edge global research to bring about a world free of the disease.

Dr Brian Dickie, Director of Research Development at the charity, said: “The researchers at the University of Bath have skilfully combined aspects of biology, chemistry and physics to answer some fundamental questions on how angiogenin can damage motor neurones. It not only advances our understanding of the disease, but may also give rise to new ideas on treatment development.”

A sudden and mysterious burst of activity originating in the retina of a developing fetus spurs brain connections that are essential to development of finely-tuned sight, Yale researchers report in the journal Nature. Interference with this spontaneous wave of activity could play a role in neurodevelopmental disorders such as autism, the scientists speculate.

The study in mice is the first to demonstrate in a living animal that this wave of activity spreads throughout large regions of the brain and is crucial to wiring of the visual system. Without the wiring, infants would not be able to distinguish details in their environment.

“If you interfere with this activity, the circuits are all messed up, the wiring details are all wrong,” said Michael Crair, the William Ziegler III Professor of Neurobiology and Professor of Ophthalmology and Visual Science and senior author of the study.

For instance, this activity might allow a newborn human baby to perceive such details as the five fingers attached to her hand or her mother’s face. This wave wires up the visual system so that infants are poised to learn from their environment soon after birth.

The development of animals from a fertilized egg into trillions of intricately connected and specialized cells is the result of a precisely timed expression of genes. However, the Nature paper introduces another necessary factor — a mysterious wave of activity arising in the retina itself that propagates through several regions of the brain. Crair terms this wave an emergent property, or a trait possessed by a complex system that cannot be directly traced to its individual parts. This experiment in living, neonatal mice shows that this wave is crucial to the proper wiring not only of the visual system but other brain areas as well.

Crair said his lab plans to explore whether interruptions of this activity might play a role in neurodevelopmental disorders such as autism or schizophrenia.

Scientists studying a rare genetic disorder have identified a molecular pathway that may play a role in schizophrenia, according to new research in the Oct. 10 issue of The Journal of Neuroscience. The findings may one day guide researchers to new treatment options for people with schizophrenia — a devastating disease that affects approximately 1 percent of the world’s population.

Schizophrenia is characterized by a multitude of symptoms, including hallucinations, social withdrawal, and learning and memory deficits, which usually appear during late adolescence or early adulthood. Efforts to identify disease causes have been complicated by the fact that no single genetic mutation is strongly associated with the disease. By studying a rare genetic disorder that increases the risk of schizophrenia, Laurie Earls, PhD, and colleagues in the laboratory of Stanislav Zakharenko, MD, PhD, at St. Jude Children’s Research Hospital identified molecular changes that affect memory and are also present in people with schizophrenia.

Approximately 30 percent of people with a genetic disorder known as 22q11 deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disease. In previous studies of mice with the 22q11 deletion, Zakharenko’s group identified changes in nerve cells leading to deficits in the hippocampus — the brain’s learning and memory center — that appear with age. In the current study, the group confirmed similar molecular changes occur in people with schizophrenia. They also zeroed in on the gene contributing to the nerve cell changes.

"This study makes some very important discoveries about the precise mechanisms underlying the learning and memory deficits seen in the genetic mouse model — problems that are a central part of the human disease," said Carrie Bearden, PhD, an expert on 22q11 deletion syndrome at the University of California, Los Angeles, who was not involved in the study. "Pinpointing the specific gene involved is the first step toward developing targeted therapies that could reverse the cognitive deficits associated with schizophrenia, both in the context of this genetic mutation and the broader population," she added.

In previous studies, Zakharenko’s group found that abnormal nerve cell communication and cognitive dysfunction was associated with elevated levels of a protein that regulates calcium in certain nerve cells known as Serca2. These abnormalities are only detectable with age in mice with the 22q11 deletion.

In the current study, the researchers identified the gene Dgcr8 as the source of the changes.It produces molecules called microRNAs that normally keep Serca2 in check. Without them, the protein becomes elevated.By adding these molecules back into the hippocampus of animals with the 22q11 deletion, the researchers were able to reduce elevated Serca2 levels and reduce the cellular deficits associated with this genetic defect.

To assess whether the findings from these genetic mouse studies might translate to schizophrenia, the authors analyzed post-mortem brain tissue from people with schizophrenia. The researchers discovered that Serca2 was elevated even in patients with schizophrenia who did not have the 22q11 deletion.

"These data suggest a link between the nerve cell changes in patients with the 22q11 deletion syndrome and those that occur in patients with schizophrenia," Zakharenko said. "Serca2 regulation represents a novel therapeutic target for schizophrenia."

Where the non-human animal research investigating reproduction-induced cognitive reorganization has focused on neural plasticity and adaptive advantage in response to the demands associated with pregnancy and parenting, human studies have primarily concentrated on pregnancy-induced memory decline. The current review updates Henry and Rendell’s 2007 meta-analysis, and examines cognitive reorganization as the result of reproductive experience from an adaptationist perspective. Investigations of pregnancy-induced cognitive change in human females may benefit by focusing on areas, such as social cognition, where a cognitive advantage would serve a protective function, and by extending the study duration beyond pregnancy into the postpartum period.

Results may help improve drugs for neurological disorders

Researchers have published the first highly detailed description of how neurotensin, a neuropeptide hormone which modulates nerve cell activity in the brain, interacts with its receptor. Their results suggest that neuropeptide hormones use a novel binding mechanism to activate a class of receptors called G-protein coupled receptors (GPCRs). 

“The knowledge of how the peptide binds to its receptor should help scientists design better drugs,” said Dr. Reinhard Grisshammer, a scientist at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and an author of the study published in Nature.

Binding of neurotensin initiates a series of reactions in nerve cells. Previous studies have shown that neurotensin may be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth.

Dr. Grisshammer and his colleagues used X-ray crystallography to show what the receptor looks like in atomic detail when it is bound to neurotensin. Their results provide the most direct and detailed views describing this interaction which may change the way scientists develop drugs targeting similar neuropeptide receptors.

X-ray crystallography is a technique in which scientists shoot X-rays at crystallized molecules to determine a molecule’s shape and structure. The X-rays change directions, or diffract, as they pass through the crystals before hitting a detector where they form a pattern that is used to calculate the atomic structure of the molecule. These structures guide the way scientists think about how proteins work.

Neurotensin receptors and other GPCRs belong to a large class of membrane proteins which are activated by a variety of molecules, called ligands. Previous X-ray crystallography studies showed that smaller ligands, such as adrenaline and retinal, bind in the middle of their respective GPCRs and well below the receptor’s surface.  In contrast, Dr. Grisshammer’s group found that neurotensin binds to the outer part of its receptor, just at the receptor surface. These results suggest that neuropeptides activate GPCRs in a different way compared to the smaller ligands.

Forming well-diffracting neuropeptide-bound GPCR crystals is very difficult. Dr. Grisshammer and his colleagues spent many years obtaining the results on the neurotensin receptor. During that time Dr. Grisshammer started collaborating with a group led by Dr. Christopher Tate, Ph.D. at the MRC Laboratory of Molecular Biology, Cambridge, England. Dr. Tate’s lab used recombinant gene technology to create a stable version of the neurotensin receptor which tightly binds neurotensin. Meanwhile Dr. Grisshammer’s lab employed the latest methods to crystallize the receptor bound to a short version of neurotensin.

The results published today are the first X-ray crystallography studies showing how a neuropeptide agonist binds to neuropeptide GPCRs. Nonetheless, more work is needed to fully understand the detailed signaling mechanism of this GPCR, said Dr. Grisshammer.