Posts tagged neuroscience
Articles and news from the latest research reports.
Veterans’ Head Injury Examined
Roadside bombs and other blasts have made head injury the “signature wound” of the Iraq and Afghanistan conflicts. Most combat veterans recover from mild traumatic brain injury, also known as concussion, but a small minority experience significant and long-term side effects.
Now, researchers at Albert Einstein College of Medicine of Yeshiva University, in cooperation with Resurrecting Lives Foundation, are investigating the effect of repeated combat-related blast exposures on the brains of veterans with the goal of improving diagnostics and treatment.
Mild traumatic brain injury can cause problems with cognition, concentration, memory and emotional control as well as post-traumatic stress disorder (PTSD). Einstein scientists are using advanced MRI technology and psychological tests to investigate the structural and biological impact of repeated head injury on the brain and to assess how these injuries affect cognitive function.
"Right now, doctors diagnose concussion purely on the basis of someone’s symptoms," said Michael Lipton, M.D., Ph.D., associate director of Einstein’s Gruss Magnetic Resonance Research Center. "We hope that our research will lead to a more scientifically valid diagnostic technique—one that uses imaging to not only detect the underlying brain injury but reveal its severity. Such a technique could also objectively evaluate therapies aimed at healing the brain injuries responsible for concussions." Dr. Lipton is also associate professor of radiology, of psychiatry and behavioral sciences and of neuroscience at Einstein and medical director of MRI services at Montefiore Medical Center, the University Hospital for Einstein.
The Einstein researchers are studying 20 veterans from Ohio and Michigan who were deployed in Iraq and Afghanistan and have exhibited symptoms of repeated concussion. Twenty of the veterans’ siblings or cousins without concussion are acting as controls. The researchers are using an advanced MRI-based imaging technique called diffusion tensor imaging (DTI) to identify injured brain areas.
DTI “sees” the movement of water molecules within and along axons, the nerve fibers that constitute the brain’s white matter. This imaging technique allows researchers to measure the uniformity of water movement (called fractional anisotropy, or FA) throughout the brain. Abnormally low FA within white matter indicates axon damage and has previously been associated with cognitive impairment in patients with traumatic brain injury. (The researchers also use DTI in an ongoing study of amateur soccer players to assess possible brain injury from repeatedly heading soccer balls.)
The final group of veterans is scheduled to visit Einstein for testing in February 2014. Preliminary results should be available later this year.
Researchers uncover secrets of newborn neurons
A new form of cell sub-division that is key to the development of the nervous system has been identified by researchers at the University of Dundee.
Image caption: Image shows two newborn neurons shedding their tip ends, or abscising
Neurons are vital to the development of the nervous system and in some regions of our brains they are continually produced throughout our lives. They are ‘born’ in a particular place in the early nervous system and then have to migrate to the correct place to make functional neural structures.
A team led by Professor Kate Storey and Dr Raman Das in the College of Life Sciences at Dundee have now identified a new process, apical abscission, which mediates the detachment of new-born neurons from the neural tube ventricle - freeing these cells to migrate.
'Neuron production is an important process within our bodies. As an example, our memory centre, the hippocampus, continues to produce neurons throughout our lives,' said Professor Storey.
'What we have identified are the molecular events, the 'letting-go' process, which allow newborn neurons to move to their correct place in the nervous system.
'This is a new form of cell sub-division so it is of significant interest as it tells us about mechanisms that control how we develop that we didn't know before. We were very surprised when we first saw cells shedding their tip-ends as they began to differentiate into neurons, it is not what we had expected at all.
'Our discovery comes with the development of novel live-tissue imaging approaches in my lab, which allows us to monitor cell behaviour over long periods. We have also been to make use of state of the art super-resolution microscopy in the Light Microscopy Facility based here within the College of Life Sciences.'
The research has been funded by the Wellcome Trust and the results are published this week in the journal Science.
The work identifies molecular events that control the shedding of the cell’s tip. It takes place as cells lose a key adhesion molecule and involves increased activity of a cell constriction mechanism.
Surprisingly, this event, also involves dismantling of an important structure in the cell, the primary cilium, known to convey signals that promote cell proliferation. Das and Storey propose that Apical Abscission mediates a pivotal cell state transition in the neuronal differentiation process, rapidly altering the polarity and signalling activity of the new-born neuron.
The researchers plan to extend the work to determine if this new mechanism also operates in other contexts including different regions of the brain, but will also address if this takes place in some cancers, where cells are known to lose polarity, shed primary cilia and detach from their neighbours as a prelude to tissue invasion.
'We need to look more widely now to establish whether this regulated mechanism allows other cells to make rapid cell state transitions and to move in other tissues of the body,' said Professor Storey.
(Source: dundee.ac.uk)
Medical implants, complex interfaces between brain and machine or remotely controlled insects: Recent developments combining machines and organisms have great potentials, but also give rise to major ethical concerns. In their review entitled “Chemie der Cyborgs – zur Verknüpfung technischer Systeme mit Lebewesen” (The Chemistry of Cyborgs – Interfacing Technical Devices with Organisms), KIT scientists discuss the state of the art of research, opportunities, and risks. The review is published now by the renowned journal “Angewandte Chemie Int. Ed.”
They are known from science fiction novels and films – technically modified organisms with extraordinary skills, so-called cyborgs. This name originates from the English term “cybernetic organism”. In fact, cyborgs that combine technical systems with living organisms are already reality. The KIT researchers Professor Christof M. Niemeyer and Dr. Stefan Giselbrecht of the Institute for Biological Interfaces 1 (IBG 1) and Dr. Bastian E. Rapp, Institute of Microstructure Technology (IMT), point out that this especially applies to medical implants.
In recent years, medical implants based on smart materials that automatically react to changing conditions, computer-supported design and fabrication based on magnetic resonance tomography datasets or surface modifications for improved tissue integration allowed major progress to be achieved. For successful tissue integration and the prevention of inflammation reactions, special surface coatings were developed also by the KIT under e.g. the multidisciplinary Helmholtz program “BioInterfaces”.
Progress in microelectronics and semiconductor technology has been the basis of electronic implants controlling, restoring or improving the functions of the human body, such as cardiac pacemakers, retina implants, hearing implants, or implants for deep brain stimulation in pain or Parkinson therapies. Currently, bioelectronic developments are being combined with robotics systems to design highly complex neuroprostheses. Scientists are working on brain-machine interfaces (BMI) for the direct physical contacting of the brain. BMI are used among others to control prostheses and complex movements, such as gripping. Moreover, they are important tools in neurosciences, as they provide insight into the functioning of the brain. Apart from electric signals, substances released by implanted micro- and nanofluidic systems in a spatially or temporarily controlled manner can be used for communication between technical devices and organisms.
BMI are often considered data suppliers. However, they can also be used to feed signals into the brain, which is a highly controversial issue from the ethical point of view. “Implanted BMI that feed signals into nerves, muscles or directly into the brain are already used on a routine basis, e.g. in cardiac pacemakers or implants for deep brain stimulation,” Professor Christof M. Niemeyer, KIT, explains. “But these signals are neither planned to be used nor suited to control the entire organism – brains of most living organisms are far too complex.”
Brains of lower organisms, such as insects, are less complex. As soon as a signal is coupled in, a certain movement program, such as running or flying, is started. So-called biobots, i.e. large insects with implanted electronic and microfluidic control units, are used in a new generation of tools, such as small flying objects for monitoring and rescue missions. In addition, they are applied as model systems in neurosciences in order to understand basic relationships.
Electrically active medical implants that are used for longer terms depend on reliable power supply. Presently, scientists are working on methods to use the patient body’s own thermal, kinetic, electric or chemical energy.
In their review the KIT researchers sum up that developments combining technical devices with organisms have a fascinating potential. They may considerably improve the quality of life of many people in the medical sector in particular. However, ethical and social aspects always have to be taken into account.
Sleep is the Price the Brain Pays for Learning
Why do animals ranging from fruit flies to humans all need to sleep? After all, sleep disconnects them from their environment, puts them at risk and keeps them from seeking food or mates for large parts of the day.
Two leading sleep scientists from the University of Wisconsin School of Medicine and Public Health say that their synaptic homeostasis hypothesis of sleep or “SHY” challenges the theory that sleep strengthens brain connections.
The SHY hypothesis, which takes into account years of evidence from human and animal studies, says that sleep is important because it weakens the connections among brain cells to save energy, avoid cellular stress, and maintain the ability of neurons to respond selectively to stimuli.
“Sleep is the price the brain must pay for learning and memory,” says Dr. Giulio Tononi, of the UW Center for Sleep and Consciousness. “During wake, learning strengthens the synaptic connections throughout the brain, increasing the need for energy and saturating the brain with new information. Sleep allows the brain to reset, helping integrate newly learned material with consolidated memories, so the brain can begin anew the next day.”
Tononi and his co-author Dr. Chiara Cirelli, both professors of psychiatry, explain their hypothesis in a review article in today’s issue of the journal Neuron. Their laboratory studies sleep and consciousness in animals ranging from fruit flies to humans; SHY takes into account evidence from molecular, electrophysiological and behavioral studies, as well as from computer simulations.”Synaptic homeostasis” refers to the brain’s ability to maintain a balance in the strength of connections within its nerve cells.
Why would the brain need to reset? Suppose someone spent the waking hours learning a new skill, such as riding a bike. The circuits involved in learning would be greatly strengthened, but the next day the brain will need to pay attention to learning a new task. Thus, those bike- riding circuits would need to be damped down so they don’t interfere with the new day’s learning.
“Sleep helps the brain renormalize synaptic strength based on a comprehensive sampling of its overall knowledge of the environment,” Tononi says, “rather than being biased by the particular inputs of a particular waking day.”
The reason we don’t also forget how to ride a bike after a night’s sleep is because those active circuits are damped down less than those that weren’t actively involved in learning. Indeed, there is evidence that sleep enhances important features of memory, including acquisition, consolidation, gist extraction, integration and “smart forgetting,” which allows the brain to rid itself of the inevitable accumulation of unimportant details.
However, one common belief is that sleep helps memory by further strengthening the neural circuits during learning while awake. But Tononi and Cirelli believe that consolidation and integration of memories, as well as the restoration of the ability to learn, all come from the ability of sleep to decrease synaptic strength and enhance signal-to-noise ratios.
While the review finds testable evidence for the SHY hypothesis, it also points to open issues. One question is whether the brain could achieve synaptic homeostasis during wake, by having only some circuits engaged, and the rest off-line and thus resetting themselves.
Other areas for future research include the specific function of REM sleep (when most dreaming occurs) and the possibly crucial role of sleep during development, a time of intense learning and massive remodeling of brain.
Researchers find rare genetic cause of Tourette syndrome
A rare genetic mutation that disrupts production of histamine in the brain is a cause of the tics and other abnormalities of Tourette syndrome, according to new findings by Yale School of Medicine researchers.
The findings, reported Jan. 8 in the journal Neuron, suggest that existing drugs that target histamine receptors in the brain might be useful in treating the disorder. Tourette syndrome afflicts up to 1% of children, and a smaller percentage of adults.
“These findings give us a new window into what’s going on in the brain in people with Tourette. That’s likely to lead us to new treatments,” said Christopher Pittenger, associate professor in the psychiatry and psychology departments and in the Yale Child Study Center, and senior author of the paper.
Histamine is commonly associated with allergy, but it also plays an important role as a signaling molecule in the brain. Interactions with this brain system explain why some allergy medications cause people to feel sleepy.
In 2010, Yale researchers showed that a family with nine members suffering from Tourette’s carried a mutation in a gene called HDC that disrupts the production of histamine. The new work demonstrates that this mutation causes the disorder. Mice with the same mutation develop symptoms similar to those found in Tourette’s, the Yale team showed. Also, these mice and the patients that carry the HDC mutation showed abnormalities in signaling by the neurotransmitter dopamine in parts of the brain associated with Tourette’s and related conditions.
Drug companies have developed medications that target brain-specific histamine receptors in an effort to treat schizophrenia and ADHD. While not approved for general use yet, those drugs or others that target histamine receptors should be tested to see whether they can treat symptoms of Tourette syndrome, Pittenger said.
Color-Coded Cells Reveal Patchwork Patterns of X Chromosome Silencing in Female Brains
Producing brightly speckled red and green snapshots of many different tissues, Johns Hopkins researchers have color-coded cells in female mice to display which of their two X chromosomes has been made inactive, or “silenced.”
(Image caption: Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice (clockwise). Cells are red or green depending on whether they have inactivated their maternal or paternal X chromosome, respectively. Hao Wu, courtesy of Neuron)
Scientists have long known that the silencing of one X chromosome in females — who have two X chromosomes in every cell — is a normal occurrence whose consequences can be significant, especially if one X chromosome carries a normal copy of a gene and the other X chromosome carries a mutated copy.
By genetically tagging different X chromosomes with genes that code for red or green fluorescent proteins, scientists say they can now peer into different tissue types to analyze genetic diversity within and between individual females at a new level of detail.
Published on Jan. 8 in the journal Neuron, a summary of the research shows wide-ranging variation in patterns of so-called X chromosome inactivation at every level: within tissues, on the left or right sides of a centrally located tissue (like the brain), among different tissue types, between paired organs (like the eyes) and among individuals.
"Calico cats, which are only ever female, have mottled coat colors. They have two different versions of a gene for coat color, which is located on the X chromosome: one version from their mother and the other from their father," explains Jeremy Nathans, M.D., Ph.D., professor of molecular biology and genetics at the Johns Hopkins University and a Howard Hughes Medical Institute investigator. "Their fur is orange or black depending on which X chromosome is silenced in a particular patch of skin cells. X chromosome inactivation actually occurs in all cells in female mammals, including humans, and it affects most of the genes on the X chromosome. Although this phenomenon has been known for over 50 years, it couldn’t be clearly visualized in internal organs and tissues until now."
Nathans adds that early in the development of most mammals, when a female embryo has only about 1,000 cells, each cell makes a “decision” to inactivate one of the two X chromosomes, a process that silences most of the genes on that chromosome. The choice of which X chromosome to inactivate appears to be random, but when those cells divide, their descendants maintain that initial decision.
In the new research, the Johns Hopkins team mated female mice carrying two copies of the gene for green fluorescent protein — one on each of the two X chromosomes — with male mice whose single X chromosome carried the gene for a red fluorescent protein. The female offspring from this mating had cells that glowed red or green based on which X chromosome was silenced. Additionally, the team engineered the mice so that not all of their cells were color-coded, since that would make it hard to distinguish one cell from another. Instead, they designed a system that allowed a single cell type in each mouse, such as heart muscle cells, to be color-coded. Their genetic trick resulted in red and green color maps with distinctive patterns for each cell and tissue type that they examined.
Nathans explains that the patterns are determined by the way each tissue develops. Some tissues are created from a very small number of “founder cells” in the early embryo; others are created from a large number. Statistically, the larger the group of founder cells, the greater the chances are of having a nearly equivalent number of red and green cells. Although the ratio in the founding group is roughly preserved as the tissue grows, the distribution of those cells is determined by how much movement occurs during the development of the tissue. For example, in a tissue like blood, where the cells move a lot, the red and green cells are finely intermingled. By contrast, in skin, where the cells show little movement, each patch of skin consists of the descendants of a single cell, which share the same inactive X chromosome — and therefore the same color — creating a coarse patchwork of red and green.
Normally, the pattern of X chromosome inactivation is not easily visualized. This color-coding technique is likely to be valuable for many studies, Nathans says, especially for research on variations caused by changes in the DNA sequence of the X chromosome, referred to as X-linked variation. X-linked genetic variations, such as hemophilia or color blindness, are relatively common, in part because the X chromosome carries many genes — approximately 1,000, or close to 4 percent of the total.
Males who inherit an X-linked disease usually suffer its effects because they have no second X chromosome to compensate for the mutant version of the gene. Female relatives, on the other hand, are more typically “carriers” of X-linked diseases. They have the ability to pass the disease along to their male progeny, but they do not suffer from it themselves due to the normal copy of the gene on their second X chromosome.
In the tissues of certain carrier females, however, the cells that have silenced the X chromosome with a mutated gene cannot compensate for the defect in the cells that have silenced the X chromosome with the normal gene. Nathans and his team saw such a pattern when they examined the retinas of mice that were carriers for mutations in the Norrie disease gene, which is located on the X chromosome. The Norrie disease gene codes for a protein, Norrin, which controls blood vessel formation in the retina. Women who are carriers for Norrie disease can have defects in their retinas, but some women are more affected than others, and sometimes one eye is more affected than the other eye in the same individual.
The team found that in female mice that were Norrie disease carriers, variation in blood vessel structure corresponded to localized variations in X chromosome inactivation. When the X chromosome carrying the normal copy of the Norrie disease gene was silenced in a group of cells, the blood vessels nearby failed to form properly. In contrast, when the X chromosome carrying the mutated copy of the Norrie disease gene was silenced, the nearby blood vessels developed normally.
“X chromosome inactivation is a fascinating aspect of mammalian biology,” says Nathans. “This new technique for visualizing the pattern of X chromosome inactivation should be particularly useful for looking at the role that this process plays in brain development, including the ways that it contributes to differences between the left and right sides of the female brain, and to differences in brain structure between males and females and among different females, including identical twins.”
Stopping tumours in their path
Glioblastoma (GBM) is the most common and deadly form of primary malignant brain cancer accounting for approximately 15% of all brain tumours and occurring mostly in adults between the ages of 45 and 70. The aggressive recurrent nature of this cancer is only temporarily contained by combined surgery, chemotherapy and radiation treatment. The recurrence of GBM is usually fatal, resulting in an average patient survival time of less than two years. A new study from the Montreal Neurological Institute and Hospital – The Neuro - at McGill University, published in Nature Communications, identifies two specific key players in the growth of GBM.
A GBM tumour contains a complex combination of different cell types, including ‘stem-like’ cells that are able to initiate brain tumour growth, even when present in very small numbers. These cells, known as brain-tumour initiating cells (BTICs), are believed to be among the cells that can re-initiate GBM if they are not completely eradicated through surgery, radiation and chemotherapy. Thus, BTICs represent an important therapeutic target for GBM treatment strategies.
“We wanted to find out how GBM-derived BTICs are able to initiate a tumour with the ultimate goal of preventing the re-growth of this deadly form of brain cancer,” says Dr. Stefano Stifani, neuroscientist at The Neuro and senior investigator on the paper. “What we found is that by impairing the activity of two transcription factors (proteins that control gene expression), termed FOXG1 and TLE, we can significantly reduce the ability of BTICs to give rise to brain tumours.” The researchers studied brain tumour growth in an in vivo mouse model using human GBM-derived BTICs. This approach provides what is called an in vivo environment that closely resembles the original human brain tumours. The demonstration that the FOXG1 and TLE proteins are important for the tumour-forming ability of human GBM-derived BTICs has long-term implications because FOXG1 and TLE control the expression of numerous genes. Identifying the genes whose expression is controlled by FOXG1 and TLE is expected to provide further information on the mechanisms involved in GBM tumourigenesis. In the long term, researchers hope to identify multiple important regulators, in order to find new potential therapeutic targets to impair the tumourigenic ability of BTICs.
“The implication of transcription factors FOXG1 and TLE in the tumour-forming ability of BTICs opens the door to possible strategies to block tumour growth – a major advance in the fight against GBM.”
(Image: ALAMY)
Scientists find a new mechanism underlying depression
The World health Organization calls depression “the leading cause of disability worldwide,” causing more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined. In any given year, 5-7% of the world’s population experiences a major depressive episode, and one in six people will at some point suffer from the disease.
Despite recent progress in understanding depression, scientists still don’t understand the biological mechanisms behind it well enough to deliver effective prevention and therapy. One possible reason is that almost all research focuses on the brain’s neurons, while the involvement of other brain cells has not been thoroughly examined.
Now researchers at the Hebrew University of Jerusalem have shown that changes in one type of non-neuronal brain cells, called microglia, underlie the depressive symptoms brought on by exposure to chronic stress. In experiments with animals, the researchers were able to demonstrate that compounds that alter the functioning of microglia can serve as novel and efficient antidepressant drugs.
The findings were published in Molecular Psychiatry, the premier scientific journal in psychiatry and one of the leading journals in medicine and the neurosciences.
The research was conducted by Prof. Raz Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with researchers at Prof. Yirmiya’s laboratory and at the University of Colorado in Boulder, USA.
The researchers examined the involvement of microglia brain cells in the development of depression following chronic exposure to stress. Comprising roughly 10% of brain cells, microglia are the representatives of the immune system in the brain; but recent studies have shown that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.
The researchers mimicked chronic unpredictable stress in humans — a leading causes of depression — by exposing mice to repeated, unpredictable stressful conditions over a period of 5 weeks. The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis) — an important biological marker of depression.
The researchers found that during the first week of stress exposure, microglia cells undergo a phase of proliferation and activation, reflected by increased size and production of specific inflammatory molecules, after which some microglia begin to die. Following the 5 weeks of stress exposure, this phenomenon led to a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in responding to stress.
When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis. However, these treatments were not effective in “depressed” mice, which were already exposed to the 5-weeks stress period and therefore had lower number of microglia. Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.
Prof. Yirmiya said, “We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment. In addition to the clinical importance of these results, our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular. This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”
The Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.
Nociceptin: Nature’s Balm for the Stressed Brain
Collaborating scientists at The Scripps Research Institute (TSRI), the National Institutes of Health (NIH) and the University of Camerino in Italy have published new findings on a system in the brain that naturally moderates the effects of stress. The findings confirm the importance of this stress-damping system, known as the nociceptin system, as a potential target for therapies against anxiety disorders and other stress-related conditions.
“We were able to demonstrate the ability of this nociceptin anti-stress system to prevent and even reverse some of the cellular effects of acute stress in an animal model,” said biologist Marisa Roberto, associate professor in TSRI’s addiction research department, known as the Committee on the Neurobiology of Addictive Disorders.
Roberto was a principal investigator for the study, which appears in the January 8, 2014 issue of the Journal of Neuroscience.
A Variety of Effects
Nociceptin, which is produced in the brain, belongs to the family of opioid neurotransmitters. But the resemblance essentially ends there. Nociceptin binds to its own specific receptors called NOP receptors and doesn’t bind well to other opioid receptors. The scientists who discovered it in the mid-1990s also noted that when nociceptin is injected into the brains of mice, it doesn’t kill pain—it makes pain worse.
The molecule was eventually named for this “nociceptive” (pain-producing) effect. However, subsequent studies demonstrated that, by activating its corresponding receptor NOP, nociceptin acted as an antiopioid and not only affected pain perception, but also blocked the rewarding properties of opioids such as morphine and heroin.
Perhaps of greatest interest, several studies in rodents have found evidence that nociceptin can act in the amygdala, a part of the brain that controls basic emotional responses, to counter the usual anxiety-producing effects of acute stress. There have been hints, too, that this activity occurs automatically as part of a natural stress-damping feedback response.
Scientists have wanted to know more about the anti-stress activity of the nociceptin/NOP system, in part because it might offer a better way to treat stress-related conditions. The latter are common in modern societies, including post-traumatic stress disorder as well as the drug-withdrawal stress that often defeats addicts’ efforts to kick the habit.
Reducing the Stress Reaction
For the new study, Roberto and her collaborators looked in more detail at the nociceptin/NOP system in the central amygdala.
First, Markus Heilig’s laboratory at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the NIH, measured the expression of NOP-coding genes in the central amygdala in rats. Heilig’s team found strong evidence that stress changes the activity of nociceptin/NOP in this region, indicating that the system does indeed work as a feedback mechanism to damp the effects of stress. In animals subjected to a standard laboratory stress condition, NOP gene activity rose sharply, as if to compensate for the elevated stress.
Roberto and her laboratory at TSRI then used a separate technique to measure the electrical activity of stress-sensitive neurons in the central amygdala. As expected, this activity rose when levels of the stress hormone CRF rose and started out at even higher levels in the stressed rats. But this stress-sensitive neuronal activity could be dialed down by adding nociceptin. The stress-blocking effect was especially pronounced in the restraint-stressed rats—probably due to their stress-induced increase in NOP receptors.
Finally, biologist Roberto Ciccocioppo and his laboratory at the University of Camerino conducted a set of behavioral experiments showing that injections of nociceptin specifically into the rat central amygdala powerfully reduced anxiety-like behaviors in the stressed rats, but showed no behavioral effect in non-stressed rats.
The three sets of experiments together demonstrate, said Roberto, that “stress exposure leads to an over-activation of the nociceptin/NOP system in the central amygdala, which appears to be an adaptive feedback response designed to bring the brain back towards normalcy.”
In future studies, she and her colleagues hope to determine whether this nociceptin/NOP feedback system somehow becomes dysfunctional in chronic stress conditions. “I suspect that chronic stress induces changes in amygdala neurons that can contribute to the development of some anxiety disorders,” said Roberto.
Compounds that mimic nociceptin by activating NOP receptors—but, unlike nociceptin, could be taken in pill form—are under development by pharmaceutical companies. Some of these appear to be safe and well tolerated in lab animals and may soon be ready for initial tests in human patients, Ciccocioppo said.
Ketamine acts as antidepressant by boosting serotonin
Ketamine is a potent anesthetic employed in human and veterinary medicine, and sometimes used illegally as a recreational drug. The drug is also a promising candidate for the fast treatment of depression in patients who do not respond to other medications. New research from the RIKEN Center for Life Science Technologies in Japan demonstrates using PET imaging studies on macaque monkeys that ketamine increases the activity of serotoninergic neurons in the brain areas regulating motivation. The researchers conclude that ketamine’s action on serotonin, often called the “feel-good neurotransmitter”, may explain its antidepressant action in humans.
The study, published today in the journal Translational Psychiatry demonstrates that Positron Emission Tomography (PET) molecular imaging studies may be useful in the diagnosis of major depressive disorder in humans, as well as the development of new antidepressants.
Ketamine has recently been shown to have an antidepressant action with short onset and long-term duration in patients suffering from treatment-resistant major depressive disorder, who do not respond to standard medications such as serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants. However, the mechanisms underlying ketamine’s action on the depressive brain have remained unclear.
To understand the effects of ketamine on the serotonergic system in the brain, Dr. Hajime Yamanaka and Dr. Hirotaka Onoe, who has pioneered PET imaging on conscious non-human primates, together with an international team, performed a PET study on rhesus monkeys.
The team performed PET imaging studies on four rhesus monkeys with two tracer molecules related to serotonin (5-HT) that bind highly selectively to the serotonin 1B receptor 5-HT1B and the serotonin transporter SERT.
From the analysis of the 3 dimensional images generated by the PET scans, the researchers could infer that ketamine induces an increase in the binding of serotonin to its receptor 5-HT1B in the nucleus accumbens and the ventral pallidum, but a decrease in binding to its transporter SERT in these brain regions. The nucleus accumbens and the ventral pallidum are brain regions associated with motivation and both have been shown to be involved in depression.
In addition, the researchers demonstrate that treatment with NBQX, a drug known to block the anti-depressive effect of ketamine in rodents by selectively blocking the glutamate AMPA receptor, cancels the action of ketamine on 5-HT1B but not on SERT binding.
Taken together, these findings indicate that ketamine may act as an antidepressant by increasing the expression of postsynaptic 5-HT1B receptors, and that this process is mediated by the glutamate AMPA receptor.