Posts tagged hippocampus
Articles and news from the latest research reports.
Investigators Discover How Key Protein Enhances Memory and Learning
Case Western Reserve researchers have discovered that a protein previously implicated in disease plays such a positive role in learning and memory that it may someday contribute to cures of cognitive impairments. The findings regarding the potential virtues of fatty acid binding protein 5 (FABP5) — usually associated with cancer and psoriasis — appear in the May 2 edition of The Journal of Biological Chemistry.
“Overall, our data show that FABP5 enhances cognitive function and that FABP5 deficiency impairs learning and memory functions in the brain hippocampus region,” said senior author Noa Noy, PhD, a professor of pharmacology at the School of Medicine. “We believe if we could find a way to upregulate the expression of FABP5 in the brain, we might have a therapeutic handle on cognitive dysfunction or memory impairment in some human diseases.”
FABP5 resides in many tissues and is especially highly expressed in the brain. Noy and her Case Western Reserve School of Medicine and National Institute on Alcohol Abuse and Alcoholism colleagues particularly wanted to understand how this protein functioned in neurons. They performed imaging studies comparing the activation of a key transcription factor in the brain tissue of normal mice and in FABP5-deficient mice. (Transcription factor is a protein the controls the flow of genetic information). The investigations revealed that FABP5 performs two different functions in neurons. First, it facilitates the degradation of endocannabinoids, which are neurological modulators controlling appetite, pain sensation, mood and memory. Second, FABP5 regulates gene expression, a process that essentially gives cells their marching orders on structure, appearance and function.
“FABP5 improves learning and memory both because it delivers endocannabinoids to cellular machinery that breaks them down and because it shuttles compounds to a transcription factor that increases the expression of cognition-associated genes,” Noy said.
Even though endocannabinoids affect essential physiological processes from appetite to memory, the “cannabinoid” part of the word signifies that these natural biological compounds act similarly to drugs such as marijuana and hashish. Too much endocannabinoid can lead to impaired learning and memory.
In simple terms, FABP5 transports endocannabinoids for processing. FABP5 functions like a bus and carries the brain’s endocannabinoids and their biological products to two stations within the neuron cell. FABP5 captures endocannabinoids entering the neuron and delivers them to an enzyme that degrades them (station 1). Then, that degraded product is picked up by the same protein (FABP5) and shuttled to the cell nucleus — specifically, to a transcription factor within it (station 2). Binding of the degraded product activates the transcription factor and allows it to induce expression of multiple genes. The genes that are induced in this case tell the cells to take steps that promote learning and memory.
Noy and associates also compared memory and learning in FABP5-deficient mice and in normal ones. In one test, both sets of mice repeatedly swam in mazes that had a platform in one established location where they could climb out of the water. During subsequent swims, the wild-type mice reached the platform quickly because they had learned — and remembered — its location. Their FABP5-deficient counterparts took much longer, typically finding the platform’s location by chance.
“In addition to regulating cell growth as in skin and in cancer cells, for example, FABP5 also plays a key role in neurons of the brain,” Noy said. “FABP5 controls the biological actions of small compounds that affect memory and learning and that activate a transcription factor, which regulates neuronal function.”
(Source: casemed.case.edu)
Atypical Form of Alzheimer’s Disease May be Present in a More Widespread Number of Patients
Neuroscientists at Mayo Clinic in Florida have defined a subtype of Alzheimer’s disease (AD) that they say is neither well recognized nor treated appropriately.
The variant, called hippocampal sparing AD, made up 11 percent of the 1,821 AD-confirmed brains examined by Mayo Clinic researchers — suggesting this subtype is relatively widespread in the general population. The Alzheimer’s Association estimates that 5.2 million Americans are living with AD. And with nearly half of hippocampal sparing AD patients being misdiagnosed, this could mean that well over 600,000 Americans make up this AD variant, researchers say.
In an oral presentation at the annual meeting of the American Academy of Neurology in Philadelphia, scientists say hippocampal sparing AD often produces symptoms that are substantially different from the most commonly known form of AD, which affects the hippocampus, the center of memory.
The patients, mostly male, are afflicted at a much younger age, and their symptoms can be bizarre — behavioral problems such as frequent and sometimes profane angry outbursts, feelings that their limbs do not belong to them and are controlled by an “alien” unidentifiable force, or visual disturbances in the absence of eye problems, researchers say.
They also decline at a much faster rate than do patients with the most common form of AD.
“Many of these patients, however, have memories that are near normal, so clinicians often misdiagnose them with a variety of conditions that do not match the underlying neuropathology,” says the study’s lead author, Melissa Murray, Ph.D., an assistant professor of neuroscience at Mayo Clinic in Florida.
Many of these patients are diagnosed with frontotemporal dementia, a disorder characterized by changes in personality and social behavior, or corticobasal syndrome, characterized by movement disorders and cognitive dysfunction. Language dysfunction is also more common in hippocampal sparing AD, although patients do not have vocal or hearing deficits.
“What is tragic is that these patients are commonly misdiagnosed and we have new evidence that suggests drugs now on the market for AD could work best in these hippocampal sparing patients — possibly better than they work in the common form of the disease,” Dr. Murray says.
The researchers benefit greatly from one of the largest brain banks in the country — more than 6,500 brain donations — as well as a collaborative environment between neuroscience research and neurology at Mayo Clinic, she says.
Both hallmark proteins of AD — amyloid beta (Aβ), which forms Aβ plaques, and tau, which produces tangles — are found across all subtypes of AD, including hippocampal sparing AD. The researchers developed a mathematical algorithm to classify AD subtypes using tangle counts. “What is fascinating is that all the AD patient subtypes had the same amount of amyloid, but for some reason tau tangles were found in strategic cortical regions disproportionate to the hippocampus.”
In these patients, tau preferentially damages and eventually destroys neurons in parts of the brain involved in behavior, motor awareness and recognition, as well as use of speech and vision, Dr. Murray says.
She says she hopes this research, the second high-profile Mayo study to highlight hippocampal sparing AD, will “open the minds” of clinicians who are trying to diagnose dementia, helping them understand that loss of memory is not present in every AD patient.
“Our studies support the notion that dementia related to AD does not necessarily equate to a loss of memory, and points to the need for more research in amyloid and tau imaging biomarkers to help clinicians accurately diagnose AD — regardless of subtype,” Dr. Murray says.
(Source: newsnetwork.mayoclinic.org)
Coming soon: a brain implant to restore memory
In the next few months, highly secretive US military researchers say they will unveil new advances toward developing a brain implant that could one day restore a wounded soldier’s memory.
The Defense Advanced Research Projects Agency (DARPA) is forging ahead with a four-year plan to build a sophisticated memory stimulator, as part of President Barack Obama’s $100 million initiative to better understand the human brain.
The science has never been done before, and raises ethical questions about whether the human mind should be manipulated in the name of staving off war injuries or managing the aging brain.
Preparing for adulthood: thousands upon thousands of new cells are born in the hippocampus during puberty, and most survive with effortful learning
The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood.
Seeking the Causes of Hyperactivity
The 60 trillion cells that comprise our bodies communicate constantly. Information travels when chemical compounds released by some cells are received by receptors in the membrane of another cell. In a paper published in the Journal of Neuroscience, the OIST Cell Signal Unit, led by Professor Tadashi Yamamoto, reported that mice lacking an intracellular trafficking protein called LMTK3, are hyperactive. Hyperactivity is a behavioral disorder that shows symptoms including restlessness, lack of coordination, and aggressive behavior. Identifying the genetic factors that contribute to such behaviors may help to explain the pathological mechanisms underlying autism and Attention Deficit Hyperactivity Disorder, ADHD, in humans.
LMTK3 is abundant in two brain regions: the cerebral cortex, which coordinates perception, movement, and thought, and the hippocampus, which governs memory and learning. In the brain, neurons communicate via connections called synapses. To send a message, a nerve terminus in the pre-synapse releases neurotransmitters to be received by the post-synaptic receptors. Yamamoto’s team discovered that LMTK3 regulates trafficking of neurotransmitter receptors at synapses. In neurons of mice deficient in LMTK3, internalization of receptors are augmented in the post-synapse, suggesting that synaptic communication is impaired. The LMTK3-deficient mice exhibited various hyperactive behaviors such as restlessness and hypersensitivity to sound. Interestingly, their dopamine levels were elevated. Dopamine is a neurotransmitter known to be involved in regulation of movement and hormone levels, motivation, learning, and expression of emotion. Excessive dopamine secretion results in schizophrenia, causing a loss of integrity of neuronal activity, and abnormal thoughts and emotions. The relationships between regulation of neurotransmitter receptor expression by LMTK3, dopamine turnover, and the biochemical pathways that induce hyperactivity, remain unknown.
Functions of many human proteins are still not understood. The Cell Signal Unit continues genetic studies of intracellular proteins that maintain and regulate complex functions such as behaviors, through their activities inside cells. “We hope to advance our research in order to elucidate genetic defects that result in behavioral abnormalities,” Yamamoto said.
Oops! Researchers find neural signature for mistake correction
Culminating an 8 year search, scientists at the RIKEN-MIT Center for Neural Circuit Genetics captured an elusive brain signal underlying memory transfer and, in doing so, pinpointed the first neural circuit for “oops”—the precise moment when one becomes consciously aware of a self-made mistake and takes corrective action.
The findings, published in Cell, verified a 20 year old hypothesis on how brain areas communicate. In recent years, researchers have been pursuing a class of ephemeral brain signals called gamma oscillations, millisecond scale bursts of synchronized wave-like electrical activity that pass through brain tissue like ripples on a pond. In 1993, German scientist Wolf Singer proposed that gamma waves enable binding of memory associations. For example, in a process called working memory, animals store and recall short-term memory associations when exploring the environment.
In 2006, the MIT team under the direction of Nobel Laureate Susumu Tonegawa began a study to understand working memory in mice. They trained animals to navigate a T maze and turn left or right at a junction for an associated food reward. They found that working memory required communication between two brain areas, the hippocampus and entorhinal cortex, but how mice knew the correct direction and the neural signal for memory transfer of this event remained unclear.
The study’s lead author Jun Yamamoto noticed that mice sometimes made mistakes, turning in the wrong direction then pausing, and turning around to go in the correct direction, trials he termed “oops” in his lab notebook. Intrigued, he recorded neural activity in the circuit and observed a burst of gamma waves just before the “oops” moment. He also saw gamma waves when mice chose the correct direction, but not when they failed to choose the correct direction or did not correct their mistakes.
The critical experiment was to block gamma oscillations and prevent mice from making correct decisions. To do this, the researchers created a transgenic mouse with a light-activated protein called archaerhodopsin (ArchT) in the hippocampus. Using an optic fiber implanted in the brain, light was flashed into the hippocampal-entorhinal circuit, shutting off gamma activity. In accord, the mice could no longer accurately choose the right direction and the number of “oops” events decreased.
The findings provide strong evidence of a role for gamma oscillations in cognition, and raise the prospect of their involvement in other behaviors requiring retrieval and evaluation of working memory. This may open the door to a class of behaviors called metacognition, or “thinking about thinking”, the self-monitoring of one’s actions. Regarding the appearance of gamma oscillations in the “oops” cases, Dr. Tonegawa stated “our data suggest that animals consciously monitor whether their behavioral choices are correct and use memory recall to improve their outcomes”
Exercise Keeps Hippocampus Healthy in People at Risk for Alzheimer’s
A study of older adults at increased risk for Alzheimer’s disease shows that moderate physical activity may protect brain health and stave off shrinkage of the hippocampus – the brain region responsible for memory and spatial orientation that is attacked first in Alzheimer’s disease. Dr. J. Carson Smith, a kinesiology researcher in the University of Maryland School of Public Health who conducted the study, says that while all of us will lose some brain volume as we age, those with an increased genetic risk for Alzheimer’s disease typically show greater hippocampal atrophy over time. The findings are published in the open-access journal Frontiers in Aging Neuroscience.
"The good news is that being physically active may offer protection from the neurodegeneration associated with genetic risk for Alzheimer’s disease," Dr. Smith suggests. "We found that physical activity has the potential to preserve the volume of the hippocampus in those with increased risk for Alzheimer’s disease, which means we can possibly delay cognitive decline and the onset of dementia symptoms in these individuals. Physical activity interventions may be especially potent and important for this group."
Dr. Smith and colleagues, including Dr. Stephen Rao from the Cleveland Clinic, tracked four groups of healthy older adults ages 65-89, who had normal cognitive abilities, over an 18-month period and measured the volume of their hippocampus (using structural magnetic resonance imaging, or MRI) at the beginning and end of that time period. The groups were classified both for low or high Alzheimer’s risk (based on the absence or presence of the apolipoprotein E epsilon 4 allele) and for low or high physical activity levels.
Of all four groups studied, only those at high genetic risk for Alzheimer’s who did not exercise experienced a decrease in hippocampal volume (3 percent) over the 18-month period. All other groups, including those at high risk for Alzheimer’s but who were physically active, maintained the volume of their hippocampus.
"This is the first study to look at how physical activity may impact the loss of hippocampal volume in people at genetic risk for Alzheimer’s disease," says Dr. Kirk Erickson, an associate professor of psychology at the University of Pittsburgh. "There are no other treatments shown to preserve hippocampal volume in those that may develop Alzheimer’s disease. This study has tremendous implications for how we may intervene, prior to the development of any dementia symptoms, in older adults who are at increased genetic risk for Alzheimer’s disease."
Individuals were classified as high risk for Alzheimer’s if a DNA test identified the presence of a genetic marker – having one or both of the apolipoprotein E-epsilon 4 allele (APOE-e4 allele) on chromosome 19 – which increases the risk of developing the disease. Physical activity levels were measured using a standardized survey, with low activity being two or fewer days/week of low intensity activity, and high activity being three or more days/week of moderate to vigorous activity.
"We know that the majority of people who carry the E4 allele will show substantial cognitive decline with age and may develop Alzheimer’s disease, but many will not. So, there is reason to believe that there are other genetic and lifestyle factors at work," Dr. Smith says. "Our study provides additional evidence that exercise plays a protective role against cognitive decline and suggests the need for future research to investigate how physical activity may interact with genetics and decrease Alzheimer’s risk."
Dr. Smith has previously shown that a walking exercise intervention for patients with mild cognitive decline improved cognitive function by improving the efficiency of brain activity associated with memory. He is planning to conduct a prescribed exercise intervention in a population of healthy older adults with genetic and other risk factors for Alzheimer’s disease and to measure the impact on hippocampal volume and brain function.
(Source: umdrightnow.umd.edu)
Loss of Memory in Alzheimer’s Mice Models Reversed through Gene Therapy
Alzheimer’s disease is the first cause of dementia and affects some 400,000 people in Spain alone. However, no effective cure has yet been found. One of the reasons for this is the lack of knowledge on the cellular mechanisms which cause alterations in nerve transmissions and the loss of memory in the initial stages of the disease.
Researchers from the Institute of Neuroscience at the Universitat Autònoma de Barcelona have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer’s disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer’s, the “Crtc1” (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.
To identify this protein, researchers compared gene expression in the hippocampus of healthy control mice with that of transgenic mice which had developed the disease. Through DNA microchips, they identified the genes (“transcriptome”) and the proteins (“proteome”) which expressed themselves in each of the mice in different phases of the disease. Researchers observed that the set of genes involved in memory consolidation coincided with the genes regulating Crtc1, a protein which also controls genes related to the metabolism of glucose and to cancer. The alteration of this group of genes could cause memory loss in the initial stages of Alzheimer’s disease.
In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer’s disease, prevents the Crtc1 protein from functioning correctly. “When the Crtc1 protein is altered, the genes responsible for the synapsis or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly”, explains Carlos Saura, researcher of the UAB Institute of Neuroscience and head of the research. According to Saura, “this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer’s disease, given that we have demonstrated that a gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice”.
The research, published today as a featured article in The Journal of Neuroscience, the official journal of the US Society of Neuroscience, paves the way for a new therapeutic approach to the disease. One of the main challenges in finding a treatment for the disease in the future is the research and development of pharmacological therapies capable of activating the Crtc1 protein, with the aim of preventing, slowing down or reverting cognitive alterations in patients.
Scientists Identify Critical New Protein Complex Involved in Learning and Memory
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a protein complex that plays a critical but previously unknown role in learning and memory formation.
The study, which showed a novel role for a protein known as RGS7, was published April 22, 2014 in the journal eLife, a publisher supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.
“This is a critical building block that regulates a fundamental process—memory,” said Kirill Martemyanov, a TSRI associate professor who led the study. “Now that we know about this important new player, it offers a unique therapeutic window if we can find a way to enhance its function.”
The team looked at RGS7 in the hippocampus, a small part of the brain that helps turn short-term memory in long-term memory.
The scientists found the RGS7 protein works in concert with another protein, R7BP, to regulate a key signaling cascade that is increasingly seen as a critical to cognitive development. The cascade involves the neurotransmitter GABA, which binds to the GABAb receptor and opens inhibitory channels known as GIRKs in the cell membrane. This process ultimately makes it more difficult for a nerve cell to fire.
This process turned out to be critical to normal functioning, as the research showed mice lacking RGS7 exhibited deficits in learning and memory.
Martemyanov believes the findings could ultimately have broad therapeutic application. “GIRK channels are implicated in a range of neuropsychiatric conditions, including drug addiction and Down’s syndrome, that result from a disproportionate increase in neuronal inhibition as a result of greater mobilization of these channels,” he said. “Now that we know the identity of the critical modulator of GIRK channels we can try to find a way to increase its power with the hopes of reducing the inhibitory overdrive, and that might potentially alleviate some of the disruptions seen in Down’s syndrome. It is possible that similar strategies might apply for dealing with addiction, where adaptations in the GABAb-GIRK pathway play a significant role.”
Targeting the RGS7 protein could allow for better therapeutic outcomes with fewer side effects because it allows for fine tuning of the signaling, according to Olga Ostrovskaya, the first author of the study and a member of Martemyanov’s lab, who sees many ways to follow up on the findings.
“We’re looking into how RGS7 is involved in neural circuitry and functions tied to the striatum, another part of the brain responsible for procedural memory, mood disorders, motivation and addiction,” Ostrovskaya said. “We may uncover the RGS7 regulation of other signaling complexes that may be very different from those in hippocampus.”
(Image caption: Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer’s. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center.)
“Chaperone” Compounds Offer New Approach to Alzheimer’s Treatment
A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer’s disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer’s.
Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer’s Disease Research Center in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer’s-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”
Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer’s. The researchers are currently testing the clinical effects of R55 in the actual mouse model .
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”