Posts tagged hippocampus
Articles and news from the latest research reports.
The Nobel Assembly at Karolinska Institutet has decided to award the 2014 Nobel Prize in Physiology or Medicine with one half to John O´Keefe and the other half jointly to May-Britt Moser and Edvard I. Moser for their discoveries of cells that constitute a positioning system in the brain.
How do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? This year´s Nobel Laureates have discovered a positioning system, an “inner GPS” in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.
In 1971, John O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O´Keefe concluded that these “place cells” formed a map of the room.
More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells”, that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.
The discoveries of John O´Keefe, May-Britt Moser and Edvard Moser have solved a problem that has occupied philosophers and scientists for centuries – how does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment?
How do we experience our environment?
The sense of place and the ability to navigate are fundamental to our existence. The sense of place gives a perception of position in the environment. During navigation, it is interlinked with a sense of distance that is based on motion and knowledge of previous positions.
Questions about place and navigation have engaged philosophers and scientists for a long time. More than 200 years ago, the German philosopher Immanuel Kant argued that some mental abilities exist as a priori knowledge, independent of experience. He considered the concept of space as an inbuilt principle of the mind, one through which the world is and must be perceived. With the advent of behavioural psychology in the mid-20th century, these questions could be addressed experimentally. When Edward Tolman examined rats moving through labyrinths, he found that they could learn how to navigate, and proposed that a “cognitive map” formed in the brain allowed them to find their way. But questions still lingered - how would such a map be represented in the brain?
John O´Keefe and the place in space
John O´Keefe was fascinated by the problem of how the brain controls behaviour and decided, in the late 1960s, to attack this question with neurophysiological methods. When recording signals from individual nerve cells in a part of the brain called the hippocampus, in rats moving freely in a room, O’Keefe discovered that certain nerve cells were activated when the animal assumed a particular place in the environment (Figure 1). He could demonstrate that these “place cells” were not merely registering visual input, but were building up an inner map of the environment. O’Keefe concluded that the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments. Therefore, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus.
May-Britt and Edvard Moser find the coordinates
May-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room when they discovered an astonishing pattern of activity in a nearby part of the brain called the entorhinal cortex. Here, certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid (Figure 2). Each of these cells was activated in a unique spatial pattern and collectively these “grid cells” constitute a coordinate system that allows for spatial navigation. Together with other cells of the entorhinal cortex that recognize the direction of the head and the border of the room, they form circuits with the place cells in the hippocampus. This circuitry constitutes a comprehensive positioning system, an inner GPS, in the brain (Figure 3).
A place for maps in the human brain
Recent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer´s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain´s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.
The discovery of the brain’s positioning system represents a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions. It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning.
(Source: nobelprize.org)
How curiosity changes the brain to enhance learning
The more curious we are about a topic, the easier it is to learn information about that topic. New research publishing online October 2 in the Cell Press journal Neuron provides insights into what happens in our brains when curiosity is piqued. The findings could help scientists find ways to enhance overall learning and memory in both healthy individuals and those with neurological conditions.
"Our findings potentially have far-reaching implications for the public because they reveal insights into how a form of intrinsic motivation—curiosity—affects memory. These findings suggest ways to enhance learning in the classroom and other settings," says lead author Dr. Matthias Gruber, of University of California at Davis.
For the study, participants rated their curiosity to learn the answers to a series of trivia questions. When they were later presented with a selected trivia question, there was a 14 second delay before the answer was provided, during which time the participants were shown a picture of a neutral, unrelated face. Afterwards, participants performed a surprise recognition memory test for the faces that were presented, followed by a memory test for the answers to the trivia questions. During certain parts of the study, participants had their brains scanned via functional magnetic resonance imaging.
The study revealed three major findings. First, as expected, when people were highly curious to find out the answer to a question, they were better at learning that information. More surprising, however, was that once their curiosity was aroused, they showed better learning of entirely unrelated information (face recognition) that they encountered but were not necessarily curious about. People were also better able to retain the information learned during a curious state across a 24-hour delay. “Curiosity may put the brain in a state that allows it to learn and retain any kind of information, like a vortex that sucks in what you are motivated to learn, and also everything around it,” explains Dr. Gruber.
Second, the investigators found that when curiosity is stimulated, there is increased activity in the brain circuit related to reward. “We showed that intrinsic motivation actually recruits the very same brain areas that are heavily involved in tangible, extrinsic motivation,” says Dr. Gruber. This reward circuit relies on dopamine, a chemical messenger that relays messages between neurons.
Third, the team discovered that when curiosity motivated learning, there was increased activity in the hippocampus, a brain region that is important for forming new memories, as well as increased interactions between the hippocampus and the reward circuit. “So curiosity recruits the reward system, and interactions between the reward system and the hippocampus seem to put the brain in a state in which you are more likely to learn and retain information, even if that information is not of particular interest or importance,” explains principal investigator Dr. Charan Ranganath, also of UC Davis.
The findings could have implications for medicine and beyond. For example, the brain circuits that rely on dopamine tend to decline in function as people get older, or sooner in people with neurological conditions. Understanding the relationship between motivation and memory could therefore stimulate new efforts to improve memory in the healthy elderly and to develop new approaches for treating patients with disorders that affect memory. And in the classroom or workplace, learning what might be considered boring material could be enhanced if teachers or managers are able to harness the power of students’ and workers’ curiosity about something they are naturally motivated to learn.
Taste memory
Have you ever eaten something totally new and it made you sick? Don’t give up; if you try the same food in a different place, your brain will be more “forgiving” of the new attempt. In a new study conducted by the Sagol Department of Neurobiology at the University of Haifa, researchers found for the first time that there is a link between the areas of the brain responsible for taste memory in a negative context and those areas in the brain responsible for processing the memory of the time and location of the sensory experience. When we experience a new taste without a negative context, this link doesn’t exist.
The area of the brain responsible for storing memories of new tastes is the taste cortex, found in a relatively insulated area of the human brain known as the insular cortex. The area responsible for formulating a memory of the place and time of the experience (the episode) is the hippocampus. Until now, researchers assumed that there was no direct connection between these areas – i.e., the processing of information about a taste is not related to the time or the place one experiences the taste. The accepted thinking was that a negative experience – for example, being exposed to a bad taste – would be negative in the same way anywhere, and the brain would create a memory of the taste itself, divorced from the time or place.
But in this new study, conducted by doctoral student Adaikkan Chinnakkaruppan in the laboratory of Prof. Kobi Rosenblum of the Sagol Department of Neurobiology at the University of Haifa, in cooperation with the Riken Institute, the leading brain research institute in Tokyo, the researchers demonstrate for the first time that there is a functional link between the two brain regions.
In the study the researchers sought to examine the relationship between the taste cortex (which is responsible for taste memory), and three different areas in the hippocampus: CA1, which is responsible for encoding the concept of space (where we are located); DG, the area responsible for encoding the time relationship between events; and CA3, responsible for filling in missing information. To do this the researchers took ordinary mice and mice that were genetically engineered by their Japanese colleagues such that these three areas of the brain functioned normally but were lacking plasticity, which did not allow new memories reliant on them to be created.
“In brain research, the manipulation we do must be very delicate and precise, otherwise the changes can make the entire experiment irrelevant to proving or refuting the research hypothesis,” said Prof. Rosenblum.
The mice were exposed to two new tastes, one that caused stomach pains (to mimic exposure to toxic food) and another that didn’t cause that feeling. By comparing the two groups it emerged that when the new taste was not accompanied by an association with toxic food, there was no difference between the normal mice and those whose various functional areas in the hippocampus didn’t allow plasticity. But when the taste caused a negative feeling, there was clear involvement of the CA1 area, which is responsible for encoding the space.
“The significance of this is that the moment we go back to the same place at which we experienced the taste associated with a bad feeling, subconsciously the negative memory will be much stronger than if we come to taste the same taste in a totally different place,” explained Prof. Rosenblum. Similarly, the DG area, which is responsible for encoding the time between incidents, was involved the more time that passed between the new taste and the stomach discomfort. “This means that even during a simple associative taste, the brain operates the hippocampus to produce an integrated experience that includes general information about the time between events and their location,” he said.
The findings, which were recently published in the Journal of Neuroscience, expose the complexity and richness of the simple sensory experiences that are engraved in our brains and that in most cases we aren’t even aware of. Moreover, the study can help explain behavioral results and the difficulty in producing memories when certain areas of the brain become dysfunctional following and illness or accident. The better we understand the encoding of simple sensory experiences in the brain and the link between the feeling, time and place of the experiences; we will better understand the complex process of creating memories and storing them in our brains.
(Source: newmedia-eng.haifa.ac.il)
(Image caption: A neuron in which the axon originates at a dendrite. Signals arriving at this dendrites become more efficiently forwarded than signals input elsewhere. Credit: Alexei V. Egorov, 2014)
Certain nerve cells take a shortcut for the transmission of information: signals are not conducted via the cell`s center, but around it like on a bypass road. The previously unknown nerve cell shape is now presented in the journal “Neuron" by a research team from Heidelberg, Mannheim and Bonn.
Nerve cells communicate by using electrical signals. Via widely ramified cell structures—the dendrites—, they receive signals from other neurons and then transmit them over a thin cell extension—the axon—to other nerve cells. Axon and dendrites are usually interconnected by the neuron’s cell body. A team of scientists at the Bernstein Center Heidelberg-Mannheim, Heidelberg University, and the University of Bonn has now discovered neurons in which the axon arises directly from one of the dendrites. Similar to taking a bypass road, the signal transmission is thus facilitated within the cell.
“Input signals at this dendrite do not need not be propagated across the cell body,” explains Christian Thome of the Bernstein Center Heidelberg-Mannheim and Heidelberg University, one of the two first authors of the study. For their analyses, the scientists specifically colored the places of origin of axons of so-called pyramidal cells in the hippocampus. This brain region is involved in memory processes. The surprising result: “We found that in more than half of the cells, the axon does not emerge from the cell body, but arises from a lower dendrite,” Thome says.
The researchers then studied the effect of signals received at this special dendrite. For this purpose, they injected a certain form of the neural transmitter substance glutamate into the brain tissue of mice that can be activated by light pulses. A high-resolution microscope allowed the neuroscientists to direct the light beam directly to a specific dendrite. By the subsequent activation of the messenger substance, they simulated an exciting input signal.
“Our measurements indicate that dendrites that are directly connected to the axon, actively propagate even small input stimuli and activate the neuron,” says second first author Tony Kelly, a member of the Sonderforschungsbereich (SFB) 1089 at the University of Bonn. A computer simulation of the scientists predicts that this effect is particularly pronounced when the information flow from other dendrites to the axon is suppressed by inhibitory input signals at the cell body.
“That way, information transmitted by this special dendrite influences the behavior of the nerve cell more than input from any other dendrite,” Kelly says. In a future step, the researchers attempt to figure out which biological function is actually strengthened through the specific dendrite—and what therefore might be the reason for the unusual shape of these neurons.
EEG Study Findings Reveal How Fear is Processed in the Brain
An estimated 8% of Americans will suffer from post traumatic stress disorder (PTSD) at some point during their lifetime. Brought on by an overwhelming or stressful event or events, PTSD is the result of altered chemistry and physiology of the brain. Understanding how threat is processed in a normal brain versus one altered by PTSD is essential to developing effective interventions.
New research from the Center for BrainHealth at The University of Texas at Dallas published online today in Brain and Cognition illustrates how fear arises in the brain when individuals are exposed to threatening images. This novel study is the first to separate emotion from threat by controlling for the dimension of arousal, the emotional reaction provoked, whether positive or negative, in response to stimuli. Building on previous animal and human research, the study identifies an electrophysiological marker for threat in the brain.
“We are trying to find where thought exists in the mind,” explained John Hart, Jr., M.D., Medical Science Director at the Center for BrainHealth. “We know that groups of neurons firing on and off create a frequency and pattern that tell other areas of the brain what to do. By identifying these rhythms, we can correlate them with a cognitive unit such as fear.”
Utilizing electroencephalography (EEG), Dr. Hart’s research team identified theta and beta wave activity that signifies the brain’s reaction to visually threatening images.
“We have known for a long time that the brain prioritizes threatening information over other cognitive processes,” explained Bambi DeLaRosa, study lead author. “These findings show us how this happens. Theta wave activity starts in the back of the brain, in it’s fear center – the amygdala – and then interacts with brain’s memory center - the hippocampus – before traveling to the frontal lobe where thought processing areas are engaged. At the same time, beta wave activity indicates that the motor cortex is revving up in case the feet need to move to avoid the perceived threat.”
For the study, 26 adults (19 female, 7 male), ages 19-30 were shown 224 randomized images that were either unidentifiably scrambled or real pictures. Real pictures were separated into two categories: threatening (weapons, combat, nature or animals) and non-threatening (pleasant situations, food, nature or animals).
While wearing an EEG cap, participants were asked to push a button with their right index finger for real items and another button with their right middle finger for nonreal/scrambled items. Shorter response times were recorded for scrambled images than the real images. There was no difference in reaction time for threatening versus non-threatening images.
EEG results revealed that threatening images evoked an early increase in theta activity in the occipital lobe (the area in the brain where visual information is processed), followed by a later increase in theta power in the frontal lobe (where higher mental functions such as thinking, decision-making, and planning occur). A left lateralized desynchronization of the beta band, the wave pattern associated with motor behavior (like the impulse to run), also consistently appeared in the threatening condition.
This study will serve as a foundation for future work that will explore normal versus abnormal fear associated with an object in other atypical populations including individuals with PTSD.
Brain inflammation dramatically disrupts memory retrieval networks
Brain inflammation can rapidly disrupt our ability to retrieve complex memories of similar but distinct experiences, according to UC Irvine neuroscientists Jennifer Czerniawski and John Guzowski.
Their study – which appears today in The Journal of Neuroscience – specifically identifies how immune system signaling molecules, called cytokines, impair communication among neurons in the hippocampus, an area of the brain critical for discrimination memory. The findings offer insight into why cognitive deficits occurs in people undergoing chemotherapy and those with autoimmune or neurodegenerative diseases.
Moreover, since cytokines are elevated in the brain in each of these conditions, the work suggests potential therapeutic targets to alleviate memory problems in these patients.
“Our research provides the first link among immune system activation, altered neural circuit function and impaired discrimination memory,” said Guzowski, the James L. McGaugh Chair in the Neurobiology of Learning & Memory. “The implications may be beneficial for those who have chronic diseases, such as multiple sclerosis, in which memory loss occurs and even for cancer patients.”
What he found interesting is that increased cytokine levels in the hippocampus only affected complex discrimination memory, the type that lets us differentiate among generally similar experiences – what we did at work or ate at dinner, for example. A simpler form of memory processed by the hippocampus – which would be akin to remembering where you work – was not altered by brain inflammation.
In the study, Czerniawski, a UCI postdoctoral scholar, exposed rats to two similar but discernable environments over several days. They received a mild foot shock daily in one, making them apprehensive about entering that specific site. Once the rodents showed that they had learned the difference between the two environments, some were given a low dose of a bacterial agent to induce a neuroinflammatory response, leading to cytokine release in the brain. Those animals were then no longer able to distinguish between the two environments.
Afterward, the researchers explored the activity patterns of neurons – the primary cell type for information processing – in the rats’ hippocampi using a gene-based cellular imaging method developed in the Guzowski lab. In the rodents that received the bacterial agent (and exhibited memory deterioration), the networks of neurons activated in the two environments were very similar, unlike those in the animals not given the agent (whose memories remained strong). This finding suggests that cytokines impaired recall by disrupting the function of these specific neuron circuits in the hippocampus.
“The cytokines caused the neural network to react as if no learning had taken place,” said Guzowski, associate professor of neurobiology & behavior. “The neural circuit activity was back to the pattern seen before learning.”
The work may also shed light on a chemotherapy-related mental phenomenon known as “chemo brain,” in which cancer patients find it difficult to efficiently process information. UCI neuro-oncologists have found that chemotherapeutic agents destroy stem cells in the brain that would have become neurons for creating and storing memories.
Dr. Daniela Bota, who co-authored that study, is currently collaborating with Guzowski’s research group to see if brain inflammation may be another of the underlying causes of “chemo brain” symptoms.
She said they’re looking for a simple intervention, such as an anti-inflammatory or steroid drug, that could lessen post-chemo inflammation. Bota will test this approach on patients, pending the outcome of animal studies.
“It will be interesting to see if limiting neuroinflammation will give cancer patients fewer or no problems,” she said. “It’s a wonderful idea, and it presents a new method to limit brain cell damage, improving quality of life. This is a great example of basic science and clinical ideas coming together to benefit patients.”
![The interactive brain
Neuroscientist explores mechanism that can cause deficit in working memory
Amy Griffin, associate professor of psychological and brain sciences at the University of Delaware, has received a five-year, $1.78 million grant from the National Institute of Mental Health to support her research into the brain mechanisms of working memory.
A neuroscientist, Griffin has been interested for some time in the interaction between the prefrontal cortex, located at the front of the brain, and the hippocampus, a region in the temporal lobe of the brain. When the two areas fail to work together, that failure appears to be correlated with deficits in working memory, a condition that commonly occurs in schizophrenia, general anxiety and other psychiatric disorders.
The hippocampus is the portion of the brain responsible for memory, while the prefrontal cortex controls executive function, a term that includes such cognitive abilities as problem-solving, planning and abstract thinking.
“These are two areas of the brain that are far apart, but their oscillations [rhythmic activities] are synchronized,” Griffin said. “When one area is active, so is the other.”
Working memory, sometimes called short-term memory, is “the kind of memory that fails when you walk into a room and forget why you came there,” she said.
When the oscillations in the hippocampus and prefrontal cortex are out of sync, deficits of working memory occur. In those cases, Griffin said, “both regions are active, but they’re not talking to each other.” The mechanism that causes that lack of communication has not been well explored, and her research will seek to do that.
Griffin and her research team plan to conduct two types of experiments. One will inhibit activity in a brain region called the nucleus reuniens, a region that is hypothesized to synchronize the hippocampus and prefrontal cortex and is expected to cause impairments with working memory. In the other experiment, researchers will activate the nucleus reuniens to increase synchrony, hoping to learn if that improves working memory.
The research will employ a cutting-edge technique called optogenetics, a process that uses proteins to make neurons sensitive to light and then uses light to control them.
“Optogenetics is becoming a common technique,” Griffin said. “It’s a way to study these processes on a millisecond timescale.”
A 2013 article in the journal Nature Neuroscience said optogenetics “is transforming the field of neuroscience. For the first time, it is now possible to use light to both trigger and silence activity in genetically defined populations of neurons with millisecond precision.”
Griffin, using a rat model, will inject the light-sensitizing substance — a harmless virus — into the nucleus reuniens and then use a laser to inhibit or activate this brain region. The rats then perform tasks that assess their working memory. Synchronization between the hippocampus and prefrontal cortex will also be recorded, with the prediction that the degree of the working memory impairment will be correlated with reductions in synchrony.
“Our experiments will not be interfering with the activities of the hippocampus or the prefrontal cortex within themselves,” Griffin said. “We want to affect only the ability of the structures to talk to each other.”](http://41.media.tumblr.com/7ad0d422d855db0111ddbd4fbc19380f/tumblr_nbsgmhGwk71rog5d1o1_500.jpg)
Neuroscientist explores mechanism that can cause deficit in working memory
Amy Griffin, associate professor of psychological and brain sciences at the University of Delaware, has received a five-year, $1.78 million grant from the National Institute of Mental Health to support her research into the brain mechanisms of working memory.
A neuroscientist, Griffin has been interested for some time in the interaction between the prefrontal cortex, located at the front of the brain, and the hippocampus, a region in the temporal lobe of the brain. When the two areas fail to work together, that failure appears to be correlated with deficits in working memory, a condition that commonly occurs in schizophrenia, general anxiety and other psychiatric disorders.
The hippocampus is the portion of the brain responsible for memory, while the prefrontal cortex controls executive function, a term that includes such cognitive abilities as problem-solving, planning and abstract thinking.
“These are two areas of the brain that are far apart, but their oscillations [rhythmic activities] are synchronized,” Griffin said. “When one area is active, so is the other.”
Working memory, sometimes called short-term memory, is “the kind of memory that fails when you walk into a room and forget why you came there,” she said.
When the oscillations in the hippocampus and prefrontal cortex are out of sync, deficits of working memory occur. In those cases, Griffin said, “both regions are active, but they’re not talking to each other.” The mechanism that causes that lack of communication has not been well explored, and her research will seek to do that.
Griffin and her research team plan to conduct two types of experiments. One will inhibit activity in a brain region called the nucleus reuniens, a region that is hypothesized to synchronize the hippocampus and prefrontal cortex and is expected to cause impairments with working memory. In the other experiment, researchers will activate the nucleus reuniens to increase synchrony, hoping to learn if that improves working memory.
The research will employ a cutting-edge technique called optogenetics, a process that uses proteins to make neurons sensitive to light and then uses light to control them.
“Optogenetics is becoming a common technique,” Griffin said. “It’s a way to study these processes on a millisecond timescale.”
A 2013 article in the journal Nature Neuroscience said optogenetics “is transforming the field of neuroscience. For the first time, it is now possible to use light to both trigger and silence activity in genetically defined populations of neurons with millisecond precision.”
Griffin, using a rat model, will inject the light-sensitizing substance — a harmless virus — into the nucleus reuniens and then use a laser to inhibit or activate this brain region. The rats then perform tasks that assess their working memory. Synchronization between the hippocampus and prefrontal cortex will also be recorded, with the prediction that the degree of the working memory impairment will be correlated with reductions in synchrony.
“Our experiments will not be interfering with the activities of the hippocampus or the prefrontal cortex within themselves,” Griffin said. “We want to affect only the ability of the structures to talk to each other.”
Stanford scientists reveal complexity in the brain’s wiring diagram
When Joanna Mattis started her doctoral project she expected to map how two regions of the brain connect. Instead, she got a surprise. It turns out the wiring diagram shifts depending on how you flip the switch.
"There’s a lot of excitement about being able to make a map of the brain with the idea that if we could figure out how it is all connected we could understand how it works," Mattis said. "It turns out it’s so much more dynamic than that."
Mattis is a co-first author on a paper describing the work published August 27 in the Journal of Neuroscience. Julia Brill, then a postdoctoral scholar, was the other co-first author.
Mattis had been a graduate student in the lab of Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences, where she helped work on a new technique called optogenetics. That technique allows neuroscientists to selectively turn parts of the brain on and off to see what happens. She wanted to use optogenetics to understand the wiring of a part of the brain involved in spatial memory – it’s what makes a mental map of your surroundings as you explore a new city, for example.
Scientists already knew that when an animal explores habitats, two parts of the brain are involved in the initial exploring phase and then in solidifying a map of the environment – the hippocampus and the septum.
When an animal is exploring an environment, the neurons in the hippocampus fire slow signals to the septum, essentially telling the septum that it’s busy acquiring information. Once the animal is done exploring, those same cells fire off intense signals letting the septum know that it’s now locking that information into memory. The scientists call this phase consolidation. The septum uses that information to then turn around and regulate other signals going into the hippocampus.
"I wanted to study the hippocampus because on the one hand so much was already known – there was already this baseline of knowledge to work off of. But then the question of how the hippocampus and septum communicate hadn’t been accessible before optogenetics," Mattis said.
Neurons in the hippocampus were known to fire in a rhythmic pattern, which is a particular expertise of John Huguenard, a professor of neurology. Mattis obtained an interdisciplinary fellowship through Stanford Bio-X, which allowed her to combine the Deisseroth lab’s expertise in optogenetics with the rhythmic brain network expertise of Julia Brill from the Huguenard lab.
Mattis and Brill used optogenetics to prompt neurons of the hippocampus to mimic either the slow firing characteristic of information acquisition or the rapid firing characteristic of consolidation. When they mimicked the slow firing they saw a quick reaction by cells in the septum. When they mimicked the fast consolidation firing, they saw a much slower response by completely different cells in the septum.
Same set of wires – different outcome. That’s like turning on different lights depending on how hard you flip the switch. “This illustrates how complex the brain is,” Mattis said.
Most scientific papers answer a question: What does this protein do? How does this part of the brain work? By contrast, this paper raised a whole new set of questions, Mattis said. They more or less understand the faster reaction, but what is causing the slower reaction? How widespread is this phenomenon in the brain?
"The other big picture thing that we opened up but didn’t answer is: How can you then tie this back to the circuit overall and learning memory?" Mattis said. "Those would be exciting things to follow up on for future projects."
Seizures and sudden death: When SUMO ‘wrestles’ potassium channels
A gene crucial for brain and heart development may also be associated with sudden unexplained death in epilepsy (SUDEP), the most common cause of early mortality in epilepsy patients.
Scientists at The University of Texas MD Anderson Cancer Center have created a new animal model for SUDEP and have shown that mice who have a partial deficiency of the gene SENP2 (Sentrin/SUMO-specific protease 2) are more likely to develop spontaneous seizures and sudden death. The finding occurred when observing mice originally bred for studying a link between SENP2 deficiency and cancer.
"SENP2 is highly present in the hippocampus, a critical brain region for seizure genesis," said Edward Yeh, M.D., chair of cardiology at MD Anderson. "Understanding the genetic basis for SUDEP is crucial given that the rate of sudden death in epilepsy patients is 20-fold that of the general population, with SUDEP the most common epilepsy-related cause of death."
Yeh’s findings were published in this month’s issue of Neuron.
Although it’s not yet known what causes SUDEP in humans, inactivation of potassium channels genes have been linked to SUDEP in animal models. Potassium channels are found in most cell types and control a large variety of cell functions.
"These animal models demonstrated an important connection between the brain and heart. However, it remains unclear whether seizure and sudden death are two separate manifestations of potassium channel deficiency in the brain and the heart, or whether seizures predispose the heart to lethal cardiac arrhythmia," said Yeh.
The study revealed that when SENP2 was deficient in the brain, seizures activated a part of the nervous system responsible for regulating the heart’s electrical system. This resulted in a phenomenon known as atrioventricular conduction block, which effectively slowed down and then stopped the heart.
Yeh’s team observed that the SENP2-deficient mice appeared normal at birth, but by 6 to 8 weeks, experienced convulsive seizures, and then sudden death. He believes the reason may lie with protein modifiers called SUMO. SENP2 deficiency results in a process known as hyper-SUMOylation, which dramatically impacts potassium channels in the brain.
"One of the channels, Kv7, is significantly diminished or ‘closed’ due to the lack of SENP2," said Yeh. "In mice this led to seizures and cardiac arrest."
In humans, the good news is that an FDA-approved drug, retigabine works by “opening” the Kv7 channel. The therapy was developed for treating partial-onset seizures. The findings in Yeh’s new mouse model clearly demonstrate a previously unknown cause of SUDEP, which may open up new opportunities for study and treatment in the future.
(Source: eurekalert.org)
Research hints at why stress is more devastating for some
Some people take stress in stride; others are done in by it. New research at Rockefeller University has identified the molecular mechanisms of this so-called stress gap in mice with very similar genetic backgrounds — a finding that could lead researchers to better understand the development of psychiatric disorders such as anxiety and depression.
“Like people, each animal has unique experiences as it goes through its life. And we suspect that these life experiences can alter the expression of genes, and as a result, affect an animal’s susceptibility to stress,” says senior author Bruce McEwen, Alfred E. Mirsky Professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. “We have taken an important step toward explaining the molecular origins of this stress gap by showing that inbred mice react differently to stress, with some developing behaviors that resemble anxiety and depression, and others remaining resilient.”
The results, published September 2 in Molecular Psychiatry, point toward potential new markers to aid the diagnosis of stress-related disorders, such as anxiety and depression, and a promising route to the development of new treatments for these devastating disorders.
In experiments, researchers stressed the mice by exposing them to daily, unpredictable bouts of cage tilting, altered dark-light cycles, confinement in tight spaces and other conditions mice dislike with the goal of reproducing the sort of stressful experiences thought to be a primary cause of depression in humans. Afterward, in tests to see if the mice displayed the rodent equivalent of anxiety and depression symptoms, they found about 40 percent showed high levels of behaviors that included a preference for a dark compartment over a brightly lit one, or a loss of interest in sugar water. The remaining 60 percent recovered well from the stress. This distinction between the susceptible mice and the resilient ones was so fundamental that it emerged even before the mice were subjected to stress; some unstressed mice showed an anxiety-like preference for a dark compartment over a lighted one.
The researchers found that the highly stress-susceptible mice had less of an important molecule known as mGlu2 in a stress-involved region of the brain known as the hippocampus. The mGlu2 decrease, they determined, resulted from an epigenetic change, which affects the expression of genes, in this case the gene that codes for mGlu2.
“If you think of the genetic code as words in a book, the book must be opened in order for you to read it. These epigenetic changes, which affect histone proteins associated with DNA, effectively close the book, so the code for mGlu2 cannot be read,” says first author Carla Nasca, a postdoc in the lab and a fellow of the American Foundation for Suicide Prevention. Previously, she and colleagues implicated mGlu2 in depression when they showed that a promising potential treatment known as acetyl carnitine rapidly alleviated depression-like symptoms in rats and mice by reversing these epigenetic changes to mGlu2 and causing its levels to increase.
“Currently, depression is diagnosed only by its symptoms,” Nasca says. “But these results put us on track to discover molecular signatures in humans that may have the potential to serve as markers for certain types of depression. Our work could also lead to a new generation of rapidly acting antidepressants, such as the candidate acetyl carnitine, which would be particularly important to reduce the risk of suicide.”
A reduction in mGlu2 matters because this molecule regulates the neurotransmitter glutamate. While glutamate plays a crucial role relaying messages between neurons as part of many important processes, too much can lead to harmful structural changes in the brain.
“The brain is constantly changing. When stressful experiences lead to anxiety and depressive disorders the brain becomes locked in a state it cannot spontaneously escape,” McEwen says. “Studies like this one are increasingly focusing on the regulation of glutamate as an underlying mechanism in depression and, we hope, opening promising new avenues for the diagnosis and treatment of this devastating disorder.”