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A team of researchers under the direction of the Medical Center - University of Freiburg has created an entirely new map of the brain’s own immune system in humans and mice. The scientists succeeded in demonstrating for the first time ever that the phagocytes in the brain, the so-called microglia, all have the same core signature but adopt in different ways depending on their function. It was previously assumed that these are different types of microglia. The discovery, made by means of a new, high-resolution method for analyzing single cells, is important for the understanding of brain diseases. Furthermore, the researchers from Freiburg, Göttingen, Berlin, Bochum, Essen, and Ghent (Belgium) demonstrated in detail how the human immune system in the brain changes in the course of multiple sclerosis (MS), which is significant for future therapeutic approaches. The study was published in the journal Nature.

“We were able to show that there is only a single type of microglia in the brain that exist in multiple flavours,” says project head Prof. Dr. Marco Prinz, medical director of the Institute of Neuropathology at the Medical Center - University of Freiburg. “These immune cells are very versatile all-rounders, not specialists, as has been the textbook opinion up to now,” sums up Prof. Prinz.

Versatile All-Rounders, Not Specialists

Since the immune cells located in the blood cannot reach the brain and spinal cord on account of the blood-brain barrier, the brain needs its own immune defense: the microglia. These phagocytes of the brain develop very early on in the process of embryonic development and later remove invading germs and dead nerve cells. They contribute to the maturation and lifelong malleability of the brain. It was previously unclear whether there are subtypes of microglia for the various functions they serve in the healthy and diseased brain.

Researchers led by Prof. Prinz and the co-first authors of the study, Dr. Takahiro Masuda, Dr. Roman Sankowski, and Dr. Ori Staszewski from the Institute of Neuropathology at the Medical Center - University of Freiburg, conducted detailed studies on microgliain the brain, both on a mouse model and on human brain tissue removed from patients.

With the help of a new method for conducting single-cell analysis, the researchers were able to demonstrate the features of microglia in great detail. To do so, they used a microscope to study microglia in different brain regions and at different stages of development. They also analyzed the RNA-levels of these cells using single-cell analysis. The analyses revealed that microglia all have the same core signatures but adapt differently at different stages of development, in different brain regions, and depending on the function they are meant to serve.

Hope for Patients with Multiple Sclerosis

Dysregulated microglia are also involved in several brain diseases. In particular, they play a key role in the development of Alzheimer’s, multiple sclerosis (MS), and a few psychiatric diseases like autism. In the healthy brain, microglia form a uniform network around the nerve cells that can change in just a few minutes in the case of disease and form numerous new phagocytes to limit the damage.

“We now possess the first high-resolution immune cell atlas of the human brain. This also enables us to understand how these cells change during course of diseases like MS,” says Prof. Prinz, who is also involved in the Signalling Research Excellence Clusters BIOSS and CIBSS of the University of Freiburg. “In MS patients, we managed to characterize microglia in a state that is specific for multiple sclerosis. We hope that it will be possible in the future to target microglia subsets in harmful state.”

Why the World Needs Bloodsucking Creatures

“Some fears are real,” Kvist says. “Disease, unfortunately, is a necessary consequence of blood-feeding.”

A Trinity College research group have made a revelation in epilepsy research by becoming the first group to describe a model of mitochondrial epilepsy. This raises the possibility of more effective therapies being developed in the future. The paper which outlines these findings was published in BRAIN, a peer reviewed journal of neurology.

Mitochondrial related diseases are extremely common affecting one in 9000 births in Ireland with serious conditions. Over one quarter of people that are affected by mitochondrial related diseases also have epilepsy. People in this situation often have more severe forms of epilepsy and are more resistant toward antiepileptic drugs.

Until these recent findings there have been no biological models available to aid researchers in understanding the mechanics of the condition.

These new models have allowed the research group from Trinity College Dublin to explain the role of astrocytes in seizure generation. Until this point, the star shaped cells found in the brain and spinal cord, have generally accepted to be “supporting-cells” that plated a passive role in the brain. However this new research produced in Trinity College Dublin shows that they actually play an integral role in seizure generation and mitochondrial epilepsy.

The team were able to recreate a brain slice model by the application of an astrocytic-specific aconitase inhibitor, fluorocitrate, concomitant with mitochondrial respiratory inhibitors, rotenone and potassium cyanide. The model was flexible and exhibited both face and predictive validity.

The group then utilised the model so they could examine how astrocytes and seizure generation are linked. They also managed to demonstrate the involvement of the GABA-glutamate-glutamine cycle. This regulates how chemical transmitters are released from neurons and then taken up by the supporting cells; the astrocytes.

It was interesting to note that glutamine appeared as an intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone.

The research team also found that a deficiency in glutamine synthetase is an important part of the pathogenic process for seizure generation in both the brain slice model and the human neuropathological study.

Explaining the importance of the research, Ellen Mayston Bates Professor of Neurophysiology of Epilepsy at Trinity, Mark Cunningham said: “We believe this is important and novel research as it produces, for the first time, a model of mitochondrial epilepsy which captures features observed in patients. The model provides mechanistic insights, demonstrating the role of astrocytes in this pathological activity.”

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Researchers reveal brain connections that disadvantage night owls

Research led by the University of Birmingham in collaboration with researchers at the University of Surrey and the University of Campinas, in Brazil, found that individuals whose internal body clock dictates that they go to bed and wake up very late (with an average bedtime of 2:30am and wake-up time of 10:15am) have lower resting brain connectivity in many of the brain regions that are linked to the maintenance of consciousness.

Importantly, this lower brain connectivity was associated with poorer attention, slower reactions and increased sleepiness throughout the hours of a typical working day.

According to the Office for National Statistics, around 12 per cent of employees work night shifts. We already know that there are huge negative health consequences for night shift workers due to the constant disruption to sleep and body clocks.

However, disruption can also be caused by being forced to fit into a societal 9-5 working day if those timings do not align with your natural biological rhythms. Since around 40-50 per cent of the population identify as having a preference for later bed times and for getting up after 8.20am the researchers say much more needs to be done to explore negative implications for this group.

The lead researcher, Dr Elise Facer-Childs, of the University of Birmingham’s Centre for Human Brain Health, says: “A huge number of people struggle to deliver their best performance during work or school hours they are not naturally suited to. There is a critical need to increase our understanding of these issues in order to minimise health risks in society, as well as maximise productivity.”

The study, published in the journal SLEEP, investigated brain function at rest and linked it to the cognitive abilities of 38 individuals who were identified as either ‘night owls’ or ‘morning larks’ using physiological rhythms (melatonin and cortisol), continuous sleep/wake monitoring and questionnaires. The volunteers underwent MRI scans, followed by a series of tasks, with testing sessions being undertaken at a range of different times during the day from 8am to 8pm. They were also asked to report on their levels of sleepiness.

Volunteers identified as morning larks reported to be least sleepy and had their fastest reaction time during the early morning tests, which was significantly better than night owls. Night owls, however, were least sleepy and had their fastest reaction time at 8pm in the evening, although this was not significantly better than the larks, highlighting that night owls are most disadvantaged in the morning. Interestingly, the brain connectivity in the regions that could predict better performance and lower sleepiness was significantly higher in larks at all time points, suggesting that the resting state brain connectivity of night owls is impaired throughout the whole day (8am-8pm).

Dr Facer-Childs, who is now based at the Monash Institute for Cognitive and Clinical Neurosciences in Melbourne, Australia, says: “This mismatch between a person’s biological time and social time – which most of us have experienced in the form of jet lag – is a common issue for night owls trying to follow a normal working day. Our study is the first to show a potential intrinsic neuronal mechanism behind why ‘night owls’ may face cognitive disadvantages when being forced to fit into these constraints.