Posts tagged hippocampus
Articles and news from the latest research reports.
New approach helps those with traumatic brain injury
Greg Noack was 24 when he moved from Ontario to Victoria, B.C. He had just graduated from college and was looking forward to a fresh start.
One early morning in 1996, as he was returning home from his graveyard shift at the hotel, Noack was attacked from behind by a group of men.
He doesn’t remember being struck on the head. He does remember waking from a 15-day coma to learn he had suffered a traumatic brain injury (TBI).
Noack, through the care of his health-care team, relearned how to walk, write, and feel particular emotions.
“I was enamoured by what my therapists were able to do for me,” said Noack. “I was lucky that I got back most of my function.”
Three years post-injury, Noack enrolled in Sault College’s Occupational Therapist Assistant/Physical Therapist Assistant Program and graduated with honours.
Shortly after, Noack was hired by the Toronto Rehab Acquired Brain Injury Rehab team as an occupational therapist assistant and later became a rehab therapist.
Most recently, he was seconded to Dr. Robin Green’s traumatic brain injury research team.
Dr. Green, Senior Scientist and Neuropsychologist, Toronto Rehab and Canada Research Chair in Traumatic Brain Injury, and her Toronto Rehab team have been studying impediments to brain injury recovery as well as treatments to offset the impediments.
Dr. Green’s work suggests that moderate-severe TBI may be a progressive neurological disorder –a whole new way of perceiving the condition.
“What may be occurring after a serious brain injury,” said Dr. Green, “is that damaged tissue is leaving healthy areas of the brain disconnected and under stimulated. Over time, healthy areas may deteriorate.”
Importantly, they discovered that in people with chronic moderate-severe TBI, environmental enrichment – increased physical, social and cognitive stimulation - can offset this deterioration.
Her research paper, entitled “Environmental enrichment may protect against hippocampal atrophy in the chronic stages of traumatic brain injury,” was published September 24 in Frontiers in Human Neuroscience.
In their study of 25 patients with moderate-severe TBI, her team found a positive reaction to environmental enrichment.
Those who reported greater amounts of environmental enrichment – for example, reading, problem solving exercises, puzzles, physical activity, socializing – at 5 months after their injury showed less shrinkage of the hippocampus (associated with memory functioning) from 5 to 28 months post-injury.
“People with moderate-severe TBI are commonly unable to return to the same level of engagement in their work, school or social lives as before the injury,” said Dr. Green. “However, those with greater environmental enrichment may be keeping vulnerable areas stimulated. Environmental enrichment is also known to increase production of neurons in the hippocampus and to promote their integration into existing brain networks.”
Based on the findings from their study, Green’s team is now engaged in research designed to proactively offset deterioration, which includes the delivery of environmental enrichment to patients. Noack is instrumental in delivering enriched therapy for TBI patients who are enrolled in one of Dr. Green’s research studies.
“One thing I loved about this study is that it facilitated greater customization of a patient’s care,” said Noack. “I could see how my patients benefited from the increased amount of stimulation through extended therapy.”
“Although the brains of patients are showing negative changes, patients are still showing recovery of their functioning in spite of it,” said Dr. Green. “If we are able to offset the negative brain changes through the treatments we are developing, we may be able to very significantly improve patients’ recovery and the quality of their aging with a brain injury.”
(Source: uhn.ca)
New Study Shows How ICU Ventilation May Trigger Mental Decline
Researchers from Penn Medicine and University of Oviedo Identify Molecular Pathway Linking ICU Ventilation to Brain Damage
At least 30 percent of patients in intensive care units (ICUs) suffer some form of mental dysfunction as reflected in anxiety, depression, and especially delirium. In mechanically-ventilated ICU patients, the incidence of delirium is particularly high, about 80 percent, and may be due in part to damage in the hippocampus, though how ventilation is increasing the risk of damage and mental impairment has remained elusive.
Now, a new study published in the American Journal of Respiratory and Critical Care Medicine fromresearchers at the University of Oviedo in Spain, St. Michael’s Hospital in Toronto, Canada, and the Perelman School of Medicine at the University Pennsylvaniafound a molecular mechanism that may explain the connection between mechanical ventilation and hippocampal damage in ICU patients.
The investigators, including Adrian González-López, PhD, in the laboratory of Guillermo M. Albaiceta, MD, PhD at the University of Oviedo , and co-authored by Konrad Talbot, PhD, an assistant research professor in Neurobiology in the Department of Psychiatry at Penn Medicine, began by studying the hippocampus in control mice and in mice on low or high-pressure mechanical ventilation for 90 minutes. Compared to the controls, those on either low- or high-pressure ventilation showed evidence of neuronal cell death in the hippocampus, as a result of a cell suicide program called apoptosis.
Searching for the molecular cause of the ventilation-induced apoptosis, the team discovered that a well-known apoptosis trigger had been set off in the hippocampus of the ventilated animals. That trigger is dopamine-induced suppression of a molecule known as Akt, which normally acts to prevent neuronal apoptosis. Akt suppression was clearly evident in the hippocampus of the ventilated mice and was associated with a hyperdopaminergic state (increased levels of dopamine) in that brain area. The ventilated mice had elevated gene expression of the enzyme tyrosine hydroxylase, which is critical in synthesizing dopamine. The resulting rise in dopamine increases the strength of dopamine receptor activation in the hippocampus.
The investigators hypothesized that ventilation-induced apoptosis in the hippocampus was at least partly mediated by elevated activation of dopamine receptors in that brain area. This was confirmed by showing that pretreatment of mice with type 2 (D2) dopamine receptor blockers injected into the ventricles of the brain significantly reduced ventilation-induced apoptosis in the hippocampus.
How mechanical ventilation manages to affect the hippocampus was answered by experiments on mice in which the vagus cranial nerve connecting the lungs with the brain was severed. In these mice, mechanical ventilation had virtually no effect on levels of the dopamine-synthesizing enzyme or on apoptosis in the hippocampus.
The investigators then studied the consequences of ventilation and elevated hippocampal dopamine on dysbindin-1, a protein known to affect levels of cell surface D2 dopamine receptors, cognition, and possibly the risk of psychosis. High-pressure ventilation in mice caused an increase in gene expression of dysbindin-1C, and later, in protein levels of dysbindin-1C. Dopamine alone had similar effects on dysbindin-1C in hippocampal slice preparations, effects that were inhibited by D2 receptor blockers.
Since dysbindin-1 can lower cell-surface D2 receptors and protect against apoptosis, the authors speculate that increased dysbindin-1C expression in the ventilated mice may reflect compensatory responses to ventilation-induced hippocampal apoptosis. That possibility applies to ICU cases given the additional finding by the authors that total dysbindin-1 was increased in hippocampal neurons of ventilated compared to non-ventilated humans who died in the ICU.
The findings could lead to new therapeutic uses of established drugs and targets for new drugs that activate a molecular pathway mediating adverse effects of ICU ventilation on brain function.
“The results prove the existence of a pathogenic mechanism of lung stretch-induced hippocampal apoptosis that could explain the development of neurobehavioral disorders in patients exposed to mechanical ventilation,” the authors write. One of the coauthors, Dr. Talbot, adds: “The study indicates the need to reevaluate use of D2 receptor antagonists in minimizing the negative cognitive effects of mechanical ventilation in ICU patients and to evaluate the novel possibility that elevation in dysbindin-1C expression can also reduce those effects.”
The corresponding author, Dr. Albaiceta, offered a look at future research on this topic: “Now that we have established the mouse model, we are mainly looking for therapeutic approaches aimed at avoiding the vagal activation caused by mechanical ventilation and therefore prevent the deleterious effects observed in the hippocampus,” he said. “We are also interested in studying the relationship between the different described gene polymorphisms of dysbindin, Akt, and type 2 dopamine receptor versus the incidence of neurological disorders in patients on ventilation in ICUs. This could help us to identify susceptible individuals to in which a preventive treatment could be effective.”
(Source: uphs.upenn.edu)
First evidence that fear memories can be reduced during sleep
A fear memory was reduced in people by exposing them to the memory over and over again while they slept. It’s the first time that emotional memory has been manipulated in humans during sleep, report Northwestern Medicine® scientists.
The finding potentially offers a new way to enhance the typical daytime treatment of phobias through exposure therapy by adding a nighttime component. Exposure therapy is a common treatment for phobia and involves a gradual exposure to the feared object or situation until the fear is extinguished.
"It’s a novel finding," said Katherina Hauner, a postdoctoral fellow in neurology at Northwestern University Feinberg School of Medicine. "We showed a small but significant decrease in fear. If it can be extended to pre-existing fear, the bigger picture is that, perhaps, the treatment of phobias can be enhanced during sleep."
Hauner did the research in the lab of Jay Gottfried, associate professor of neurology at Feinberg and senior author of the paper.
The study will be published Sept. 22 in the journal Nature Neuroscience.
Previous projects have shown that spatial learning and motor sequence learning can be enhanced during sleep. It wasn’t previously known that emotions could be manipulated during sleep, Northwestern investigators said.
In the study, 15 healthy human subjects received mild electric shocks while seeing two different faces. They also smelled a specific odorant while viewing each face and being shocked, so the face and the odorant both were associated with fear. Subjects received different odorants to smell with each face such as woody, clove, new sneaker, lemon or mint.
Then, when a subject was asleep, one of the two odorants was re-presented, but in the absence of the associated faces and shocks. This occurred during slow wave sleep when memory consolidation is thought to occur. Sleep is very important for strengthening new memories, noted Hauner, also a research scientist at the Rehabilitation Institute of Chicago.
"While this particular odorant was being presented during sleep, it was reactivating the memory of that face over and over again which is similar to the process of fear extinction during exposure therapy," Hauner said.
When the subjects woke up, they were exposed to both faces. When they saw the face linked to the smell they had been exposed to during sleep, their fear reactions were lower than their fear reactions to the other face.
Fear was measured in two ways: through small amounts of sweat in the skin, similar to a lie detector test, and through neuroimaging with fMRI (functional magnetic resonance imaging). The fMRI results showed changes in regions associated with memory, such as the hippocampus, and changes in patterns of brain activity in regions associated with emotion, such as the amygdala. These brain changes reflected a decrease in reactivity that was specific to the targeted face image associated with the odorant presented during sleep.
A Brake in the Head: German researchers gain new insights into the working of the brain
Scientists of the Charité – Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have managed to acquire new insights into the functioning of a region in the brain that normally is involved in spatial orientation, but is damaged by the Alzheimer’s disease. They investigated how nerve signals are suppressed inside the so-called entorhinal cortex. According to the researchers, this neuronal inhibition leads nerve cells to synchronize their activity. The results of this study are now published in Neuron.
The entorhinal cortex is a link between the brain’s memory centre, the hippocampus, and the other areas of the brain. It is, however, more than an interface that only transfers nervous impulses. The entorhinal cortex also has an independent role in learning and thinking processes. This is particularly applicable for spatial navigation. “We know precious little about how this happens,” says Prof. Dietmar Schmitz, a researcher at the Cluster of Excellence NeuroCure at the Charité – Universitätsmedizin Berlin and Site Speaker for the DZNE in Berlin. “This is why we are investigating in animal models how the nerve cells within the entorhinal cortex are connected with each other.“
Signals wander inside the brain as electrical impulses from nerve cell to nerve cell. In general, signals are not merely forwarded. Rather, operation of the brain critically depends on the fact that the nerve impulses in some situations are activated and in other cases suppressed. A correct balance between suppression and excitation is decisive for all brain processes. “Until now research has mainly concentrated on signal excitation within the entorhinal cortex. This is why we looked into inhibition and detected a gradient inside the entorhinal cortex,” explains Dr. Prateep Beed, lead author of the study. “This means that nerve signals are not suppressed equally. The blockage of the nerve signals is weaker in certain parts of the entorhinal cortex and stronger in others. The inhibition has, so to speak, a spatial profile.”
When the brain is busy, nerve cells often coordinate their operation. In an electroencephalogram (EEG) – a recording of the brain’s electrical activity – the synchronous rhythm of the nerve cells manifests as a periodic pattern. “It is a moot question as to how nerve cells synchronize their behavior and how they bring about such rhythms,” says Beed. As he explains, it is also unclear whether these oscillations are only just a side effect or whether they trigger other phenomena. “But it has been demonstrated that neuronal oscillations accompany learning processes and even happen during sleep. They are a typical feature of the brain’s activity,” describes the scientist. “In our opinion, the inhibitory gradient, which we detected, plays an important role in creating the synchronous rhythm of the nerve cells and the related oscillations.”
In the case of Alzheimer’s, the entorhinal cortex is among the regions of the brain that are the first to be affected. “In recent times, studies related to this brain structure have increased. Here, already in the early stages of Alzheimer’s, one finds the protein deposits that are typical of this disease,” explains Schmitz, who headed the research. “It is also known that patients affected by Alzheimer’s have a striking EEG. Our studies help us to understand how the nerve cells in the entorhinal cortex operate and how electrical activities might get interrupted in this area of the brain.”
Coma: researchers observe never-before- detected brain activity
Researchers from the University of Montreal and their colleagues have found brain activity beyond a flat line EEG, which they have called Nu-complexes (from the Greek letter n). According to existing scientific data, researchers and doctors had established that beyond the so-called “flat line” (flat electroencephalogram or EEG), there is nothing at all, no brain activity, no possibility of life. This major discovery suggests that there is a whole new frontier in animal and human brain functioning.
The researchers observed a human patient in an extreme deep hypoxic coma under powerful anti-epileptic medication that he had been required to take due to his health issues. “Dr. Bogdan Florea from Romania contacted our research team because he had observed unexplainable phenomena on the EEG of a coma patient. We realized that there was cerebral activity, unknown until now, in the patient’s brain,” says Dr. Florin Amzica, director of the study and professor at the University of Montreal’s School of Dentistry.
Dr. Amzica’s team then decided to recreate the patient’s state in cats, the standard animal model for neurological studies. Using the anesthetic isoflurane, they placed the cats in an extremely deep—but completely reversible—coma. The cats passed the flat (isoelectric) EEG line, which is associated with silence in the cortex (the governing part of the brain). The team observed cerebral activity in 100% of the cats in deep coma, in the form of oscillations generated in the hippocampus, the part of the brain responsible for memory and learning processes. These oscillations, unknown until now, were transmitted to the master part of the brain, the cortex. The researchers concluded that the observed EEG waves, or Nu-complexes, were the same as those observed in the human patient.
Dr. Amzica stresses the importance of understanding the implications of these findings. “Those who have decided to or have to ‘unplug’ a near-brain-dead relative needn’t worry or doubt their doctor. The current criteria for diagnosing brain death are extremely stringent. Our finding may perhaps in the long term lead to a redefinition of the criteria, but we are far from that. Moreover, this is not the most important or useful aspect of our study,” Dr. Amzica said.
From Nu-complexesto therapeutic comas
The most useful aspect of this finding is the therapeutic potential, the neuroprotection, of the extreme deep coma. After a major injury, some patients are in such serious condition that doctors deliberately place them in an artificial coma to protect their body and brain so they can recover. But Dr. Amzica believes that the extreme deep coma experimented on the cats may be more protective.
“Indeed, an organ or muscle that remains inactive for a long time eventually atrophies. It is plausible that the same applies to a brain kept for an extended period in a state corresponding to a flat EEG,” says Professor Amzica. “An inactive brain coming out of a prolonged coma may be in worse shape than a brain that has had minimal activity. Research on the effects of extreme deep coma during which the hippocampus is active, through Nu-complexes. is absolutely vital for the benefit of patients.”
“Another implication of this finding is that we now have evidence that the brain is able to survive an extremely deep coma if the integrity of the nervous structures is preserved,” said lead author of the study, Daniel Kroeger. “We also found that the hippocampus can send ‘orders’ to the brain’s commander in chief, the cortex. Finally, the possibility of studying the learning and memory processes of the hippocampus during a state of coma will help further understanding of them. In short, all sorts of avenues for basic research are now open to us.”
Discovery of a gene essential for memory extinction could lead to new PTSD treatments.
If you got beat up by a bully on your walk home from school every day, you would probably become very afraid of the spot where you usually met him. However, if the bully moved out of town, you would gradually cease to fear that area.
Neuroscientists call this phenomenon “memory extinction”: Conditioned responses fade away as older memories are replaced with new experiences.
A new study from MIT reveals a gene that is critical to the process of memory extinction. Enhancing the activity of this gene, known as Tet1, might benefit people with posttraumatic stress disorder (PTSD) by making it easier to replace fearful memories with more positive associations, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory.
The Tet1 gene appears to control a small group of other genes necessary for memory extinction. “If there is a way to significantly boost the expression of these genes, then extinction learning is going to be much more active,” says Tsai, the Picower Professor of Neuroscience at MIT and senior author of a paper appearing in the Sept. 18 issue of the journal Neuron.
The paper’s lead authors are Andrii Rudenko, a postdoc at the Picower Institute, and Meelad Dawlaty, a postdoc at the Whitehead Institute.
New and old memories
Tsai’s team worked with researchers in MIT biology professor Rudolf Jaenisch’s lab at the Whitehead to study mice with the Tet1 gene knocked out. Tet1 and other Tet proteins help regulate the modifications of DNA that determine whether a particular gene will be expressed or not. Tet proteins are very abundant in the brain, which made scientists suspect they might be involved in learning and memory.
To their surprise, the researchers found that mice without Tet1 were perfectly able to form memories and learn new tasks. However, when the team began to study memory extinction, significant differences emerged.
To measure the mice’s ability to extinguish memories, the researchers conditioned the mice to fear a particular cage where they received a mild shock. Once the memory was formed, the researchers then put the mice in the cage but did not deliver the shock. After a while, mice with normal Tet1 levels lost their fear of the cage as new memories replaced the old ones.
“What happens during memory extinction is not erasure of the original memory,” Tsai says. “The old trace of memory is telling the mice that this place is dangerous. But the new memory informs the mice that this place is actually safe. There are two choices of memory that are competing with each other.”
In normal mice, the new memory wins out. However, mice lacking Tet1 remain fearful. “They don’t relearn properly,” Rudenko says. “They’re kind of getting stuck and cannot extinguish the old memory.”
In another set of experiments involving spatial memory, the researchers found that mice lacking the Tet1 gene were able to learn to navigate a water maze, but were unable to extinguish the memory.
Control of memory genes
The researchers found that Tet1 exerts its effects on memory by altering the levels of DNA methylation, a modification that controls access to genes. High methylation levels block the promoter regions of genes and prevent them from being turned on, while lower levels allow them to be expressed.
Many proteins that methylate DNA have been identified, but Tet1 and other Tet proteins have the reverse effect, removing DNA methylation. The MIT team found that mice lacking Tet1 had much lower levels of hydroxymethylation — an intermediate step in the removal of methylation — in the hippocampus and the cortex, which are both key to learning and memory.
These changes in demethylation were most dramatic in a group of about 200 genes, including a small subset of so-called “immediate early genes,” which are critical for memory formation. In mice without Tet1, the immediate early genes were very highly methylated, making it difficult for those genes to be turned on.
In the promoter region of an immediate early gene known as Npas4 — which Yingxi Li, the Frederick A. and Carole J. Middleton Career Development Assistant Professor of Neuroscience at MIT, recently showed regulates other immediate early genes — the researchers found methylation levels close to 60 percent, compared to 8 percent in normal mice.
“It’s a huge increase in methylation, and we think that is most likely to explain why Npas4 is so drastically downregulated in the Tet1 knockout mice,” Tsai says.
“By demonstrating some of the ways that regulatory genes are methylated in response to Tet1 knockout and behavioral experience, the authors have taken an important step in identifying potential pharmacological treatment targets for disorders such as PTSD and addiction,” says Matthew Lattal, an associate professor of behavioral neuroscience at Oregon Health and Science University, who was not part of the research team.
Keeping genes poised
The researchers also discovered why the Tet1-deficient mice are still able to learn new things. During fear conditioning, methylation of the Npas4 gene goes down to around 20 percent, which appears to be low enough for the expression of Npas4 to turn on and help create new memories. The researchers suspect the fear stimulus is so strong that it activates other demethylation proteins — possibly Tet2 or Tet3 — that can compensate for the lack of Tet1.
During the memory-extinction training, however, the mice do not experience such a strong stimulus, so methylation levels remain high (around 40 percent) and Npas4 does not turn on.
The findings suggest that a threshold level of methylation is necessary for gene expression to take place, and that the job of Tet1 is to maintain low methylation, ensuring that the genes necessary for memory formation are poised and ready to turn on at the moment they are needed.
The researchers are now looking for ways to increase Tet1 levels artificially and studying whether such a boost could enhance memory extinction. They are also studying the effects of eliminating two or all three of the Tet enzymes.
“This will not only help us further delineate epigenetic regulation of memory formation and extinction, but will also unravel other potential functions of Tets and methylation in the brain beyond memory extinction,” Dawlaty says.
Researchers Pinpoint Molecular Path that Makes Antidepressants Act Quicker in Mouse Model
Understanding alternate pathways for how mental meds work could lead to faster-acting drug targets
The reasons behind why it often takes people several weeks to feel the effect of newly prescribed antidepressants remains somewhat of a mystery – and likely, a frustration to both patients and physicians.
(Image: Mouse hippocampus expressing the Cre- virus. Credit: Julie Blendy, PhD; Brigitta Gunderson, PhD; Perelman School of Medicine, University of Pennsylvania)
Julie Blendy, PhD, professor of Pharmacology, at the Perelman School of Medicine, University of Pennsylvania; Brigitta Gunderson, PhD, a former postdoctoral fellow in the Blendy lab, and colleagues, have been working to find out why and if there is anything that can be done to shorten the time in which antidepressants kick in.
“Our goal is to find ways for antidepressants to work faster,” says Blendy.
The proteins CREB and CREM are both transcription factors, which bind to specific DNA sequences to control the “reading” of genetic information from DNA to messenger RNA (mRNA). Both CREB and CREM bind to the same 8-base-pair DNA sequence in the cell nucleus. But, the comparative influence of CREM versus CREB on the action of antidepressants is a “big unknown,” says Blendy.
CREB, and CREM to some degree, has been implicated in the pathophysiology of depression, as well as in the efficacy of antidepressants. However, whenever CREB is deleted, CREM is upregulated, further complicating the story.
Therefore, how an antidepressant works on the biochemistry and behavior in a mouse in which the CREB protein is deleted only in the hippocampus versus a wild type mouse in which CREM is overexpressed let the researchers tease out the relative influence of CREB and CREM on the pharmacology of an antidepressant. They saw the same results in each type of mouse line – increased nerve-cell generation in the hippocampus and a quicker response to the antidepressant. Their findings appear in the Journal of Neuroscience.
“This is the first demonstration of CREM within the brain playing a role in behavior, and specifically in behavioral outcomes, following antidepressant treatment,” says Blendy.
A Flood of Neurotransmitters
Antidepressants like SSRIs, NRIs, and older tricyclic drugs work by causing an immediate flood of neurotransmitters like serotonin, norepinephrine, and in some cases dopamine, into the synaptic space. However, it can take three to four weeks for patients to feel changes in mental state. Long-term behavioral effects of the drugs may take longer to manifest themselves, because of the need to activate CREB downstream targets such as BDNF and trkB, or as of yet unidentified targets, which could also be developed as new antidepressant drug targets.
The Penn team compared the behavior of the control, wild-type mice to the CREB mutant mice using a test in which the mouse is trained to eat a treat – Reese’s Pieces, to be exact – in the comfort of their home cage. The treat-loving mice are then placed in a new cage to make them anxious. They are given the treat again, and the time it takes for the mouse to approach the treat is recorded.
Animals that receive no drug treatment take a long time to venture out into the anxious environment to retrieve the treat, however, if given an antidepressant drug for at least three weeks, the time it takes a mouse to get the treat decreases significantly, from about 400 seconds to 100 seconds. In mice in which CREB is deleted or in mice in which CREM is upregulated, this reduction happens in one to two days versus the three weeks seen in wild-type mice.
The accelerated time to approach the treat in mice on the medication was accompanied by an increase in new nerve growth in the hippocampus.
“Our results suggest that activation of CREM may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment,” says Blendy. Upregulation of CREM observed after CREB deletion, appears to functionally compensate for CREB loss at a behavioral level and leads to maintained or increased expression of some CREB target genes. The researchers’ next step is to identify any unique CREM target genes in brain areas such as the hippocampus, which may lead to the development of faster-acting antidepressants.
(Source: uphs.upenn.edu)
Modifying the activity of neuronal networks that encode spatial memories leads to the formation of an incorrect fear memory in mice
The formation and retrieval of memories allows all kinds of organisms, including humans, to learn and thrive in their environment. Yet our memories are not always accurate, and mistaken remembrances can have important consequences, such as in the justice system and in our navigation of the world. Susumu Tonegawa, Steve Ramirez, Xu Liu and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics, have gained insight into the creation of mistaken memories by using light activation of neurons to generate an incorrect fear memory in mice.
The researchers allowed mice to explore a novel location and used genetic techniques to label neurons in the hippocampus—a part of the brain linked to spatial memory—that were activated in the process with a special channel called channelrhodopsin-2. The cells that expressed this channel could then be artificially activated by light. In this way, the researchers were able to reactivate neurons that fired in that particular location, even if the mice were no longer there.
They then moved the mice to another location where they were exposed to foot shocks, causing the mice to exhibit immobility, a fear behavior. At the same time, the researchers used light to activate the channelrhodopsin-2-expressing neurons that had fired in the first location.
When Tonegawa and his colleagues moved the animals to a third location, they did not show fear behavior. Yet when the mice went back to the first location, where they had never experienced a foot shock, the mice now exhibited prominent freezing behavior. The researchers had generated a ‘false memory’ in the mice of foot shocks in a location in which they had never been exposed to them.
The researchers showed that light reactivation of neuronal networks in the central area of the hippocampus, called the dentate gyrus, could create false memories, while reactivation of the outer ‘CA1’ area of the hippocampus could not. Tonegawa and his colleagues suggest that this is because mouse exploration of different locations leads to activation of more overlapping neuronal networks in the CA1 than in the dentate gyrus. “This may reflect the fundamental differences of how memories are encoded in these two regions,” explains Liu.
The findings provide insight into how the brain encodes and processes memories and could one day lead to treatments for post-traumatic stress disorder. “Our work may also have implications for situations where patients mix reality with their own imaginations, such as in schizophrenia,” says Liu.
Brain circuitry loss may be a very early sign of cognitive decline in healthy elderly people
The degeneration of a small, wishbone-shaped structure deep inside the brain may provide the earliest clues to future cognitive decline, long before healthy older people exhibit clinical symptoms of memory loss or dementia, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.
The longitudinal study found that the only discernible brain differences between normal people who later developed cognitive impairment and those who did not were changes in their fornix, an organ that carries messages to and from the hippocampus, and that has long been known to play a role in memory.
“This could be a very early and useful marker for future incipient decline,” said Evan Fletcher, the study’s lead author and a project scientist with the UC Davis Alzheimer’s Disease Center.
“Our results suggest that fornix variables are measurable brain factors that precede the earliest clinically relevant deterioration of cognitive function among cognitively normal elderly individuals,” Fletcher said.
The research is published online today in JAMA Neurology.
Hippocampal atrophy occurs in the later stages of cognitive decline and is one of the most studied changes associated with the Alzheimer’s disease process. However, changes to the fornix and other regions of the brain structurally connected to the hippocampus have not been as closely examined. The study found that degeneration of the fornix in relation to cognition was detectable even earlier than changes in the hippocampus.
“Although hippocampal measures have been studied much more deeply in relation to cognitive decline, our direct comparison between fornix and hippocampus measures suggests that fornix properties have a superior ability to identify incipient cognitive decline among healthy individuals,” Fletcher said.
The study was conducted over five years in a group of 102 diverse, cognitively normal people with an average age of 73 who were recruited through community outreach at the Alzheimer’s Disease Center. The researchers conducted magnetic resonance imaging (MRI) studies of the participants’ brains that described their volumes and integrity. A different type of MRI was used to determine the integrity of the myelin, the fatty coating that sheaths and protects the axons. The axons are analogous to the copper wiring of the brain’s circuitry and the myelin is like the wiring’s plastic insulation.
Either one of those things being lost will “degrade the signal transmission” in the brain, Fletcher said.
The researchers also conducted psychological tests and cognitive evaluations of the study participants to gauge their level of cognitive functioning. The participants returned for updated MRIs and cognitive testing at approximately one-year intervals. At the outset, none of the study participants exhibited symptoms of cognitive decline. Over time about 20 percent began to show symptoms that led to diagnoses with either mild cognitive impairment (MCI) and, in a minority of cases, Alzheimer’s disease.
“We found that if you looked at various brain factors there was one — and only one — that seemed to be predictive of whether a person would have cognitive decline, and that was the degradation of the fornix,” Fletcher said.
The study measured two relevant fornix characteristics predicting future cognitive impairment — low fornix white matter volume and reduced axonal integrity. Each of these was stronger than any other brain factor in models predicting cognitive loss, Fletcher said.
He said that routine MRI examination of the fornix could conceivably be used clinically in the future as a predictor of abnormal cognitive decline.
“Our findings suggest that if your fornix volume or integrity is within a certain range you’re at an increased risk of cognitive impairment down the road. But developing the use of the fornix as a predictor in a clinical setting will take some time, in the same way that it took time for evaluation of cholesterol levels to be used to predict future heart disease,” he said.
Fletcher also said that the finding may mark a paradigm shift toward evaluation of the brain’s white matter, rather than its gray matter, as among the very earliest indicators of developing cognitive loss. There is currently a strong research focus on understanding brain processes that lead eventually to Alzheimer’s disease. He said the current finding could fill in one piece of the picture and motivate new directions in research to understand why and how fornix and other white matter change is such an important harbinger of cognitive impairment.
“The key importance of this finding is that it suggests that white matter tract measures may prove to be promising candidate biomarkers for predicting incipient cognitive decline among cognitively normal individuals in a clinical setting, possibly more so than gray matter measures,” he said.
(Source: ucdmc.ucdavis.edu)
Cell transplants may be a novel treatment for schizophrenia
Rodent research suggests feasibility of restoring neuron function
Research from the School of Medicine at The University of Texas Health Science Center at San Antonio suggests the exciting possibility of using cell transplants to treat schizophrenia.
Cells called “interneurons” inhibit activity within brain regions, but this braking or governing function is impaired in schizophrenia. Consequently, a group of nerve cells called the dopamine system go into overdrive. Different branches of the dopamine system are involved in cognition, movement and emotions.
“Since these cells are not functioning properly, our idea is to replace them,” said study senior author Daniel Lodge, Ph.D., assistant professor of pharmacology in the School of Medicine.
Transplant restored normal function
Dr. Lodge and lead author Stephanie Perez, graduate student in his laboratory, biopsied tissue from rat fetuses, isolated cells from the tissue and injected the cells into a brain center called the hippocampus. This center regulates the dopamine system and plays a role in learning, memory and executive functions such as decision making. Rats treated with the transplanted cells have restored hippocampal and dopamine function.
Stem cells are able to become different types of cells, and in this case interneurons were selected. “We put in a lot of cells and not all survived, but a significant portion did and restored hippocampal and dopamine function back to normal,” Dr. Lodge said.
‘You can essentially fix the problem’
Unlike traditional approaches to treating schizophrenia, such as medications and deep-brain stimulation, transplantation of interneurons potentially can produce a permanent solution. “You can essentially fix the problem,” Dr. Lodge said. “Ultimately, if this is translated to humans, we want to reprogram a patient’s own cells and use them.”
After meeting with other students, Perez brought the research idea to Dr. Lodge. “The students have journal club, and somebody had done a similar experiment to restore motor deficits and had good results,” Perez said. “We thought, why can’t we use it for schizophrenia and have good results, and so far we have.”
The study is in Molecular Psychiatry.
(Source: uthscsa.edu)