Posts tagged science

Blood-circulating immune cells can take over the essential immune surveillance of the brain, this is shown by scientists of the German Center for Neurodegenerative Diseases (DZNE) and the Hertie Institute for Clinical Brain Research in Tübingen. Their study, now published in PNAS, might indicate new ways of dealing with diseases of the nervous system.

The immune system is comprised of multiple cell types each capable of specialized functions to protect the body from invading pathogens and promote tissue repair after injury. One cell type, known as monocytes, circulates throughout the organism in the blood and enters tissues to actively phagocytose (eat!) foreign cells and assist in tissue healing. While monocytes can freely enter most bodily tissues, the healthy, normal brain is different as it is sequestered from circulating blood by a tight network of cells known as the blood brain barrier. Thus, the brain must maintain a highly specialized, resident immune cell, known as microglia, to remove harmful invaders and respond to tissue damage.

In certain situations, such as during disease, monocytes can enter the brain and also contribute to tissue repair or disease progression. However, the potential for monocytes to actively replace old or injured microglia is under considerable debate. To address this, Nicholas Varvel, Stefan Grathwohl and colleagues from the German Center for Neurodegenerative Diseases (DZNE) Tübingen and the Hertie Institute for Clinical Brain Research in Tübingen used a transgenic mouse model in which almost all brain microglia cells (>95%) can be removed within two weeks. This was done by introducing a so-called suicide gene into microglia cells and administering a pharmaceutical agent that leads to acute death of the cells. Surprisingly, after the ablation of the microglia, the brain was rapidly repopulated by blood-circulating monocytes. The monocytes appeared similar, but not identical to resident microglia. The newly populated monocytes, evenly dispersed throughout the brain, responded to acute neuronal injury and other stimuli — all activities normally assumed by microglia. Most interestingly, the monocytes were still present in the brain six months - nearly a quarter of the life of a laboratory mouse - after initial colonization.

These studies now published in PNAS provide evidence that blood-circulating monocytes can replace brain resident microglia and take over the essential immune surveillance of the brain. Furthermore, the findings highlight a strong homeostatic mechanism to maintain a resident immune cell within the brain. The observation that the monocytes took up long-term residence in the brain raises the possibility that these cells can be utilized to deliver therapeutic agents into the diseased brain or replace microglia when they become dysfunctional. Can monocytes be exploited to combat the consequences of Alzheimer’s disease and other neurodegenerative diseases? The scientists and their colleagues in the research groups headed by Mathias Jucker are now following exactly this research avenue.

(Source: dzne.de)

In 1906, when Alois Alzheimer discovered the neurodegenerative disease that would later be named for him, he saw amyloid-beta plaques and neurofibrillary tangles inside the brain. Several decades later, abnormal protein structures called Hirano bodies also were frequently observed in patients with neurodegenerative diseases.

A hundred years and many millions of suffering patients and families later, scientists still don’t know what these structures do. They do know, thanks to new research from the University of Georgia, that Hirano bodies may have a protective role in the brain of Alzheimer’s patients.

Matthew Furgerson, a doctoral candidate in the UGA Franklin College of Arts and Sciences department of biochemistry and molecular biology, used cell culture models to study the role of Hirano bodies in cell death induced by AICD, or a fragment of AICD called c31, that are released inside the cell during cleavage of the amyloid precursor protein. This cleavage also produces amyloid-beta, which forms extracellular plaques.

Furgerson found mixtures of amyloid precursor protein, c31 and tau-the protein that forms the intracellular neurofibrillary tangles-or of AICD and tau cause synergistic cell death that is significantly higher than cell death from amyloid precursor protein, c31, AICD or tau alone.

"This synergistic cell death is very exciting," Furgerson said. "Other groups have shown synergy between extracellular amyloid beta or amyloid precursor protein with tau, but these new results show that there may be an important interaction that occurs inside the cells."

The results of this study were published in the September issue of PLoS One. Ruth Furukawa, associate research scientist, and Marcus Fechheimer, University Professor in cellular biology, are co-authors on the paper.

Furgerson also found cell death is significantly reduced in cells that contain Hirano bodies compared to cells without Hirano bodies. The protective effect of Hirano bodies was observed in cell cultures in both the presence and absence of tau. The findings reveal that Hirano bodies may have a protective role during the progression of Alzheimer’s disease.

While this research offers no cure for the disease, it does offer some understanding about how the disease operates. The lab has been a leader of Hirano body research for more than a decade due to their development of cell culture and mouse model systems.

Before the development of model systems, the only way to study these abnormal structures was in post-mortem brain tissue. The recently developed Hirano body mouse model is currently being used with an Alzheimer’s model mouse to investigate whether cell culture results can translate to a complex animal.

"I feel privileged to lead a team that might be able to contribute knowledge to help us understand Alzheimer’s disease processes," Fechheimer said. "Other groups have focused on plaques and tangles, and we don’t know as much about Hirano bodies. Results from the cell culture studies are exciting and reveal the protective role of Hirano bodies. Our ongoing studies with mouse models are essential to defining the role of Hirano bodies in Alzheimer’s disease progression in a whole animal."

(Source: news.uga.edu)

Perceive first, act afterwards. The architecture of most of today’s robots is underpinned by this control strategy. The eSMCs project has set itself the aim of changing the paradigm and generating more dynamic computer models in which action is not a mere consequence of perception but an integral part of the perception process. It is about improving robot behaviour by means of perception models closer to those of humans.

"The concept of how science understands the mind when it comes to building a robot or looking at the brain is that you take a photo, which is then processed as if the mind were a computer, and a recognition of patterns is carried out. There are various types of algorithms and techniques for identifying an object, scenes, etc. However, organic perception, that of human beings, is much more active. The eye, for example, carries out a whole host of saccadic movements -small rapid ocular movements- that we do not see. Seeing is establishing and recognising objects through this visual action, knowing how the relationship and sensation of my body changes with respect to movement," explains Xabier Barandiaran, a PhD-holder in Philosophy and researcher at IAS-Research (UPV/EHU) which under the leadership of Ikerbasque researcher Ezequiel di Paolo is part of the European project eSMCs (Extending Sensorimotor Contingencies to Cognition).

Until now, the belief has been that sensations were processed, and the perception was created, and this in turn then led to reasoning and action. As Barandiaran sees it, action is an integral part of perception:”Our basic idea is that when we perceive, what is there is active exploration, a particular co-ordination with the surroundings, like a kind of invisible dance than makes vision possible.”

The eSMCs project aims to apply this idea to the computer models used in robots, improve their behaviour and thus understand the nature of the animal and human mind. For this purpose, the researchers are working on sensorimotor contingencies: regular relationships existing between actions and changes in the sensory variations associated with these actions.

An example of this kind of contingency is when you drink water and speak at the same time, almost without realising it. Interaction with the surroundings has taken place “without any need to internally represent that this is a glass and then compute needs and plan an action,” explains Barandiaran, “seeing the glass draws one’s attention, it is coordinated with thirst while the presence of the water itself on the table is enough for me to coordinate the visual-motor cycle that ends up with the glass at my lips.”The same thing happens in the robots in the eSMCs project, “they are moving the whole time, they don’t stop to think; they think about the act using the body and the surroundings,” he adds.

The researchers in the eSMCs project maintain that actions play a key role not only in perception, but also in the development of more complex cognitive capacities. That is why they believe that sensorimotor contingencies can be used to specify habits, intentions, tendencies and mental structures, thus providing the robot with a more complex, fluid behaviour.

So one of the experiments involves a robot simulation (developed by Thomas Buhrmann, who is also a member of this team at the UPV/EHU) in which an agent has to discriminate between what we could call an acne pimple and a bite or lump on the skin.”The acne has a tip, the bite doesn’t. Just as people do, our agent stays with the tip and recognises the acne, and when it goes on to touch the lump, it ignores it. What we are seeking to model and explain is that moment of perception that is built with the active exploration of the skin, when you feel ‘ah! I’ve found the acne pimple’ and you go on sliding your finger across it,” says Barandiaran. The model tries to identify what kind of relationship is established between the movement and sensation cycles and the neurodynamic patterns that are simulated in the robot’s “mini brain”.

In another robot, built at the Artificial Intelligence Laboratory of Zürich University, Puppy, a robot dog, is capable of adapting and “feeling” the texture of the terrain on which it is moving (slippery, viscous, rough, etc.) by exploring the sensorimotor contingencies that take place when walking.

The work of the UPV/EHU’s research team is focusing on the theoretical part of the models to be developed.”As philosophers, what we mostly do is define concepts. Our main aim is to be able to define technical concepts like the sensorimotor habitat, or that of the pattern of sensorimotor co-ordination, as well as that of habit or of mental life as a whole. “Defining concepts and giving them a mathematical form is essential so that the scientist can apply it to specific experiments, not only with robots, but also with human beings. The partners at the University Medical Centre Hamburg-Eppendorf, for example, are studying in dialogue with the theoretical development of the UPV/EHU team how the perception of time and space changes in Parkinson’s patients.

(Source: basqueresearch.com)

Researchers identify brain mechanisms that regulating cocaine-seeking behavior

Researchers from the University of Wisconsin-Milwaukee (UWM) have identified mechanisms in the brain responsible for regulating cocaine-seeking behavior, providing an avenue for drug development that could greatly reduce the high relapse rate in cocaine addiction.

The research reveals that stimulation of certain brain receptors promotes inhibition of cocaine-associated memories, helping addicts to stop drug use. This inhibition is achieved through enhancing a process called “extinction learning,” in which cocaine-associated memories are replaced with associations that have no drug “reward.” This reduces drug-seeking behavior in rats.

The work was presented at the annual meeting of the Society for Neuroscience in New Orleans by Devin Mueller, UWM assistant professor of psychology, and doctoral student James Otis.

There are currently no FDA-approved medications to treat cocaine abuse, only treatments that address withdrawal symptoms, says Mueller. Abuse is maintained, in part, through exposure to environmental cues that trigger cocaine-related memories which lead to craving and relapse in recovering addicts. Currently, exposure therapy is used to help recovering addicts suppress their drug-seeking behavior, but with limited success. In exposure therapy, a patient is repeatedly exposed to stimuli that provoke craving. With repeated exposure, the patient experiences extinction, leading to reduced craving when presented with those stimuli.

If extinction could be strengthened, it would increase the effectiveness of exposure therapies in preventing relapse.

Isolating the receptor

The team found that a specific variant of the NMDA receptor, those which contain the NR2B subunit, are critical for extinction learning. They also discovered that drugs known to enhance NR2B function strengthened extinction because they act specifically in a region of the brain that regulates learned behaviors. In their investigation, researchers conditioned rats to associate one distinct chamber, but not another, with cocaine. Following conditioning, the rats were tested for a place preference by allowing drug-free access to both chambers. Rats demonstrating cocaine-seeking behavior spent significantly more time in the previously cocaine-associated chamber. Over several cocaine-free test sessions, addicted rats lost their place preference through extinction learning.

To examine the neural mechanisms of extinction, the researchers administered ifenprodil, which blocks NR2B-containing NMDA receptors, immediately after an extinction test. Ifenprodil-treated rats continued to spend more time in the cocaine-associated chamber even in the absence of cocaine, while saline-treated rats did not. These results were also replicated through specific infusion of ifenprodil into the brain’s infralimbic cortex, localizing a key brain structure in arresting cocaine-seeking.

Other avenues

The results indicate that enhancing NR2B function would boost the effectiveness of extinction-based exposure therapies. Although there are currently no NR2B-enhancing drugs, the NR2B containing receptor can be stimulated using other molecular pathways, says Mueller.

An example is the brain derived neurotrophic factor (BDNF) signaling cascade, which is implicated in neuron survival and growth. The authors targeted this cascade by directly administering BDNF into the infralimbic cortex. In extinction tests, administration of BDNF caused rats to lose their preference for the cocaine-associated chamber faster than rats given a placebo.

Mueller and Otis took these findings even further toward possible therapeutic intervention for addicts.

One issue with giving BDNF to humans is that it is unable to reach the brain through the bloodstream. Therefore, researchers next targeted the TrkB receptor, which is where BDNF normally binds. They did so with a newly synthesized drug that is able to reach the brain due to its small molecular size. This TrkB receptor agonist, known as 7,8 dihydroxyflavone, also strengthened extinction when given to rats during extinction training. The authors conclude that combining TrKB receptor stimulation simultaneously with exposure therapy could be an effective treatment for cocaine abuse, reducing craving and the potential for relapse.

(Source: eurekalert.org)