Posts tagged hippocampus
Articles and news from the latest research reports.
In the brain, timing is everything
Suppose you heard the sound of skidding tires, followed by a car crash. The next time you heard such a skid, you might cringe in fear, expecting a crash to follow — suggesting that somehow, your brain had linked those two memories so that a fairly innocuous sound provokes dread.
MIT neuroscientists have now discovered how two neural circuits in the brain work together to control the formation of such time-linked memories. This is a critical ability that helps the brain to determine when it needs to take action to defend against a potential threat, says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of a paper describing the findings in the Jan. 23 issue of Science.
“It’s important for us to be able to associate things that happen with some temporal gap,” says Tonegawa, who is a member of MIT’s Picower Institute for Learning and Memory. “For animals it is very useful to know what events they should associate, and what not to associate.”
The interaction of these two circuits allows the brain to maintain a balance between becoming too easily paralyzed with fear and being too careless, which could result in being caught off guard by a predator or other threat.
The paper’s lead authors are Picower Institute postdocs Takashi Kitamura and Michele Pignatelli.
Linking memories
Memories of events, known as episodic memories, always contain three elements — what, where, and when. Those memories are created in a brain structure called the hippocampus, which must coordinate each of these three elements.
To form episodic memories, the hippocampus also communicates with the region of the cerebral cortex just outside the hippocampus, known as the entorhinal cortex. The entorhinal cortex, which has several layers, receives sensory information, such as sights and sounds, from sensory processing areas of the brain and sends the information on to the hippocampus.
Previous research has revealed a great deal about how the brain links the place and object components of memory. Certain neurons in the hippocampus, known as place cells, are specialized to fire when an animal is in a specific location, and also when the animal is remembering that location. However, when it comes to associating objects and time, “our understanding has fallen behind,” Tonegawa says. “Something is known, but relatively little compared to the object-place mechanism.”
The new Science paper builds on a 2011 study from Tonegawa’s lab in which he identified a brain circuit necessary for mice to link memories of two events — a tone and a mild electric shock — that occur up to 20 seconds apart. This circuit connects layer 3 of the entorhinal cortex to the CA1 region of the hippocampus. When that circuit, known as the monosynaptic circuit, was disrupted, the animals did not learn to fear the tone.
In the new paper, the researchers report the discovery of a previously unknown circuit that suppresses the monosynaptic circuit. This signal originates in a type of excitatory neurons discovered in Tonegawa’s lab, dubbed “island cells” because they form circular clusters within layer 2. Those cells stimulate inhibitory neurons in CA1 that suppress the set of excitatory CA1 neurons that are activated by the monosynaptic circuit.
This circuit creates a counterbalance that limits the window of opportunity for two events to become linked. “This pathway might provide a mechanism for preventing constant learning of unimportant temporal associations,” says Michael Hasselmo, a professor of psychology at Boston University who was not part of the research team.
The findings are “an important demonstration of the functional role of different populations of neurons in entorhinal cortex that provide input to the hippocampus,” Hasselmo adds.
Deciphering circuits
The researchers used optogenetics, a technology that allows specific populations of neurons to be turned on or off with light, to demonstrate the interplay of these two circuits.
In normal mice, the maximum time gap between events that can be linked is about 20 seconds, but the researchers could lengthen that period by either boosting activity of layer 3 cells or suppressing layer 2 island cells. Conversely, they could shorten the window of opportunity by inhibiting layer 3 cells or stimulating input from layer 2 island cells, which both result in turning down CA1 activity.
The researchers hypothesize that prolonged CA1 activity keeps the memory of the tone alive long enough so that it is still present when the shock takes place, allowing the two memories to be linked. They are now investigating whether CA1 neurons remain active throughout the entire gap between events.
Watching Molecules Morph into Memories
In two studies in the January 24 issue of Science (1, 2), researchers at Albert Einstein College of Medicine of Yeshiva University used advanced imaging techniques to provide a window into how the brain makes memories. These insights into the molecular basis of memory were made possible by a technological tour de force never before achieved in animals: a mouse model developed at Einstein in which molecules crucial to making memories were given fluorescent “tags” so they could be observed traveling in real time in living brain cells.
Efforts to discover how neurons make memories have long confronted a major roadblock: Neurons are extremely sensitive to any kind of disruption, yet only by probing their innermost workings can scientists view the molecular processes that culminate in memories. To peer deep into neurons without harming them, Einstein researchers developed a mouse model in which they fluorescently tagged all molecules of messenger RNA (mRNA) that code for beta-actin protein – an essential structural protein found in large amounts in brain neurons and considered a key player in making memories. mRNA is a family of RNA molecules that copy DNA’s genetic information and translate it into the proteins that make life possible.
"It’s noteworthy that we were able to develop this mouse without having to use an artificial gene or other interventions that might have disrupted neurons and called our findings into question," said Robert Singer, Ph.D., the senior author of both papers and professor and co-chair of Einstein’s department of anatomy & structural biology and co-director of the Gruss Lipper Biophotonics Center at Einstein. He also holds the Harold and Muriel Block Chair in Anatomy & Structural Biology at Einstein.
In the research described in the two Science papers, the Einstein researchers stimulated neurons from the mouse’s hippocampus, where memories are made and stored, and then watched fluorescently glowing beta-actin mRNA molecules form in the nuclei of neurons and travel within dendrites, the neuron’s branched projections. They discovered that mRNA in neurons is regulated through a novel process described as “masking” and “unmasking,” which allows beta-actin protein to be synthesized at specific times and places and in specific amounts.
"We know the beta-actin mRNA we observed in these two papers was ‘normal’ RNA, transcribed from the mouse’s naturally occurring beta-actin gene," said Dr. Singer. "And attaching green fluorescent protein to mRNA molecules did not affect the mice, which were healthy and able to reproduce."
Neurons come together at synapses, where slender dendritic “spines” of neurons grasp each other, much as the fingers of one hand bind those of the other. Evidence indicates that repeated neural stimulation increases the strength of synaptic connections by changing the shape of these interlocking dendrite “fingers.” Beta-actin protein appears to strengthen these synaptic connections by altering the shape of dendritic spines. Memories are thought to be encoded when stable, long-lasting synaptic connections form between neurons in contact with each other.
The first paper describes the work of Hye Yoon Park, Ph.D., a postdoctoral student in Dr. Singer’s lab at the time and now an instructor at Einstein. Her research was instrumental in developing the mice containing fluorescent beta-actin mRNA—a process that took about three years.
Dr. Park stimulated individual hippocampal neurons of the mouse and observed newly formed beta-actin mRNA molecules within 10 to 15 minutes, indicating that nerve stimulation had caused rapid transcription of the beta-actin gene. Further observations suggested that these beta-actin mRNA molecules continuously assemble and disassemble into large and small particles, respectively. These mRNA particles were seen traveling to their destinations in dendrites where beta-actin protein would be synthesized.
In the second paper, lead author and graduate student Adina Buxbaum of Dr. Singer’s lab showed that neurons may be unique among cells in how they control the synthesis of beta-actin protein.
"Having a long, attenuated structure means that neurons face a logistical problem," said Dr. Singer. "Their beta-actin mRNA molecules must travel throughout the cell, but neurons need to control their mRNA so that it makes beta-actin protein only in certain regions at the base of dendritic spines."
Ms. Buxbaum’s research revealed the novel mechanism by which brain neurons handle this challenge. She found that as soon as beta-actin mRNA molecules form in the nucleus of hippocampal neurons and travel out to the cytoplasm, the mRNAs are packaged into granules and so become inaccessible for making protein. She then saw that stimulating the neuron caused these granules to fall apart, so that mRNA molecules became unmasked and available for synthesizing beta-actin protein.
But that observation raised a question: How do neurons prevent these newly liberated mRNAs from making more beta-actin protein than is desirable? “Ms. Buxbaum made the remarkable observation that mRNA’s availability in neurons is a transient phenomenon,” said Dr. Singer. “She saw that after the mRNA molecules make beta-actin protein for just a few minutes, they suddenly repackage and once again become masked. In other words, the default condition for mRNA in neurons is to be packaged and inaccessible.”
These findings suggest that neurons have developed an ingenious strategy for controlling how memory-making proteins do their job. “This observation that neurons selectively activate protein synthesis and then shut it off fits perfectly with how we think memories are made,” said Dr. Singer. “Frequent stimulation of the neuron would make mRNA available in frequent, controlled bursts, causing beta-actin protein to accumulate precisely where it’s needed to strengthen the synapse.”
To gain further insight into memory’s molecular basis, the Singer lab is developing technologies for imaging neurons in the intact brains of living mice in collaboration with another Einstein faculty member in the same department, Vladislav Verkhusha, Ph.D. Since the hippocampus resides deep in the brain, they hope to develop infrared fluorescent proteins that emit light that can pass through tissue. Another possibility is a fiberoptic device that can be inserted into the brain to observe memory-making hippocampal neurons.
Researchers discover an epigenetic lesion in the hippocampus of Alzheimer’s patients
Alzheimer’s disease can reach epidemic range in the coming decades, by the increasing average age of society. There are two key issues for Alzheimer’s disease: there is currently no effective treatment and it has been described very few associated genetic changes (mutations) which reduces the number of targets for future therapies.
Alzheimer’s disease
Pathologically, Alzheimer’s disease is characterized by the accumulation of protein deposits in the brain of patients. These deposits are formed by plates of a protein called amyloid-beta and rolled tangles of tau protein. The root cause of these lesions in most cases is unknown, but specific alterations in regulating genes expression might be involved.
Today, the prestigious international journal in neurology Hippocampus publishes an article led by Manel Esteller, Director of Epigenetics and Cancer Biology, Institute of Biomedical Research of Bellvitge (IDIBEL), ICREA researcher and Professor of Genetics at the University of Barcelona, with the collaboration of the Institute of Neuropathology IDIBELL led by Isidre Ferrer, demonstrating for the first time the existence of an epigenetic lesion in the hippocampus of the brain of patients with Alzheimer.
Switches in the hippocampus
"We first started studying 30,000 molecular switches that turn on and off genes in the hippocampal region in the brains of Alzheimer patients in different stages of disease and compared with that of healthy patients of the same age. We note that dusp22 gene switches off (methylates) as the disease advances" explained Manel Esteller, director of the study.
"But more importantly" continues "was the discovery that this gene regulates tau protein. Perhaps therefore the accumulation of tau protein produced in the brain of patients with Alzheimer results from dusp22 epigenetic inactivation".
According Esteller “the finding is relevant not only to determine the causes of the disease, but also to test potential treatments in the future to act on these epigenetic molecular switches”.
Nearly 8 million Americans suffer from posttraumatic stress disorder (PTSD), a condition marked by severe anxiety stemming from a traumatic event such as a battle or violent attack.
Many patients undergo psychotherapy designed to help them re-experience their traumatic memory in a safe environment so as to help them make sense of the events and overcome their fear. However, such memories can be so entrenched that this therapy doesn’t always work, especially when the traumatic event occurred many years earlier.
MIT neuroscientists have now shown that they can extinguish well-established traumatic memories in mice by giving them a type of drug called an HDAC2 inhibitor, which makes the brain’s memories more malleable, under the right conditions. Giving this type of drug to human patients receiving psychotherapy may be much more effective than psychotherapy alone, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory.
“By inhibiting HDAC2 activity, we can drive dramatic structural changes in the brain. What happens is the brain becomes more plastic, more capable of forming very strong new memories that will override the old fearful memories,” says Tsai, the senior author of a paper describing the findings in the Jan. 16 issue of Cell.
The new study also reveals the molecular mechanism explaining why older memories are harder to extinguish. Lead authors of the paper are former Picower Institute postdoc Johannes Graff and Nadine Joseph, a technical assistant at the Picower Institute.
Genes and memories
Tsai’s lab has previously shown that when memories are formed, neurons’ chromatin — DNA packaged with proteins — undergoes extensive remodeling. These chromatin modifications make it easier to activate the genes necessary to create new memories.
In this study, the researchers focused on chromatin modifications that occur when previously acquired memories are extinguished. To do this, they first trained mice to fear a particular chamber — by administering a mild foot shock — and then tried to recondition the mice so they no longer feared it, which was done by placing the mice in the chamber where they received the shock, without delivering the shock again.
This training proved successful in mice that had experienced the traumatic event only 24 hours before the reconditioning. However, in mice whose memories were 30 days old, it was impossible to eliminate the fearful memory.
The researchers also found that in the brains of mice with 24-hour-old memories, extensive chromatin remodeling occurred during the reconditioning. For several hours after the mice were placed back in the feared chamber, there was a dramatic increase in histone acetylation of memory-related genes, caused by inactivation of the protein HDAC2. That histone acetylation makes genes more accessible, turning on the processes needed to form new memories or overwrite old ones.
In mice with 30-day-old memories, however, there was no change in histone acetylation. This suggests that re-exposure to a fearful memory opens a window of opportunity during which the memory can be altered, but only if the memory has recently been formed, Tsai says.
“If you do something within this window of time, then you have the possibility of modifying the memory or forming a new trace of memory that actually instructs the animal that this is not such a dangerous place,” she says. “However, the older the memory is, the harder it is to really change that memory.”
Based on this finding, the researchers decided to treat mice with 30-day-old memories with an HDAC2 inhibitor shortly after re-exposure to the feared chamber. Following this treatment, the traumatic memories were extinguished just as easily as in the mice with 24-hour-old memories.
The researchers also found that HDAC2 inhibitor treatment turns on a group of key genes known as immediate early genes, which then activate other genes necessary for memory formation. They also saw an increase in the number of connections among neurons in the hippocampus, where memories are formed, and in the strength of communication among these neurons.
“Our experiments really strongly argue that either the old memories are permanently being modified, or a new much more potent memory is formed that completely overwrites the old memory,” Tsai says.
“This could be a very promising way to bring older memories back, process them in the hippocampus, and then extinguish them with the correct paradigm,” says Jelena Radulovic, a professor of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine who was not part of the research team.
Treating anxiety
Some HDAC2 inhibitors have been approved to treat cancer, and Tsai says she believes it is worth trying such drugs to treat PTSD. “I hope this will convince people to seriously think about taking this into clinical trials and seeing how well it works,” she says.
Such drugs might also be useful in treating people who suffer from phobias and other anxiety disorders, she adds.
Tsai’s lab is now studying what happens to memory traces when re-exposure to traumatic memories occurs at different times. It is already known that memories are formed in the hippocampus and then transferred to the cortex for longer-term storage. It appears that the HDAC2 inhibitor treatment may somehow restore the memory to the hippocampus so it can be extinguished, Tsai says.
Recall of stressful events caught in pictures
The study is of patients with conversion disorder (what Freud would have called Hysteria), which is still a very common disorder though rarely discussed or researched today.
“Freud started his whole theory by arguing that patients with hysteria repressed their memories of traumatic events and that this led to their developing their symptoms (of paralysis, for example) - what he called ‘conversion,” said Professor Richard Kanaan from the Department of Psychiatry, University of Melbourne and Austin Health.
“The world has pretty much given up on that theory largely because they thought it couldn’t be tested,” he said.
Published recently in the Journal of the American Medical Association, Psychiatry, the fMRI findings support Freud’s theories for the first time in over a century.
Researchers first painstakingly identified what they thought were the traumatic events that led to them becoming sick using the Life Events and Difficulties Schedule (LEDS) as a guide. This is a well-known psychological measurement for assessing life stress levels and experience.
“We got our patients to remember the traumatic events while we scanned their brains. Results showed something that looked like it could be them repressing their memories and possibly what could be them developing symptoms in response.”
“While it is still a preliminary study, in the history of psychiatry as a science it is potentially a significant breakthrough,” he said.
Caffeine has positive effect on memory
Whether it’s a mug full of fresh-brewed coffee, a cup of hot tea, or a can of soda, consuming caffeine is the energy boost of choice for millions who want to wake up or stay up.
Now, researchers at Johns Hopkins University have found another use for the popular stimulant: memory enhancer.
Michael Yassa, an assistant professor of psychological and brain sciences at Johns Hopkins, and his team of scientists found that caffeine has a positive effect on our long-term memory. Their research, published by the journal Nature Neuroscience, shows that caffeine enhances certain memories at least up to 24 hours after it is consumed.
"We’ve always known that caffeine has cognitive-enhancing effects, but its particular effects on strengthening memories and making them resistant to forgetting has never been examined in detail in humans," said Yassa, senior author of the paper. "We report for the first time a specific effect of caffeine on reducing forgetting over 24 hours."
The Johns Hopkins researchers conducted a double-blind trial in which participants who did not regularly eat or drink caffeinated products received either a placebo or a 200-milligram caffeine tablet five minutes after studying a series of images. Salivary samples were taken from the participants before they took the tablets to measure their caffeine levels. Samples were taken again one, three, and 24 hours afterwards.
The next day, both groups were tested on their ability to recognize images from the previous day’s study session. On the test, some of the visuals were the same as those from the day before, some were new additions, and some were similar but not the same.
More members of the caffeine group were able to correctly identify the new images as “similar” to previously viewed images rather than erroneously citing them as the same.
The brain’s ability to recognize the difference between two similar but not identical items, called pattern separation, reflects a deeper level of memory retention, the researchers said.
"If we used a standard recognition memory task without these tricky similar items, we would have found no effect of caffeine," Yassa said. "However, using these items requires the brain to make a more difficult discrimination—what we call pattern separation, which seems to be the process that is enhanced by caffeine in our case."
The memory center in the human brain is the hippocampus, a seahorse-shaped area in the medial temporal lobe of the brain. The hippocampus is the switchbox for all short- and long-term memories. Most research done on memory—the effects of concussions in athletes, of war-related head injuries, and of dementia in the aging population—focuses on this area of the brain.
Until now, caffeine’s effects on long-term memory had not been examined in detail. Of the few studies done, the general consensus was that caffeine has little or no effect on long-term memory retention.
The research is different from prior experiments because the subjects took the caffeine tablets only after they had viewed and attempted to memorize the images.
"Almost all prior studies administered caffeine before the study session, so if there is an enhancement, it’s not clear if it’s due to caffeine’s effects on attention, vigilance, focus, or other factors," Yassa said. "By administering caffeine after the experiment, we rule out all of these effects and make sure that if there is an enhancement, it’s due to memory and nothing else."
According to the U.S. Food and Drug Administration, 90 percent of people worldwide consume caffeine in one form or another. In the United States, 80 percent of adults consume caffeine every day. The average adult has an intake of about 200 milligrams—the same amount used in the Yassa study—or roughly one cup of strong coffee per day.
Yassa’s team completed the research at Johns Hopkins before his lab moved to the University of California, Irvine, at the start of this year.
"The next step for us is to figure out the brain mechanisms underlying this enhancement," Yassa said. "We can use brain-imaging techniques to address these questions. We also know that caffeine is associated with healthy longevity and may have some protective effects from cognitive decline like Alzheimer’s disease. These are certainly important questions for the future."
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)
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.
This is how your brain tells time
Did you make it to work on time this morning? Go ahead and thank the traffic gods, but also take a moment to thank your brain. The brain’s impressively accurate internal clock allows us to detect the passage of time, a skill essential for many critical daily functions. Without the ability to track elapsed time, our morning shower could continue indefinitely. Without that nagging feeling to remind us we’ve been driving too long, we might easily miss our exit.
But how does the brain generate this finely tuned mental clock? Neuroscientists believe that we have distinct neural systems for processing different types of time, for example, to maintain a circadian rhythm, to control the timing of fine body movements, and for conscious awareness of time passage. Until recently, most neuroscientists believed that this latter type of temporal processing – the kind that alerts you when you’ve lingered over breakfast for too long – is supported by a single brain system. However, emerging research indicates that the model of a single neural clock might be too simplistic. A new study, recently published in the Journal of Neuroscience by neuroscientists at the University of California, Irvine, reveals that the brain may in fact have a second method for sensing elapsed time. What’s more, the authors propose that this second internal clock not only works in parallel with our primary neural clock, but may even compete with it.
Toward a Molecular Explanation for Schizophrenia
Surprisingly little is known about schizophrenia. It was only recognized as a medical condition in the past few decades, and its exact causes remain unclear. Since there is no objective test for schizophrenia, its diagnosis is based on an assortment of reported symptoms. The standard treatment, antipsychotic medication, works less than half the time and becomes increasingly ineffective over time.
Now, Prof. Illana Gozes — the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, the director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine, and a member of the Sagol School of Neuroscience at Tel Aviv University — has discovered that an important cell-maintenance process called autophagy is reduced in the brains of schizophrenic patients. The findings, published in Nature’s Molecular Psychiatry, advance the understanding of schizophrenia and could enable the development of new diagnostic tests and drug treatments for the disease.
"We discovered a new pathway that plays a part in schizophrenia," said Prof. Gozes. "By identifying and targeting the proteins known to be involved in the pathway, we may be able to diagnose and treat the disease in new and more effective ways."
Graduate students Avia Merenlender-Wagner, Anna Malishkevich, and Zeev Shemer of TAU, Prof. Brian Dean and colleagues of the University of Melbourne, and Prof. Galila Agam and Joseph Levine of Ben Gurion University of the Negev and Beer Sheva’s Psychiatry Research Center and Mental Health Center collaborated on the research.
Mopping up
Autophagy is like the cell’s housekeeping service, cleaning up unnecessary and dysfunctional cellular components. The process — in which a membrane engulfs and consumes the clutter — is essential to maintaining cellular health. But when autophagy is blocked, it can lead to cell death. Several studies have tentatively linked blocked autophagy to the death of brain cells seen in Alzheimer’s disease.
Brain-cell death also occurs in schizophrenics, so Prof. Gozes and her colleagues set out to see if blocked autophagy could be involved in the progression of that condition as well. They found RNA evidence of decreased levels of the protein beclin 1 in the hippocampus of schizophrenia patients, a brain region central to learning and memory. Beclin 1 is central to initiating autophagy — its deficit suggests that the process is indeed blocked in schizophrenia patients. Developing drugs to boost beclin 1 levels and restart autophagy could offer a new way to treat schizophrenia, the researchers say.
"It is all about balance," said Prof Gozes. "Paucity in beclin 1 may lead to decreased autophagy and enhanced cell death. Our research suggests that normalizing beclin 1 levels in schizophrenia patients could restore balance and prevent harmful brain-cell death."
Next, the researchers looked at protein levels in the blood of schizophrenia patients. They found no difference in beclin 1 levels, suggesting that the deficit is limited to the hippocampus. But the researchers also found increased levels of another protein, activity-dependent neuroprotective protein (ADNP), discovered by Prof. Gozes and shown to be essential for brain formation and function, in the patients’ white blood cells. Previous studies have shown that ADNP is also deregulated in the brains of schizophrenia patients.
The researchers think the body may boost ADNP levels to protect the brain when beclin 1 levels fall and autophagy is derailed. ADNP, then, could potentially serve as a biomarker, allowing schizophrenia to be diagnosed with a simple blood test.
An illuminating discovery
To further explore the involvement of ADNP in autophagy, the researchers ran a biochemical test on the brains of mice. The test showed that ADNP interacts with LC3, another key protein regulating autophagy — an interaction predicted by previous studies. In light of the newfound correlation between autophagy and schizophrenia, they believe that this interaction may constitute part of the mechanism by which ADNP protects the brain.
Prof. Gozes discovered ADNP in 1999 and carved a protein fragment, NAP, from it. NAP mimics the protein nerve cell protecting properties. In follow-up studies Prof. Gozes helped develop the drug candidate davunetide (NAP). In Phase II clinical trials, davunetide (NAP) improved the ability of schizophrenic patients to cope with daily life. A recent collaborative effort by Prof. Gozes and Dr. Sandra Cardoso and Dr. Raquel Esteves showed that NAP improved autophagy in cultures of brain-like cells. The current study further shows that NAP facilitates the interaction of ADNP and LC3, possibly accounting for NAP’s results in schizophrenia patients. The researchers hope NAP will be just the first of their many discoveries to improve understanding and treatment of schizophrenia.
(Image: Shutterstock)