Life presents us with choices all the time: salad or pizza for lunch? Tea or coffee afterward? How we make these everyday decisions has been a topic of great interest to economists, who have devised theories about how we assign values to our options and use those values to make decisions.

An emerging field of study known as neuroeconomics is combining the economists’ insights with scientific study of the brain to learn more about decision-making processes and how they can go awry. In the Dec. 8 issue of Neuron, one of the field’s founders reports new links between brain cell activity and choices where two options have equal appeal.

“Neuroeconomics is not only helpful for the development of better economic theory, it is also relevant from a clinical point of view,” said author Camillo Padoa-Schioppa, PhD, assistant professor of neurobiology, economics and of biomedical engineering at Washington University School of Medicine in St. Louis. “There are a number of conditions that involve impaired economic decision-making, including drug addiction, brain injury, some forms of dementia, schizophrenia and obsessive-compulsive disorder.”

Scientists know that the orbitofrontal cortex, a region of the brain behind and above the eyes, plays a key role in making decisions. Patients with injuries to this part of the brain are often spectacularly bad at making decisions. They may do things like abandon longstanding relationships, gamble away money or lose it to swindlers, or become addicted to drugs.

To study the roles brain cells play in decision-making, Padoa-Schioppa developed a system for presenting primates a choice between two drinks, such as grape juice or apple juice. The type and amount of the drink varies, and researchers record the activity of individual brain neurons as the primates choose.

Based on the decisions of a single animal over multiple trials, scientists infer the subjective value the animal assigns to each drink and then look for ways this value is encoded in brain cells.

“For example, if we offer a larger amount of apple juice versus a smaller amount of grape juice, and the primate chooses each option equally often, we infer that this primate likes the grape juice better than the apple juice,” he explained. “The primate could be getting more juice by choosing the cup with apple juice, but it doesn’t always do so. That implies that the primate values grape juice more than apple juice.”

In 2006, Padoa-Schioppa and Harvard colleague John Assad, PhD, won international attention for using this system to identify brain cells whose firing rates encoded the subjective value of drink choices.

In a new analysis of data from the original experiment, Padoa-Schioppa showed that different groups of cells in the orbitofrontal cortex reflect different stages of the decision-making process.

“Some neurons encode the value of individual drinks; other neurons encode the choice outcome in a binary way ‒ these cells are either firing or silent depending on the chosen drink,” he explained. “Yet other neurons encode the value of the chosen option.”

Padoa-Schioppa then examined how different groups of cells determine decisions between options of equal value. He showed that toss-up decisions seemed to depend on changes in the initial state of the network of neurons in the orbitofrontal cortex.

“The fluctuations in the network took place before the primates were even offered a choice of juices, but they seem to somehow bias the decision,” Padoa-Schioppa said. “Neuronal signals are always noisy. In essence, close-call decisions are partly determined by random noise.”

He also found that decisions on choices of equal value were linked to the ease or difficulty with which nerve cells in parts of the orbitofrontal cortex communicate with each other. This property, known as synaptic efficacy, can be adjusted by the brain as part of the process of encoding information.

According to Padoa-Schioppa, these results provide new insights into the neuronal circuits that underlie economic decisions. He and his colleagues are using them to create a computational model of decision-making.

“The next step is to test that model,” Padoa-Schioppa said. “For example, we would like to bias decisions by artificially manipulating the activity of specific groups of cells.”

(Source: news.wustl.edu)

Researchers from the University of Bonn use reprogrammed patient neurons for drug testing

Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise LIFE & BRAIN GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal “Stem Cell Reports”.

In the brains of Alzheimer patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.

"The reasons for these negative results have remained unclear for a long time", says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of LIFE & BRAIN GmbH. "Remarkably, these compounds were never tested directly on the actual target cells – the human neuron", adds lead author Dr. Jerome Mertens of Prof. Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.

Scientists transform skin cells into nerve cells

Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the LIFE & BRAIN GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting so-called “jack-of-all-trades cells” into nerve cells.

Using these human neurons, the scientists tested several compounds in the group of non-steroidal anti-inflammatory drugs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.

Metabolic processes in animal models differ from humans

"In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells", concludes Prof. Brüstle’s colleague Dr. Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. "The results are simply not transferable", says Dr. Koch.

The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, says Prof. Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.

(Source: www3.uni-bonn.de)

The body is structured to ensure that any invading organisms have a tough time reaching the brain, an organ obviously critical to survival. Known as the blood-brain barrier, cells that line the brain and spinal cord are tightly packed, making it difficult for anything besides very small molecules to cross from the bloodstream into the central nervous system. While beneficial, this blockade also stands in the way of delivering drugs intended to treat neurological disorders, such as Alzheimer’s.

In a new study published in the journal Molecular Therapy, University of Pennsylvania researchers have found a way of traversing the blood-brain barrier, as well as a similar physiological obstacle in the eye, the retinal-blood barrier. By pairing a receptor that targets neurons with a molecule that degrades the main component of Alzheimer’s plaques, the biologists were able to substantially dissolve these plaques in mice brains and human brain tissue, offering a potential mechanism for treating the debilitating disease, as well as other conditions that involve either the brain or the eyes.

The work was led by Henry Daniell, a professor in Penn’s School of Dental Medicine’s departments of biochemistry and pathology and director of translational research. The research team included Penn Dental Medicine’s Neha Kohli, Donevan R. Westerveld, Alexandra C. Ayache and Sich L. Chan. Co-authors at the University of Florida College of Medicine, including Amrisha Verma, Pollob Shil, Tuhina Prasad, Ping Zhu and Quihong Li, analyzed retinal tissues. 

The researchers began their work by considering how they might breach the blood-brain barrier. Daniell hypothesized that a molecule might be permitted to cross if it was attached to a carrier that is able to pass over, as a sort of molecular crossing guard. The protein cholera toxin B, or CTB, a non-toxic carrier currently approved for use in humans by the Food and Drug Administration, is used in this study to traverse the blood-brain barrier.

They next identified a protein that could clear the plaques that are found in the brains of Alzheimer’s patients. These plaques, which are believed to cause the dementia associated with the disease, are made up of tangles of amyloid beta (Aβ), a protein that is found in soluble form in healthy individuals. Noting that myelin basic protein (MBP) has been shown to degrade Aβ chains, the team decided to couple it with CTB to see if MBP would be permitted to cross.

“These tangles of beta amyloid are known to be the problem in Alzheimer’s,” says Daniell. “So our idea was to chop the protein back to their normal size so they wouldn’t form these tangles.”

To test this idea, the Penn-led team first exposed healthy mice to the CTB-MBP compound by feeding them capsules of freeze-dried leaves that had been genetically engineered to express the fused proteins, a method developed and perfected by Daniell over many years as a means of orally administering various drugs and vaccines. Adding a green-fluorescent protein to the CTB carrier, the researchers tracked the “glow” to see where the mice took up the protein. They found the glowing protein in both the brain and retina.

“When we found the glowing protein in the brain and the retina we were quite thrilled,” said Daniell. “If the protein could cross the barrier in healthy mice, we thought it was likely that it could cross in Alzheimer’s patients brains, because their barrier is somewhat impaired.”

When CTB was not part of the fused protein, they did not see this expression, suggesting that their carrier protein, the crossing guard, was an essential part of delivering their protein of interest.

To then see what MBP would do once it got to the brain, Daniell and colleagues exposed the CTB-MBP protein to the brains of mice bred to have an Alzheimer’s disease. They used a stain that binds to the brain plaques and found that exposure to the CTB-MBP compound resulted in reductions of staining up to 60 percent, indicating that the plaques were dissolving.

Gaining confidence that their compound was appropriately targeting the plaques, the researchers worked with the National Institutes of Health to obtain brain tissue from people who died of Alzheimer’s and performed the same type of staining. Their results showed a 47 percent decrease in staining in the inferior parietal cortex, a portion of the brain found to play an important role in the development of Alzheimer’s-associated dementia.

As a final step, the researchers fed the CTB-MBP-containing capsules to 15-month-old mice, the equivalent of 80 or more human years, bred to develop Alzheimer’s disease. After three months of feeding, the mice had reductions in Aβ plaques of up to 70 percent in the hippocampus and up to 40 percent in the cortex, whereas mice fed capsules that contained lettuce leaves without CTB-MBP added and mice that were not fed any capsules did not have any reduction in evidence of brain plaques.

Because Alzheimer’s patients have also been found to have plaques in their eyes, the researchers examined the eyes of the mice fed the protein. They found that, indeed, the Alzheimer’s-mice did have retinal plaques, but those fed the CBP-MBP compound had undetectable Aβ plaques in their retinae.

“Really no one knows whether the memory problems that people who have Alzheimer’s disease are due to the dementia or problems with their eyes,” Daniell said. “Here we show it may be both, and that we can dissolve the plaques through an oral route.”

Daniell hopes that this technique of delivering proteins across the blood-brain and blood-retina barriers could serve to treat a variety of diseases beyond Alzheimer’s. Several current clinical trials have failed because of an inability to deliver drugs to the brain.  Currently, treatments of some eye conditions must physically penetrate the retina with an injection, an approach that requires anesthesia and risks retinal detachment. Treatment with an ingestible capsule would be safer, easier, and more cost-effective.

As a next step, Daniell hopes to collaborate with Alzheimer’s experts at Penn to advance these studies and add a behavioral component to determine whether the CBP-MBP compound not only removes plaques but also improves the memory and functioning of mice with the Alzheimer’s disease.

A discovery by Emory Alzheimer’s Disease Research Center and Scripps Research Institute scientists could lead to drugs that slow Alzheimer’s disease progression.

A straightforward drug strategy against Alzheimer’s is to turn down the brain’s production of beta-amyloid, the key component of the disease’s characteristic plaques. A toxic fragment of a protein found in healthy brains, beta-amyloid accumulates in the brains of people affected by the disease.

The enzyme that determines how much beta-amyloid brain cells generate is called BACE (beta-secretase or beta-site APP cleaving enzyme). Yet finding drugs that inhibit that elusive enzyme has been far from straightforward.

Now researchers have identified a way to shut down production of beta-amyloid by diverting BACE to a different part of the cell and inhibiting its activity. The results were published this week in Journal of Neuroscience.

"This is an indirect but highly effective way of blocking BACE, which controls the chokepoint step in beta-amyloid production," says lead author Jeremy Herskowitz, PhD, instructor in neurology at Emory’s Alzheimer’s Disease Research Center.

"Jeremy has found a promising approach toward reducing beta-amyloid production and potentially modifying Alzheimer’s disease progression, something for which there is immense need," says senior author James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Drugs that reduce beta-amyloid production would probably be mostly preventive. However, since amyloid-beta is toxic, such drugs could have some immediate effect on cognitive impairment."

In the paper, Herskowitz and his colleagues demonstrate that a specific inhibitor of the enzyme ROCK2 can cut beta-amyloid production in brain cells by more than 75 percent. Co-author Yangbo Feng, PhD, associate director of medicinal chemistry at Scripps Research Institute in Florida, previously discovered the ROCK2 inhibitor, called SR3677.

Alzheimer’s researchers were already interested in ROCK2 and a related enzyme, ROCK1, because of a connection with NSAIDs (non-steroid anti-inflammatory drugs) such as ibuprofen. Some NSAIDS can inhibit production of a particularly toxic form of beta-amyloid, and scientists believed NSAIDs were exerting their effects through the ROCKs.

Herskowitz first showed that in cultured cells, “knocking down” the ROCK2 gene reduced beta-amyloid production, but knocking down ROCK1 had the opposite effect.

"This says that anytime you’re hitting both ROCKs at once, the effects cancel each other out," he says.

The known drugs that affect the ROCKs seemed to affect both and thus have diminished effects. In contrast, SR3677 inhibits ROCK2 much more effectively than ROCK1, and it offered a way around the obstacle. Herskowitz found that by inhibiting ROCK2, SR3677 diverts BACE to a different part of the cell, where it is less likely to act on beta-amyloid’s parent protein.

He and ADRC colleagues found that ROCK2 levels are higher than usual in tissue samples from brains of patients with Alzheimer’s, including those with mild cognitive impairment, thought to be a precursor stage of the disease.

"There is plenty of ROCK2 in the brain, and its levels are elevated in Alzheimer’s patients, indicating that it’s an excellent drug target," Herskowitz says. "We are eager to pursue more extensive studies of this strategy in animal models of Alzheimer’s."

SR3677 can substantially inhibit beta-amyloid production in an animal model of Alzheimer’s, but so far, this effect has been observed when the drug is injected directly into the brain. More studies are required to learn if SR3677 or related drugs can pass the blood-brain barrier and thus be given by injection or orally, and what side effects could appear. ROCK inhibitors are also being investigated for treating other conditions such as glaucoma, hypertension and multiple sclerosis. 

(Source: news.emory.edu)

Using a powerful gene-hunting technique for the first time in mammalian brain cells, researchers at Johns Hopkins report they have identified a gene involved in building the circuitry that relays signals through the brain. The gene is a likely player in the aging process in the brain, the researchers say. Additionally, in demonstrating the usefulness of the new method, the discovery paves the way for faster progress toward identifying genes involved in complex mental illnesses such as autism and schizophrenia — as well as potential drugs for such conditions. A summary of the study appears in the Dec. 12 issue of Cell Reports.

(Image: A mouse neuron with synapses shown: Red dots mark excitatory synapses, while green dots mark so-called inhibitory synapses. Credit: Kamal Sharma/Johns Hopkins University School of Medicine)

“We have been looking for a way to sift through large numbers of genes at the same time to see whether they affect processes we’re interested in,” says Richard Huganir, Ph.D., director of the Johns Hopkins University Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, who led the study. “By adapting an automated process to neurons, we were able to go through 800 genes to find one needed for forming synapses — connections — among those cells.”

Although automated gene-sifting techniques have been used in other areas of biology, Huganir notes, many neuroscience studies instead build on existing knowledge to form a hypothesis about an individual gene’s role in the brain. Traditionally, researchers then disable or “knock out” the gene in lab-grown cells or animals to test their hypothesis, a time-consuming and laborious process.

In this study, Huganir’s group worked to test many genes all at once using plastic plates with dozens of small wells. A robot was used to add precise allotments of cells and nutrients to each well, along with molecules designed to knock out one of the cells’ genes — a different one for each well.

“The big challenge was getting the neurons, which are very sensitive, to function under these automated conditions,” says Kamal Sharma, Ph.D., a research associate in Huganir’s group. The team used a trial-and-error approach, adjusting how often the nutrient solution was changed and adding a washing step, and eventually coaxed the cells to thrive in the wells. In addition, Sharma says, they fine-tuned an automated microscope used to take pictures of the circuitry that had formed in the wells and calculated the numbers of synapses formed among the cells.

The team screened 800 genes in this way and found big differences in the well of cells with a gene called LRP6 knocked out. LRP6 had previously been identified as a player in a biochemical chain of events known as the Wnt pathway, which controls a range of processes in the brain. Interestingly, Sharma says, the team found that LRP6 was only found on a specific kind of synapse known as an excitatory synapse, suggesting that it enables the Wnt pathway to tailor its effects to just one synapse type.

“Changes in excitatory synapses are associated with aging, and changes in the Wnt pathway in later life may accelerate aging in general. However, we do not know what changes take place in the synaptic landscape of the aging brain. Our findings raise intriguing questions: Is the Wnt pathway changing that landscape, and if so, how?” says Sharma. “We’re interested in learning more about what other proteins LRP6 interacts with, as well as how it acts in different types of brain cells at different developmental stages of circuit development and refinement.”

Another likely outcome of the study is wider use of the gene-sifting technique, he says, to explore the genetics of complex mental illnesses. The automated method could also be used to easily test the effects on brain cells of a range of molecules and see which might be drug candidates.

While the human brain is in a resting state, patterns of neuronal activity which are associated to specific memories may spontaneously reappear. Such recurrences contribute to memory consolidation – i.e. to the stabilization of memory contents. Scientists of the DZNE and the University of Bonn are reporting these findings in the current issue of The Journal of Neuroscience. The researchers headed by Nikolai Axmacher performed a memory test on a series of persons while monitoring their brain activity by functional magnetic resonance imaging (fMRI). The experimental setup comprised several resting states including a nap inside a neuroimaging scanner. The study indicates that resting periods can generally promote memory performance.

Depending on one’s mood and activity different regions are active in the human brain. Perceptions and thoughts also influence this condition and this results in a pattern of neuronal activity which is linked to the experienced situation. When it is recalled, similar patterns, which are slumbering in the brain, are reactivated. How this happens, is still largely unknown.

The prevalent theory of memory formation assumes that memories are stored in a gradual manner. At first, the brain stores new information only temporarily. For memories to remain in the long term, a further step is required. „We call it consolidation“, Dr. Nikolai Axmacher explains, who is a researcher at the Department of Epileptology of the University of Bonn and at the Bonn site of the DZNE. “We do not know exactly how this happens. However, studies suggest that a process we call reactivation is of importance. When this occurs, the brain replays activity patterns associated with a particular memory. In principle, this is a familiar concept. It is a fact that things that are actively repeated and practiced are better memorized. However, we assume that a reactivation of memory contents may also happen spontaneously without there being an external trigger.”

A memory test inside the scanner
Axmacher and his team tested this hypothesis in an experiment that involved ten healthy participants with an average age of 24 years. They were shown a series of pictures, which displayed – among other things – frogs, trees, airplanes and people. Each of these pictures was associated with a white square as a label at a different location. The subjects were asked to memorize the position of the square. At the end of the experiment all images were shown again, but this time without the label. The study participants were then asked to indicate with a mouse cursor where the missing mark was originally located. Memory performance was measured as the distance between the correct and the indicated position.

“This is an associative task. Visual and spatial perceptions have to be linked together”, the researcher explains. “Such tasks involve several brain regions. These include the visual cortex and the hippocampus, which takes part in many memory processes.”

Brain activity was recorded by fMRI during the entire experiment, which lasted several hours and included resting periods and a nap inside the neuroimaging scanner.

Recurrent brain patterns increased the accuracy
For data processing a pattern recognition algorithm was trained to look for similarities between neuronal patterns observed during initial encoding and patterns appearing at later occasions. “This method is complex, but quite effective”, Axmacher says. “Analysis showed that neuronal activity associated with images that were shown initially did reappear during subsequent resting periods and in the sleeping phase.”

Memory performance correlated with the replay of neuronal activity patterns. “The more frequently a pattern had reappeared, the more accurate test participants could label the corresponding image”, Axmacher summarizes the findings. “These results support our assumption that neural patterns can spontaneously reappear and that they promote the formation of long-lasting memory contents. There was already evidence for this from animal studies. Our experiment shows that this phenomenon also happens in humans.”

Memory performance benefits from resting periods
The study indicates that resting periods can generally foster memory performance. “Though, our data did not show whether sleeping had a particular effect. This may be due to the experimental setup, which only allowed for a comparatively short nap”, Axmacher reckons. “By contrast, night sleep is considered to be beneficial for the consolidation of memory contents. But it usually takes many hours and includes multiple transitions between different stages of sleep. However, other studies suggest that even short naps may positively affect memory consolidation.”

An objective look at memory contents
It is up to speculation whether the recurring brain patterns triggered conscious memories or whether they remained below the threshold of perception. “I think it is reasonable to assume that during resting periods the test participants let their mind wander and that they recalled images they had just seen before. But this is a matter of subjective perception of the test participants. That’s something we did not look at because it is not essential for our investigation“, Axmacher says. “The strength of our approach lies rather in the fact that we look at memory contents from the outside, in an objective manner. And that we can evaluate them by pattern recognition. This opens ways to many questions of research. For example, brain patterns that reoccur spontaneously are also of interest in the context of experimental dream research.”

(Source: dzne.de)