Treatment to prevent Alzheimer’s disease moves a step closer

A new drug to prevent the early stages of Alzheimer’s disease could enter clinical trials in a few years’ time according to scientists.

Alzheimer’s is the most common type of dementia, which currently affects 820,000 people in the UK, with numbers expected to more than double by 2050. One in three people over 65 will die with dementia.

The disease begins when a protein called amyloid-β (Aβ) starts to clump together in senile plaques in the brain, damaging nerve cells and leading to memory loss and confusion.

Professor David Allsop and Dr Mark Taylor at Lancaster University have successfully created a new drug which can reduce the number of senile plaques by a third, as well as more than doubling the number of new nerve cells in a particular region of the brain associated with memory.  It also markedly reduced the amount of brain inflammation and oxidative damage associated with the disease.

The drug was tested on transgenic mice containing two mutant human genes linked to inherited forms of Alzheimer’s, so that they would develop some of the changes associated with the illness. The drug is designed to cross the blood-brain barrier and prevent the Aβ molecules from sticking together to form plaques.

Professor Allsop, who led the research and was the first scientist to isolate senile plaques from human brain, said: “When we got the test results back, we were highly encouraged. The amount of plaque in the brain had been reduced by a third and this could be improved if we gave a larger dose of the drug, because at this stage, we don’t know what the optimal dose is.”

The drug needs to be tested for safety before it can enter human trials, but, if it passes this hurdle, the aim would be to give the drug to people with mild symptoms of memory loss before they develop the illness.

“Many people who are mildly forgetful may go on to develop the disease because these senile plaques start forming years before any symptoms manifest themselves. The ultimate aim is to give the drug at that stage to stop any more damage to the brain, before it’s too late.”

Support for the research was given by Alzheimer’s Research UK, and the results are published in the open access journal PLOS ONE.

Scientists Uncover a Previously Unknown Mechanism of Memory Formation

It takes a lot to make a memory. New proteins have to be synthesized, neuron structures altered. While some of these memory-building mechanisms are known, many are not. Some recent studies have indicated that a unique group of molecules called microRNAs, known to control production of proteins in cells, may play a far more important role in memory formation than previously thought.

Now, a new study by scientists on the Florida campus of The Scripps Research Institute has for the first time confirmed a critical role for microRNAs in the development of memory in the part of the brain called the amygdala, which is involved in emotional memory. The new study found that a specific microRNA—miR-182—was deeply involved in memory formation within this brain structure.

“No one had looked at the role of microRNAs in amygdala memory,” said Courtney Miller, a TSRI assistant professor who led the study. “And it looks as though miR-182 may be promoting local protein synthesis, helping to support the synapse-specificity of memories.”

In the new study, published in the Journal of Neuroscience, the scientists measured the levels of all known microRNAs following an animal model of learning. A microarray analysis, which enables rapid genetic testing on a large scale, showed that more than half of all known microRNAs are expressed in the amygdala. Seven of those microRNAs increased and 32 decreased when learning occurred.

The study found that, of the microRNAs expressed in the brain, miR-182 had one of the lowest levels and these decreased further with learning. Despite these very low levels, its overexpression prevented the formation of memory and led to a decrease in proteins that regulate neuronal plasticity (neurons’ ability to adapt) through changes in structure.

These findings suggest that learning-induced suppression of miR-182 is a main supporting factor in the formation of long-term memory in the amagdala, as well as an underappreciated mechanism for regulating protein synthesis during memory consolidation, Miller said.

Further analysis identified miR-182 as a repressor of proteins that control actin—a major component of the cytoskeleton, the scaffolding that holds cells together.

“We know that memory formation requires changes in dendritic spines on the neurons through regulation of the actin cytoskeleton,” Miller said. “When miR-182 is suppressed through learning it halts, at least in part, repression of actin-regulating proteins, so there’s a good chance that miR-182 exerts important control over the actin cytoskeleton.”

Miller is now interested in whether or not high levels of miR-182 accumulate in the aging brain, something that would help to explain a tendency toward memory loss in the elderly. She also notes that other research has shown that animal models lacking miR-182 had no significant physical or cellular abnormalities, suggesting that miR-182 could be a viable target for drug discovery.

(Image: stockfresh)

In-brain monitoring shows memory network

Working with patients with electrodes implanted in their brains, researchers at the University of California, Davis, and The University of Texas Health Science Center at Houston (UTHealth) have shown for the first time that areas of the brain work together at the same time to recall memories. The unique approach promises new insights into how we remember details of time and place.

"Previous work has focused on one region of the brain at a time," said Arne Ekstrom, assistant professor at the UC Davis Center for Neuroscience. "Our results show that memory recall involves simultaneous activity across brain regions." Ekstrom is senior author of a paper describing the work published Jan. 27 in the journal Nature Neuroscience.

Ekstrom and UC Davis graduate student Andrew Watrous worked with patients being treated for a severe seizure condition by neurosurgeon Dr. Nitin Tandon and his UTHealth colleagues.

To pinpoint the origin of the seizures in these patients, Tandon and his team place electrodes on the patient’s brain inside the skull. The electrodes remain in place for one to two weeks for monitoring.

Six such patients volunteered for Ekstrom and Watrous’ study while the electrodes were in place. Using a laptop computer, the patients learned to navigate a route through a virtual streetscape, picking up passengers and taking them to specific places. Later, they were asked to recall the routes from memory.

Correct memory recall was associated with increased activity across multiple connected brain regions at the same time, Ekstrom said, rather than activity in one region followed by another.

However, the analysis did show that the medial temporal lobe is an important hub of the memory network, confirming earlier studies, he said.

Intriguingly, memories of time and of place were associated with different frequencies of brain activity across the network. For example, recalling, “What shop is next to the donut shop?” set off a different frequency of activity from recalling “Where was I at 11 a.m.?”

Using different frequencies could explain how the brain codes and recalls elements of past events such as time and location at the same time, Ekstrom said.

"Just as cell phones and wireless devices work at different radio frequencies for different information, the brain resonates at different frequencies for spatial and temporal information," he said.

The researchers hope to explore further how the brain codes information in future work.

The neuroscientists analyzed their results with graph theory, a new technique that is being used for studying networks, ranging from social media connections to airline schedules.

"Previously, we didn’t have enough data from different brain regions to use graph theory. This combination of multiple readings during memory retrieval and graph theory is unique," Ekstrom said.

Placing electrodes inside the skull provides clearer resolution of electrical signals than external electrodes, making the data invaluable for the study of cognitive functions, Tandon said. “This work has yielded important insights into the normal mechanisms underpinning recall, and provides us with a framework for the study of memory dysfunction in the future.”

Research Institute Study Shows How Brain Cells Shape Temperature Preferences

While the wooly musk ox may like it cold, fruit flies definitely do not. They like it hot, or at least warm. In fact, their preferred optimum temperature is very similar to that of humans—76 degrees F.

Scientists have known that a type of brain cell circuit helps regulate a variety of innate and learned behavior in animals, including their temperature preferences. What has been a mystery is whether or not this behavior stems from a specific set of neurons (brain cells) or overlapping sets.

Now, a new study from The Scripps Research Institute (TSRI) shows that a complex set of overlapping neuronal circuits work in concert to drive temperature preferences in the fruit fly Drosophila by affecting a single target, a heavy bundle of neurons within the fly brain known as the mushroom body. These nerve bundles, which get their name from their bulbous shape, play critical roles in learning and memory.

The study, published in the January 30, 2013 edition of the Journal of Neuroscience, shows that dopaminergic circuits—brain cells that synthesize dopamine, a common neurotransmitter—within the mushroom body do not encode a single signal, but rather perform a more complex computation of environmental conditions.

“We found that dopamine neurons process multiple inputs to generate multiple outputs—the same set of nerves process sensory information and reward-avoidance learning,” said TSRI Assistant Professor Seth Tomchik. “This discovery helps lay the groundwork to better understand how information is processed in the brain. A similar set of neurons is involved in behavior preferences in humans—from basic rewards to more complex learning and memory.”

Using imaging techniques that allow scientists to visualize neuron activity in real time, the study illuminated the response of dopaminergic neurons to changes in temperature. The behavioral roles were then examined by silencing various subsets of these neurons. Flies were tested using a temperature gradient plate; the flies moved from one place to another to express their temperature preferences.

As it turns out, genetic silencing of dopaminergic neurons innervating the mushroom body substantially reduces cold avoidance behavior. “If you give the fly a choice, it will pick San Diego weather every time,” Tomchik said, “but if you shut down those nerves, they suddenly don’t mind being in Minnesota.”

The study also showed dopaminergic neurons respond to cooling with sudden a burst of activity at the onset of a drop in temperature, before settling down to a lower steady-state level. This initial burst of dopamine could function to increase neuronal plasticity—the ability to adapt—during periods of environmental change when the organism needs to acquire new associative memories or update previous associations with temperature changes.

(Image: ALAMY)

Neuroscientists pinpoint location of fear memory in amygdala

A rustle of undergrowth in the outback: it’s a sound that might make an animal or person stop sharply and be still, in the anticipation of a predator. That “freezing” is part of the fear response, a reaction to a stimulus in the environment and part of the brain’s determination of whether to be afraid of it.

A neuroscience group at Cold Spring Harbor Laboratory (CSHL) led by Assistant Professor Bo Li Ph.D., together with collaborator Professor Z. Josh Huang Ph.D., today release the results of a new study that examines the how fear responses are learned, controlled, and memorized. They show that a particular class of neurons in a subdivision of the amygdala plays an active role in these processes.

Locating fear memory in the amygdala

Previous research had indicated that structures inside the amygdalae, a pair of almond-shaped formations that sit deep within the brain and are known to be involved in emotion and reward-based behavior, may be part of the circuit that controls fear learning and memory. In particular, a region called the central amygdala, or CeA, was thought to be a passive relay for the signals relayed within this circuit.

Li’s lab became interested when they observed that neurons in a region of the central amygdala called the lateral subdivision, or CeL, “lit up” in a particular strain of mice while studying this circuit.

“Neuroscientists believed that changes in the strength of the connections onto neurons in the central amygdala must occur for fear memory to be encoded,” Li says, “but nobody had been able to actually show this.”

This led the team to further probe into the role of these neurons in fear responses and furthermore to ask the question: If the central amygdala stores fear memory, how is that memory trace read out and translated into fear responses?

To examine the behavior of mice undergoing a fear test the team first trained them to respond in a Pavlovian manner to an auditory cue. The mice began to “freeze,” a very common fear response, whenever they heard one of the sounds they had been trained to fear.

To study the particular neurons involved, and to understand them in relation to the fear-inducing auditory cue, the CSHL team used a variety of methods. One of these involved delivering a gene that encodes for a light-sensitive protein into the particular neurons Li’s group wanted to look at.

By implanting a very thin fiber-optic cable directly into the area containing the photosensitive neurons, the team was able to shine colored laser light with pinpoint accuracy onto the cells, and in this manner activate them. This is a technique known as optogenetics. Any changes in the behavior of the mice in response to the laser were then monitored.

A subset of neurons in the central amygdala controls fear expression

The ability to probe genetically defined groups of neurons was vital because there are two sets of neurons important in fear-learning and memory processes. The difference between them, the team learned, was in their release of message-carrying neurotransmitters into the spaces called synapses between neurons. In one subset of neurons, neurotransmitter release was enhanced; in another it was diminished. If measurements had been taken across the total cell population in the central amygdala, neurotransmitter levels from these two distinct sets of neurons would have been averaged out, and thus would not have been detected.

Li’s group found that fear conditioning induced experience-dependent changes in the release of neurotransmitters in excitatory synapses that connect with inhibitory neurons – neurons that suppress the activity of other neurons – in the central amygdala. These changes in the strength of neuronal connections are known as synaptic plasticity.

Particularly important in this process, the team discovered, were somatostatin-positive (SOM+) neurons. Somatostatin is a hormone that affects neurotransmitter release. Li and colleagues found that fear-memory formation was impaired when they prevent the activation of SOM+ neurons.

SOM+ neurons are necessary for recall of fear memories, the team also found. Indeed, the activity of these neurons alone proved sufficient to drive fear responses. Thus, instead of being a passive relay for the signals driving fear learning and responses in mice, the team’s work demonstrates that the central amygdala is an active component, and is driven by input from the lateral amygdala, to which it is connected.

“We find that the fear memory in the central amygdala can modify the circuit in a way that translates into action — or what we call the fear response,” explains Li.

In the future Li’s group will try to obtain a better understanding of how these processes may be altered in post-traumatic stress disorder (PTSD) and other disorders involving abnormal fear learning. One important goal is to develop pharmacological interventions for such disorders.

Li says more research is needed, but is hopeful that with the discovery of specific cellular markers and techniques such as optogenetics, a breakthrough can be made.

Poor sleep in old age prevents the brain from storing memories

The connection between poor sleep, memory loss and brain deterioration as we grow older has been elusive. But for the first time, scientists at the University of California, Berkeley, have found a link between these hallmark maladies of old age. Their discovery opens the door to boosting the quality of sleep in elderly people to improve memory.

UC Berkeley neuroscientists have found that the slow brain waves generated during the deep, restorative sleep we typically experience in youth play a key role in transporting memories from the hippocampus – which provides short-term storage for memories – to the prefrontal cortex’s longer term “hard drive.”

However, in older adults, memories may be getting stuck in the hippocampus due to the poor quality of deep ‘slow wave’ sleep, and are then overwritten by new memories, the findings suggest.

“What we have discovered is a dysfunctional pathway that helps explain the relationship between brain deterioration, sleep disruption and memory loss as we get older – and with that, a potentially new treatment avenue,” said UC Berkeley sleep researcher Matthew Walker, an associate professor of psychology and neuroscience at UC Berkeley and senior author of the study published in the journal Nature Neuroscience.

Learning and Memory May Play a Central Role in Synesthesia

People with color-grapheme synesthesia experience color when viewing written letters or numerals, usually with a particular color evoked by each grapheme (i.e., the letter ‘A’ evokes the color red). In a new study, researchers Nathan Witthoft and Jonathan Winawer of Stanford University present data from 11 color grapheme synesthetes who had startlingly similar color-letter pairings that were traceable to childhood toys containing magnetic colored letters.

Their findings are published in Psychological Science, a journal of the Association for Psychological Science.

Matching data from the 11 participants showed reliably consistent letter-color matches, both within and between testing sessions (data collected online at http://www.synesthete.org/). Participants’ matches were consistent even after a delay of up to seven years since their first session.

Participants also performed a timed task, in which they were presented with colored letters for 1 second each and required to indicate whether the color was consistent with their synesthetic association. Their data show that they were able to perform the task rapidly and accurately.

Together, these data suggest that the participants’ color-letter associations are specific, automatic, and relatively constant over time, thereby meeting the criteria for true synesthesia.

The degree of similarity in the letter-color pairings across participants, along with the regular repeating pattern in the colors found in each individual’s letter-color pairings, indicates that the pairings were learned from the magnetic colored letters that the participants had been exposed to in childhood.

According to the researchers, these are the first and only data to show learned synesthesia of this kind in more than a single individual.

They point out that this does not mean that exposure to the colored letter magnets was sufficient to induce synesthesia in the participants, though it may have increased the chances. After all, many people who do not have synesthesia played with the same colored letter magnets as kids.

Based on their findings, Witthoft and Winawer conclude that a complete explanation of synesthesia must incorporate a central role for learning and memory.

(Image: Shutterstock)

Pavlov’s Rats? Rodents Trained to Link Rewards to Visual Cues

In experiments on rats outfitted with tiny goggles, scientists say they have learned that the brain’s initial vision processing center not only relays visual stimuli, but also can “learn” time intervals and create specifically timed expectations of future rewards. The research, by a team at the Johns Hopkins University School of Medicine and the Massachusetts Institute of Technology, sheds new light on learning and memory-making, the investigators say, and could help explain why people with Alzheimer’s disease have trouble remembering recent events.

Results of the study, in the journal Neuron, suggest that connections within nerve cell networks in the vision-processing center can be strengthened by the neurochemical acetylcholine (ACh), which the brain is thought to secrete after a reward is received. Only nerve cell networks recently stimulated by a flash of light delivered through the goggles are affected by ACh, which in turn allows those nerve networks to associate the visual cue with the reward. Because brain structures are highly conserved in mammals, the findings likely have parallels in humans, they say.

“We’ve discovered that nerve cells in this part of the brain, the primary visual cortex, seem to be able to develop molecular memories, helping us understand how animals learn to predict rewarding outcomes,” says Marshall Hussain Shuler, Ph.D., assistant professor of neuroscience at the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.

To maximize survival, an animal’s brain has to remember what cues precede a positive or negative event, allowing the animal to alter its behavior to increase rewards and decrease mishaps. In the Hopkins-MIT study, the researchers sought clarity about how the brain links visual information to more complex information about time and reward.

The presiding theory, Hussain Shuler says, assumed that this connection was made in areas devoted to “high-level” processing, like the frontal cortex, which is known to be important for learning and memory. The primary visual cortex seemed to simply receive information from the eyes and “re-piece” the visual world together before presenting it to decision-making parts of the brain.

Reviewing alcohol’s effects on normal sleep

Sleep is supported by natural cycles of activity in the brain and consists of two basic states: rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. Typically, people begin the sleep cycle with NREM sleep followed by a very short period of REM sleep, then continue with more NREM sleep and more REM sleep, this 90 minute cycle continuing through the night. A review of all known scientific studies on the impact of drinking on nocturnal sleep has clarified that alcohol shortens the time it takes to fall asleep, increases deep sleep, and reduces REM sleep.

Results will be published in the April 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"This review has for the first time consolidated all the available literature on the immediate effects of alcohol on the sleep of healthy individuals," said Irshaad Ebrahim, medical director at The London Sleep Centre as well as corresponding author for the study.

"Certainly a mythology seems to have developed around the impact of alcohol on sleep," added Chris Idzikowski, director of the Edinburgh Sleep Centre. "It is a good time to review the research as the mythology seems to be flourishing more rapidly than the research itself. Also, our understanding of sleep has accelerated in the past 30 years, which has meant that some of the initial interpretations need to be revisited."

Some of the review’s key themes are:

• At all dosages, alcohol causes a reduction in sleep onset latency, a more consolidated first half sleep, and an increase in sleep disruption in the second half of sleep.

  "This review confirms that the immediate and short-term impact of alcohol is to reduce the time it takes to fall asleep," said Ebrahim. "In addition, the higher the dose, the greater the impact on increasing deep sleep. This effect on the first half of sleep may be partly the reason some people with insomnia use alcohol as a sleep aid. However, the effect of consolidating sleep in the first half of the night is offset by having more disrupted sleep in the second half of the night."

• The majority of studies, across alcohol dose, age, and gender, confirm an increase in slow-wave sleep (SWS) in the first half of the night. SWS, often referred to as deep sleep, consists of stages 3 and 4 of NREM. During SWS, the body repairs and regenerates tissues, builds bone and muscle, and appears to strengthen the immune system. Alcohol’s impact on SWS in the first half of the night appears to be more robust than its effect on REM sleep.

  "SWS or deep sleep generally promotes rest and restoration," said Ebrahim. "However, when alcohol increases SWS, this may also increase vulnerability to certain sleep problems such as sleepwalking or sleep apnoea in those who are predisposed."

• Alcohol’s effects on REM sleep in the first half of sleep appear to be dose related. Low and moderate doses show no clear effects on REM sleep in the first half of the night, whereas at high doses, REM sleep reduction in the first part of sleep is significant. Total night REM sleep percent is decreased in the majority of studies at moderate and high doses.

  "Dreams generally occur in the REM stage of sleep," said Ebrahim. "During REM sleep the brain is more active, and may be regarded as ‘defragmenting the drive.’ REM sleep is also important because it can influence memory and serve restorative functions. Conversely, lack of REM sleep can have a detrimental effect on concentration, motor skills, and memory. REM sleep typically accounts for 20 to 25 percent of the sleep period."

• The onset of the first REM sleep period is significantly delayed at all doses and appears to be the most recognizable effect of alcohol on REM sleep, followed by a reduction in total night REM sleep.

"One consequence of a delayed onset of the first REM sleep would be less restful sleep," said Idzikowski. "The first REM episode is often delayed in stressful environments. There is also a linkage with depression."