Posts tagged neuroscience
Articles and news from the latest research reports.
Scientists Identify Key Brain Circuits that Control Compulsive Drinking in Rats
Gallo Center Research Could Have Direct Application For Treating Human Drinking Problems
A research team led by scientists from the Ernest Gallo Clinic and Research Center at UC San Francisco has identified circuitry in the brain that drives compulsive drinking in rats, and likely plays a similar role in humans.
The scientists found they could reduce compulsive drinking in rats by inhibiting key neural pathways that run between the prefrontal cortex, which is involved with higher functions such as critical thinking and risk assessment, and the nucleus accumbens, a critical area for reward and motivation.
The authors noted that there are already several FDA-approved medications that target activity in these pathways, thus potentially opening an accelerated track to new treatments for compulsive drinking.
The study describing their finding was published online on June 30 in Nature Neuroscience.
The study was conducted on rats that regularly drank 20 percent alcohol. The rats drank both unmixed alcohol and alcohol mixed with extremely bitter quinine, said senior investigator F. Woodward Hopf, PhD, an assistant adjunct professor of neurology at UCSF.
Hopf explained that this alcohol-quinine solution, which he described as “like a vodka tonic without the sugar,” is often used as a rodent model of compulsive drinking, or “drinking in the face of negative consequences.” In rats, he said, the negative consequence is the bitter taste, while in humans who drink compulsively, “the negative consequences are profound: people continue to drink despite the potential loss of jobs, marriages, freedom, even their lives.”
In the United States, alcoholism is estimated to cost $224 billion per year – almost $2 per drink – mostly from lost productivity and crime, and leads to 100,000 preventable deaths per year.
The drinking rats showed a notable increase in the NMDA receptor (NMDAR), which lead author Taban Seif, PhD, a Gallo Center researcher, called “a molecule that excites the brain.” When the rats were injected with an NMDAR blocker, their consumption of quinine-laced alcohol dropped significantly, while regular alcohol use was unaffected. “In other words, only the compulsive drinking was affected,” said Seif.
Focus on Two Regions of the Prefrontal Cortex
The team then focused its research on connections from two specific regions of the rats’ prefrontal cortex where they had discovered the presence of unusual types of NMDARs: the medial prefrontal cortex, which mediates conflict during decision-making, and the insula, which is critical for self-awareness and feelings.
“In a non-addict, these brain areas tell you when something is potentially harmful and bad, and to run away as fast as possible,” said Hopf. “But if you’re a compulsive drinker, it seems instead that they give you a comforting pat on the back, in effect telling you it’s OK to have another drink, nothing to worry about.”
Using a technique called optogenetics, the scientists inserted halorhodopsin, a light-sensitive protein, into these areas. They then used fiber-optic cables implanted in the rats’ brains to send pulses of laser light that activated the halorhodopsin, which in turn inhibited the regions’ connections to the nucleus accumbens. The researchers found that rats inhibited in this way drank significantly less quinine-laced alcohol, while their intake of regular alcohol solution remained unaffected.
“The fact that we reduced the rats’ compulsive drinking using two different methods – an NMDAR blocker and direct inhibition of connections – tells us that we have probably identified the right areas,” said Hopf.
Potential Treatments for Humans
The next logical step for the research team, said Hopf, would be to work with clinical researchers on an NMDAR blocker trial in human subjects.
“What is interesting is that we have a new drug which could perhaps treat compulsive aspects of drinking,” said Hopf, “but only if you are in conflict about your drinking – if you care. Any therapy with NMDAR blockers would need a strong behavioral and cognitive component to make sure the patient stayed mentally engaged.”
Seif and Hopf also plan further experimental studies focusing on how the insula drives behavior and connects to other areas of the brain.
Scientists identify key to learning new words
For the first time scientists have identified how a pathway in the brain which is unique to humans allows us to learn new words.
The average adult’s vocabulary consists of about 30,000 words. This ability seems unique to humans as even the species closest to us - chimps - manage to learn no more than 100.
It has long been believed that language learning depends on the integration of hearing and repeating words but the neural mechanisms behind learning new words remained unclear. Previous studies have shown that this may be related to a pathway in the brain only found in humans and that humans can learn only words that they can articulate.
Now researchers from King’s College London Institute of Psychiatry, in collaboration with Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona, have mapped the neural pathways involved in word learning among humans. They found that the arcuate fasciculus, a collection of nerve fibres connecting auditory regions at the temporal lobe with the motor area located at the frontal lobe in the left hemisphere of the brain, allows the ‘sound’ of a word to be connected to the regions responsible for its articulation. Differences in the development of these auditory-motor connections may explain differences in people’s ability to learn words.
The results of the study are published in the journal Proceedings of the National Academy of Sciences (PNAS).
Dr Marco Catani, co-author from the NatBrainLab at King’s College London Institute of Psychiatry said: “Often humans take their ability to learn words for granted. This research sheds new light on the unique ability of humans to learn a language, as this pathway is not present in other species. The implications of our findings could be wide ranging – from how language is taught in schools and rehabilitation from injury, to early detection of language disorders such as dyslexia. In addition these findings could have implications for other disorders where language is affected such as autism and schizophrenia.”
The study involved 27 healthy volunteers. Researchers used diffusion tensor imaging to image the structure of the brain before a word learning task and functional MRI, to detect the regions in the brain that were most active during the task. They found a strong relationship between the ability to remember words and the structure of arcuate fasciculus, which connects two brain areas: the territory of Wernicke, related to auditory language decoding, and Broca’s area, which coordinates the movements associated with speech and the language processing.
In participants able to learn words more successfully their arcuate fasciculus was more myelinated i.e. the nervous tissue facilitated faster conduction of the electrical signal. In addition the activity between the two regions was more co-ordinated in these participants.
Dr Catani concludes, “Now we understand that this is how we learn new words, our concern is that children will have less vocabulary as much of their interaction is via screen, text and email rather than using their external prosthetic memory. This research reinforces the need for us to maintain the oral tradition of talking to our children.”
(Source: kcl.ac.uk)
MS study targets damage affecting nerves
Multiple sclerosis treatments that repair damage to the brain could be developed thanks to new research.
A study has shed light on how cells are able to regenerate protective sheaths around nerve fibres in the brain.
These sheaths, made up of a substance called myelin, are critical for the quick transmission of nerve signals, enabling vision, sensation and movement, but break down in patients with multiple sclerosis (MS).
In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.
-Dr Veronique Miron(MRC for Regenerative Medicine at the University of Edinburgh)
Macrophages
The study, by the Universities of Edinburgh and Cambridge, found that immune cells, known as macrophages, help trigger the regeneration of myelin.
Researchers found that following loss of or damage to myelin, macrophages can release a compound called activin-A, which activates production of more myelin.
Approved therapies for multiple sclerosis work by reducing the initial myelin injury – they do not promote myelin regeneration. This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.
-Dr Veronique Miron (Medical Council Centre for Regenerative Medicine at the University of Edinburgh)
Study
The study, which looked at myelin regeneration in human tissue samples and in mice, is published in Nature Neuroscience.
It was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.
Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.
We urgently need therapies that can help slow the progression of MS and so we’re delighted researchers have identified a new, potential way to repair damage to myelin. We look forward to seeing this research develop further.
-Dr Susan Kohlhaas (Head of Biomedical Research at the MS Society)
We are pleased to fund MS research that may lead to treatment benefits for people living with MS. We look forward to advances in treatments that address repair specifically, so that people with MS may be able to manage the unpredictable symptoms of the disease.
-Dr Karen Lee (Vice-President, Research at the MS Society of Canada
(Source: ed.ac.uk)
For a healthy brain, don’t let the trash pile up
Recycling is not only good for the environment, it’s good for the brain. A study using rat cells indicates that quickly clearing out defective proteins in the brain may prevent loss of brain cells.
Results of a study in Nature Chemical Biology suggest that the speed at which damaged proteins are cleared from neurons may affect cell survival and may explain why some cells are targeted for death in neurodegenerative disorders. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
One of the mysteries surrounding neurodegenerative diseases is why some nerve cells are marked for destruction whereas their neighbors are spared. It is especially puzzling because the protein thought to be responsible for cell death is found throughout the brain in many of these diseases, yet only certain brain areas or cell types are affected.
In Huntington’s disease and many other neurodegenerative disorders, proteins that are misfolded (have abnormal shapes), accumulate inside and around neurons and are thought to damage and kill nearby brain cells. Normally, cells sense the presence of malformed proteins and clear them away before they do any damage. This is regulated by a process called proteostasis, which the cell uses to control protein levels and quality.
In the study, Andrey S. Tsvetkov and his colleagues from the University of California, San Francisco (UCSF) and Duke University, Durham, N.C., showed that differences in the rate of proteostasis may be the clue to understanding why certain nerve cells die in Huntington’s, a genetic brain disorder that leads to uncontrolled movements and death.
To measure how quickly proteins are cleared away from cells, the researchers developed a new technique called optical pulse-labeling, allowing them to follow specific proteins in individual living cells. To test the technique, they grew brain cells in a dish and turned on Dendra2, a photoswitchable protein that glows from green to red after being hit by a specific type of light. Both the red and green glow can be followed until the protein is cleared from the cell. In this way, the researchers could track the lifetime of newly produced Dendra2 (which glows green) and older, photoswitched Dendra2 (which glows red) until the protein was cleared away from the cell.
"Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved," said Margaret Sutherland, Ph.D., program director at NINDS.
The researchers followed Dendra2 in a set of striatal neurons, which they obtained from rats. The striatum (where striatal neurons are located) is a brain region involved in a number of brain functions including planning movements and is most heavily affected in Huntington’s disease. They discovered that the mean lifetime of the protein (how long it remained in the cell) varied three- to fourfold, suggesting that rates of proteostasis were different among individual neurons. In other words, some cells may process an identical protein much slower than others.
Then, the researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington’s. They fused Dendra2 on the end of a normal or mutant version of huntingtin to track how long the protein remained in cells. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease. As predicted, in their experiments, the mutant form of huntingtin caused more rat cells to die than did the normal form of the protein.
The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington’s brains may improve neuronal survival.
To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer.
"Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin," said Dr. Steven Finkbeiner, senior author of the paper.
Although both striatal and cortical neurons are affected by mutant huntingtin, striatal neurons are more susceptible to cell death. The investigators found that striatal neurons were not as effective as cortical neurons in recognizing and clearing away the mutant protein.
"One surprising finding from these experiments was the significance of single cells’ ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain – the striatum, or the cortex, which is less vulnerable," said Dr. Finkbeiner. The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons.
"The results should remind us that focusing on the disease-causing proteins is only one side of the coin. To understand why some cells die and others are spared, we may need to recognize that there are major, largely unrecognized cell-specific differences in the ways that various types of neurons recognize and dispose of disease-causing proteins," continued Dr. Finkbeiner.
The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy — a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.
"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good," said Dr. Finkbeiner.
Future research is needed to determine why coping mechanisms fail as brain cells age and how neurons in the healthy brain keep the proteostasis system functioning.
"New research methods that help us understand how individual neurons function will increase our understanding of central nervous system disorders and help identify new treatments. It is critical to continue working on the methods such as those described in this paper," said Dr. Sutherland.
(Source: eurekalert.org)
Stem cells reprogrammed using chemicals alone
Scientists have demonstrated a new way to reprogram adult tissue to become cells as versatile as embryonic stem cells — without the addition of extra genes that could increase the risk of dangerous mutations or cancer.
Researchers have been striving to achieve this since 2006, when the creation of so-called induced pluripotent (iPS) cells was first reported. Previously, they had managed to reduce the number of genes needed using small-molecule chemical compounds (1, 2), but those attempts always required at least one gene, Oct4.
Now, writing in Science, researchers report success in creating iPS cells using chemical compounds only — what they call CiPS cells.
Hongkui Deng, a stem-cell biologist at Peking University in Beijing, and his team screened 10,000 small molecules to find chemical substitutes for the gene. Whereas other groups looked for compounds that would directly stand in for Oct4, Deng’s team took an indirect approach: searching for small-molecule compounds that could reprogram the cells in the presence of all the usual genes except Oct4.
Then came the most difficult part. When the group teamed the Oct4 replacements with replacements for the other three genes, the adult cells did not become pluripotent, or able to turn into any cell type, says Deng.
Fine-tuning
The researchers tinkered with the combinations of chemicals for more than a year, until they finally found one that produced some cells that were in an early stage of reprogramming. But the cells still lacked the hallmark genes indicating pluripotency. By adding DZNep, a compound known to catalyse late reprogramming stages, they finally got fully reprogrammed cells, but in only very small numbers. One further chemical increased efficiency by 40 times. Finally, using a cocktail of seven compounds, the group was able to get 0.2% of cells to convert — results comparable to those from standard iPS production techniques.
The team proved that the cells were pluripotent by introducing them into developing mouse embryos. In the resulting animals, the CiPS cells had contributed to all major cell types, including liver, heart, brain, skin and muscle.
“People have always wondered whether all factors can be replaced by small molecules. The paper shows they can,” says Rudolf Jaenisch, a cell biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who was among the first researchers to produce iPS cells. Studies of CiPS cells could give insight into the mechanisms of reprogramming, says Jaenisch.
The frog’s secret
The achievement could even help regenerative biologists to work out how amphibians grow new limbs. Deng’s group found that one gene indicative of pluripotency, Sall4, was expressed much earlier in the CiPS-cell reprogramming process than in iPS-cell reprogramming. The same Sall4 involvement is seen in frogs that regenerate a lost a limb: before the regeneration, cells in the limb de-differentiate, a process akin to reprogramming, and Sall4 is active early in that process.
The discovery “provides an important framework to decipher the signalling pathways leading to Sall4 expression” in regulating limb regeneration, says Anton Neff, who studies organ regeneration at Indiana University in Bloomington.
Sheng Ding, a reprogramming researcher at the Gladstone Institutes in San Francisco, California, says that the study marks “significant progress” in the field, but notes that chemical reprogramming is unlikely to be used widely until the team can show that it can work for human cells, not just mouse ones. Other strategies, including one that uses RNA, can complete reprogramming with less risk of disturbing the genes than the original iPS-generation method, and are already in use in humans. Indeed, clinical trials with iPS cells derived through such means are already being planned.
Deng has made some progress towards using his method in human cells, but it will require tweaks. ”Maybe some additional small molecules are needed,” he says.
If it the technique is found to be safe and effective in humans, it could be useful for the clinic. It does not risk causing mutations, and the compounds themselves seem to be safe — four of them are in fact already in clinical use. The small molecules can easily pass through cell membranes, so they can be washed away after they have initiated the reprogramming.
Stem cell research reveals clues to brain disease
The development of new drugs for improving treatment of Alzheimer’s and Parkinson’s disease is a step closer after recent research into how stem cells migrate and form circuits in the brain.
The results from a study by researchers at The University of Auckland’s Centre for Brain Research may hold important clues into why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease, and links to insulin resistance and diabetes.
The major five-year project to understand how stem cells start and stop migrating in the brain has also helped to unlock the secrets of how stem cells migrate during development and in adulthood.
The study revealed new information on how connectivity between brain cells is improved or worsened, says senior study author, Dr Maurice Curtis who conceived and directed the research. The experiments were carried out at the Centre for Brain Research laboratories by Dr Hector Monzo. Collaborators included a director of the CBR, Distinguished Professor Richard Faull, Dr Thomas Park, Dr Birger Dieriks, Deidre Jansson and Professor Mike Dragunow.
“We have begun testing new novel drug compounds that target how polysialic acid is removed from the cell in the hope of improving neuron connectivity,” says Dr Curtis.
He explains that stem cells in the brain are immature brain cells that must migrate from their birthplace to a position in the brain where they will connect with other brain cells, turn into adult brain cells (neurons) and become part of the brain’s circuitry.
“Even once the neuron has found its location, the neuron’s tentacles (or dendrites) need to forage to find other neurons to connect with to form circuits. This would be easy except that in the adult brain the cells are surrounded by a fairly rigid matrix (extracellular matrix) and so migration or foraging becomes almost impossible in this high friction environment.”
“The way the cell overcomes this ‘friction’ is by placing large amounts of a special slippery molecule called ‘polysialic acid-neural cell adhesion molecule’ onto the cell surface,” says Dr Curtis. “This allows the cell to migrate or forage with only a fraction of the friction it once had and this also reduces the energy requirements of the cell.”
Once the cell has migrated to its destination, the slippery coating is removed and the cell becomes locked in place ready to connect with other cells. In the case of the dendritic foraging, the polysialic acid must be removed in order for the dendrite to connect with another cell (synapse formation).
“We have known for at least 20 years that this process occurs but despite extensive studies by a number of groups internationally we have been in the dark about what controls this process,” he says. “Studies in my laboratory have demonstrated what happens to the slippery molecules once the cell no longer needs them.”
There were three possibilities for this process:
- that enzymes cut them off the outside of the cell
- that the friction wears it off the cell or
- the cell internalises the slippery substance and recycles it ready for future use.
“For the past five years, we have systematically studied how this process is controlled,” says Dr Curtis. “Our findings have demonstrated that cells internalise the slippery molecule after receiving two specific cues.”
One of these cues is from collagen which makes up part of the rigid structure outside of the cell and the other is from a gaseous molecule called nitric oxide which triggers the outer membrane of the cell to internalise the slippery molecules.
“What we also discovered is that when there is an increased amount of insulin and insulin-like growth factor 1 (which has some similar functions to insulin) present in the culture, the cell cannot internalise the slippery molecules and instead they remain on the cell surface.”
“The key to the breakthrough was in determining that the process by which the polysialic acid is added to the cell surface was so persistent that it needed to be stopped in order to study how the polysialic acid was removed,” says Dr Curtis. “This required extensive trialling of many different cell growth conditions, enzyme concentrations and growing the cells in many different extracellular matrices.”
This is interesting because it is well known that in Parkinson’s disease and Alzheimer’s disease the brain is less sensitive to insulin, he says.
“In our studies in cells the insulin blocks the removal of polysialic acid and therefore the cell cannot connect properly and form synapses with other nearby cells.”
“This may hold major clues to why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease in adults as well as helping to unlock the secrets of how stem cells migrate during development of the brain”, says Dr Curtis.
The Gus Fisher Postdoctoral Fellowship, the Auckland Medical Research Foundation and the Manchester Trust were the main sponsors of this research work.
The study results were published online this month in an ‘ahead of print’ version of The Journal of Neurochemistry.
(Source: auckland.ac.nz)
Drinking alcohol during pregnancy affects learning and memory function in offspring?
Maternal alcohol consumption during pregnancy has detrimental effects on fetal central nervous system development. Maternal alcohol consumption prior to and during pregnancy significantly affects cognitive functions in offspring, which may be related to changes in cyclin-dependent kinase 5 because it is associated with modulation of synaptic plasticity and impaired learning and memory. Prof. Ruiling Zhang and team from Xinxiang Medical University explored the correlation between cyclin-dependent kinase 5 expression in the hippocampus and neurological impairments following prenatal ethanol exposure, and found that prenatal ethanol exposure could affect cyclin-dependent kinase 5 and its activator p35 in the hippocampus of offspring rats. These findings, which reported in the Neural Regeneration Research (Vol. 8, No. 18, 2013), propose new insights into the mechanisms underlying the role of ethanol exposure in central nervous system injuries, and provide a new strategy for treating the consequences of prenatal ethanol exposure.
Is sexual addiction the real deal?
Controversy exists over what some mental health experts call “hypersexuality,” or sexual “addiction.” Namely, is it a mental disorder at all, or something else? It failed to make the cut in the recently updated Diagnostic and Statistical Manual of Mental Disorders, or DSM-5, considered the bible for diagnosing mental disorders. Yet sex addiction has been blamed for ruining relationships, lives and careers.
Now, for the first time, UCLA researchers have measured how the brain behaves in so-called hypersexual people who have problems regulating their viewing of sexual images. The study found that the brain response of these individuals to sexual images was not related in any way to the severity of their hypersexuality but was instead tied only to their level of sexual desire.
In other words, hypersexuality did not appear to explain brain differences in sexual response any more than simply having a high libido, said senior author Nicole Prause, a researcher in the department of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA.
"Potentially, this is an important finding," Prause said. "It is the first time scientists have studied the brain responses specifically of people who identify as having hypersexual problems."
The study appears in the current online edition of the journal Socioaffective Neuroscience and Psychology.
A diagnosis of hypersexuality or sexual addiction is typically associated with people who have sexual urges that feel out of control, who engage frequently in sexual behavior, who have suffered consequences such as divorce or economic ruin as a result of their behaviors, and who have a poor ability to reduce those behaviors.
But, said Prause and her colleagues, such symptoms are not necessarily representative of an addiction — in fact, non-pathological, high sexual desire could also explain this cluster of problems.
One way to tease out the difference is to measure the brain’s response to sexual-image stimuli in individuals who acknowledge having sexual problems. If they indeed suffer from hypersexuality, or sexual addiction, their brain response to visual sexual stimuli could be expected be higher, in much the same way that the brains of cocaine addicts have been shown to react to images of the drug in other studies.
The study involved 52 volunteers: 39 men and 13 women, ranging in age from 18 to 39, who reported having problems controlling their viewing of sexual images. They first filled out four questionnaires covering various topics, including sexual behaviors, sexual desire, sexual compulsions, and the possible negative cognitive and behavioral outcomes of sexual behavior. Participants had scores comparable to individuals seeking help for hypersexual problems.
While viewing the images, the volunteers were monitored using electroencephalography (EEG), a non-invasive technique that measures brain waves, the electrical activity generated by neurons when they communicate with each other. Specifically, the researchers measured event-related potentials, brain responses that are the direct result of a specific cognitive event.
"The volunteers were shown a set of photographs that were carefully chosen to evoke pleasant or unpleasant feelings," Prause said. "The pictures included images of dismembered bodies, people preparing food, people skiing — and, of course, sex. Some of the sexual images were romantic images, while others showed explicit intercourse between one man and one woman."
The researchers were most interested in the response of the brain about 300 milliseconds after each picture appeared, commonly called the “P300” response. This basic measure has been used in hundreds of neuroscience studies internationally, including studies of addiction and impulsivity, Prause said. The P300 response is higher when a person notices something new or especially interesting to them.
The researchers expected that P300 responses to the sexual images would correspond to a person’s sexual desire level, as shown in previous studies. But they further predicted that P300 responses would relate to measures of hypersexuality. That is, in those whose problem regulating their viewing of sexual images could be characterized as an “addiction,” the P300 reaction to sexual images could be expected to spike.
Instead, the researchers found that the P300 response was not related to hypersexual measurements at all; there were no spikes or decreases tied to the severity of participants’ hypersexuality. So while there has been much speculation about the effect of sexual addiction or hypersexuality in the brain, the study provided no evidence to support any difference, Prause said.
"The brain’s response to sexual pictures was not predicted by any of the three questionnaire measures of hypersexuality," she said. "Brain response was only related to the measure of sexual desire. In other words, hypersexuality does not appear to explain brain responses to sexual images any more than just having a high libido."
But debate continues over whether sex addiction is indeed an addiction. A study published in 2012 by Prause’s colleague Rory Reid, a UCLA assistant professor of psychiatry, supported the reliability of the proposed DSM-5 diagnostic criteria for hypersexual disorder. However, Prause notes, that study was not focused on the validity of sex addiction or impulsivity, and did not use any biophysiological data in the analysis.
"If our study can be replicated," she said, "these findings would represent a major challenge to existing theories of a sex ‘addiction.’ "
(Source: newsroom.ucla.edu)
Gene mutation in dogs offers clues for neural tube defects in humans
A gene related to neural tube defects in dogs has for the first time been identified by researchers at the University of California, Davis, and University of Iowa.
The researchers also found evidence that the gene may be an important risk factor for human neural tube defects, which affect more than 300,000 babies born each year around the world, according to the U.S. Centers for Disease Control and Prevention. Neural tube defects, including anencephaly and spina bifida, are caused by the incomplete closure or development of the spine and skull.
The new findings appear this week in the journal PLOS Genetics.
“The cause of neural tube defects is poorly understood but has long been thought to be associated with genetic, nutritional and environmental factors,” said Noa Safra, lead author on the study and a postdoctoral fellow in the laboratory of Professor Danika Bannasch in the UC Davis School of Veterinary Medicine.
She noted that dogs provide an excellent biomedical model because they receive medical care comparable to what humans receive, share in a home environment and develop naturally occurring diseases that are similar to those found in humans. More specifically, several conditions associated with neural-tube defects are known to occur naturally in dogs. All DNA samples used in the study were taken from household pets, rather than laboratory animals, Safra said.
She and colleagues carried out genome mapping in four Weimaraner dogs affected by spinal dysraphism, a naturally occurring spinal-cord disorder, and in 96 such dogs that had no neural tube defects. Spinal dysraphism, previously reported in the Weimaraner breed, causes symptoms that include impaired motor coordination or partial paralysis in the legs, abnormal gait, a crouched stance and abnormal leg or paw reflexes.
Analysis of a specific region on canine chromosome eight led the researchers to a mutation in a gene called NKX2-8, one of a group of genes known as “homeobox genes,” known to be involved with regulating patterns of anatomical development in the embryo.
The researchers determined that the NKX2-8 mutation occurred in the Weimaraner breed with a frequency of 1.4 percent — 14 mutations in every 1,000 dogs.
Additionally, they tested nearly 500 other dogs from six different breeds that had been reported to be clinically affected by neural tube defects, but did not find copies of the NKX2-8 gene mutation among the non-Weimaraner dogs.
“The data indicate that this mutation does not appear as a benign mutation in some breeds, while causing defects in other breeds,” Safra said. “Our results suggest that the NKX2-8 mutation is a ‘private’ mutation in Weimaraners that is not shared with other breeds.”
The researchers say that identification of such a breed-specific gene may help veterinarians diagnose spinal dysraphism in dogs and enable Weimaraner breeders to use DNA screening to select against the mutation when developing their breeding plans.
In an effort to investigate a potential role for the NKX2-8 mutation in cases of neural tube defects in people, the researchers also sequenced 149 unrelated samples from human patients with spina bifida. They found six cases in which the patients carried mutations of the NKX2-8 gene but stress that further studies are needed to confirm whether these mutations are responsible for the diagnosed neural tube defects.
(Source: news.ucdavis.edu)
Haste and waste on neuronal pathways
Researchers of the Department of Biosystems Science and Engineering of ETH Zurich were able to measure the speed of neuronal signal conduction along segments of single axons in neuronal cultures by using a high-resolution electrical method. The bioengineers are now searching for plausible explanations for the large conduction speed variations.
To write this little piece of text, the brain sends commands to arms and fingers to tap on the keyboard. Neuronal cells with their cable-like extensions, such as axons, transfer this information as electrical pulses that trigger muscles to move. The axonal signal speed can be to up to 100m/s in myelinated axons along the spinal cord. For a long time, scientists assumed that axonal signal conduction is by and large digital: either there is a signal, “1”, or there is no signal, “0”.
Strong propagation speed variations
Now, a team of researchers under Douglas Bakkum and Andreas Hierlemann at the Department BSSE of ETH Zurich in Basel presents evidence that there may be more to axons than only digital signal conduction. They could directly measure and demonstrate that the speed of an axonal signal varies considerably within different segments of the very same axon by placing hundreds of electrodes along the axon. Moreover, the velocity pattern changed from day to day or within hours as did the morphology and position of the axon.
The exact meaning of these speed variations and the origin cannot be explained yet, as there is too little information available about axonal conduction. This may, to a large part, be a consequence of the tiny diameter of the axons. The length of an axon can be more than a meter, e.g., in the spinal cord, but the average diameter is in between 80 nm and a few micrometers. This small diameter makes any measurement of axonal potentials difficult, which, of course, also renders establishing the mechanisms that may produce the large speed variations a difficult task.
Unclear cause
Up to now, only hypotheses concerning these speed variations exist. The temporal characteristics of axonal conduction may form part of the overall information processing abilities of ensembles of neurons or contribute to how neurons adapt to new information. The research group plans on further investigating these effects in collaboration with researchers in other disciplines and research institutions that have complementary expertise and technologies. The related research work is also facilitated through Hierlemann’s 5-year ERC Advanced Grant and Bakkum’s SNF Ambizione Grant awarded in 2010/2011. However, the researchers do not expect a fast elucidation of the axonal speed variations. Considering the small dimensions of axons, it will probably take years to collect conclusive evidence.
Up to now, a detailed and long-term investigation of signals of ensembles of neurons and their axons was hardly possible. The BSSE research group, during the last 10 years, devoted a lot of time and efforts to develop the high-resolution microelectronic chips, hosting thousands of microelectrodes. The now published, detailed and precise axonal propagation speed measurements reward the scientists for their investment and validate the approach. “We hope to acquire important new evidence with our technology,” they state. Other technologies have not yet provided a high enough spatio-temporal resolution to characterize details of axonal signal conduction.
High-resolution chip developed
The microelectrode array chip of the BSSE research group has 11’000 electrodes within a very small area (3150 electrodes per square millimeter) that record from or stimulate neuronal cells or ensembles. Data from 126 arbitrarily selectable electrodes can be simultaneously recorded by means of custom-developed on-chip microelectronic circuits. The neuronal cells grow directly atop the circuitry units on the microelectronic chip, which is fabricated in industrial complementary-metal-oxide-semiconductor (CMOS) technology. Signals traveling along the axons of the neurons can be measured and localized at high spatial and temporal resolution, owing to the small electrode diameter and tight electrode spacing. Moreover, electrodes can be used to stimulate single axons with the aim to evoke action potentials that propagate back to the respective cell body or soma and elicit action potentials there.
In his opinion, the neuroscience community has underestimated the potential of microelectrodes arrays for quite some time, says Prof. Hierlemann. With the work published now in “Nature Communications”, he hopes to further establish this method. “These results show that the microelectrode array technology is enabling access to data that are currently not accessible through other technologies,” says the bioengineer.
Neurons, axons and signal propagation
Nerve cells or neurons communicate with other neurons via electrical and chemical signals. If an electrical signal within a cell body, close to the axon initial segment, is large enough, it enters the axon and propagates along its length at a high speed. This is achieved by alterations in the so-called resting potential of the axon membrane, which usually has a steady negative value. Sodium ion channels open, and because of a concentration gradient, positively charged sodium ions from outside the axon travel into the axon. As a consequence, the membrane potential is briefly reversed in polarity until potassium channels open and positively charged potassium ions are released into the external liquid. This brief change in membrane potential, a so-called action potential, can be detected with the microelectrode array chip. An action potential travels without attenuation to synapses, neuron-to-neuron junctions, where the electrical signal is translated into a chemical signal: neurotransmitters are released, diffuse through the small synaptic cleft and initiate electrical activity in the neighboring postsynaptic cell. After an action potential event, the original sodium and potassium ion concentrations outside and inside of the axonal membrane and the associated resting potential across the membrane are restored through membrane pumps. The overall duration of an action potential event is on the order of 2 milliseconds.
Reference
Bakkum DJ, Frey U, Radivojevic M, Russell TL, Müller J, Fiscella M, Takahashi H & Hierlemann A. Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites. Nature Communications, first published online 19th July 2013. DOI: 10.1038/ncomms3181