Neuroscience

Results may help improve drugs for neurological disorders

Researchers have published the first highly detailed description of how neurotensin, a neuropeptide hormone which modulates nerve cell activity in the brain, interacts with its receptor. Their results suggest that neuropeptide hormones use a novel binding mechanism to activate a class of receptors called G-protein coupled receptors (GPCRs). 

“The knowledge of how the peptide binds to its receptor should help scientists design better drugs,” said Dr. Reinhard Grisshammer, a scientist at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and an author of the study published in Nature.

Binding of neurotensin initiates a series of reactions in nerve cells. Previous studies have shown that neurotensin may be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth.

Dr. Grisshammer and his colleagues used X-ray crystallography to show what the receptor looks like in atomic detail when it is bound to neurotensin. Their results provide the most direct and detailed views describing this interaction which may change the way scientists develop drugs targeting similar neuropeptide receptors.

X-ray crystallography is a technique in which scientists shoot X-rays at crystallized molecules to determine a molecule’s shape and structure. The X-rays change directions, or diffract, as they pass through the crystals before hitting a detector where they form a pattern that is used to calculate the atomic structure of the molecule. These structures guide the way scientists think about how proteins work.

Neurotensin receptors and other GPCRs belong to a large class of membrane proteins which are activated by a variety of molecules, called ligands. Previous X-ray crystallography studies showed that smaller ligands, such as adrenaline and retinal, bind in the middle of their respective GPCRs and well below the receptor’s surface.  In contrast, Dr. Grisshammer’s group found that neurotensin binds to the outer part of its receptor, just at the receptor surface. These results suggest that neuropeptides activate GPCRs in a different way compared to the smaller ligands.

Forming well-diffracting neuropeptide-bound GPCR crystals is very difficult. Dr. Grisshammer and his colleagues spent many years obtaining the results on the neurotensin receptor. During that time Dr. Grisshammer started collaborating with a group led by Dr. Christopher Tate, Ph.D. at the MRC Laboratory of Molecular Biology, Cambridge, England. Dr. Tate’s lab used recombinant gene technology to create a stable version of the neurotensin receptor which tightly binds neurotensin. Meanwhile Dr. Grisshammer’s lab employed the latest methods to crystallize the receptor bound to a short version of neurotensin.

The results published today are the first X-ray crystallography studies showing how a neuropeptide agonist binds to neuropeptide GPCRs. Nonetheless, more work is needed to fully understand the detailed signaling mechanism of this GPCR, said Dr. Grisshammer.

(Image credit: chichacha)

Recent studies have linked caffeine consumption to a reduced risk of Alzheimer’s disease, and a new University of Illinois study may be able to explain how this happens.

“We have discovered a novel signal that activates the brain-based inflammation associated with neurodegenerative diseases, and caffeine appears to block its activity. This discovery may eventually lead to drugs that could reverse or inhibit mild cognitive impairment,” said Gregory Freund, a professor in the U of I’s College of Medicine and a member of the U of I’s Division of Nutritional Sciences.

Freund’s team examined the effects of caffeine on memory formation in two groups of mice—one group given caffeine, the other receiving none. The two groups were then exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow, and then allowed to recover.

The caffeine-treated mice recovered their ability to form a new memory 33 percent faster than the non-caffeine-treated mice. In fact, caffeine had the same anti-inflammatory effect as blocking IL-1 signaling. IL-1 is a critical player in the inflammation associated with many neurodegenerative diseases, he said.

“It’s not surprising that the insult to the brain that the mice experienced would cause learning memory to be impaired. But how does that occur?” he wondered.

The scientists noted that the hypoxic episode triggered the release of adenosine by brain cells.

“Your cells are little powerhouses, and they run on a fuel called ATP that’s made up of molecules of adenosine. When there’s damage to a cell, adenosine is released,” he said.

Just as gasoline leaking out of a tank poses a danger to everything around it, adenosine leaking out of a cell poses a danger to its environment, he noted.

The extracellular adenosine activates the enzyme caspase-1, which triggers production of the cytokine IL-1β, a critical player in inflammation, he said.

“But caffeine blocks all the activity of adenosine and inhibits caspase-1 and the inflammation that comes with it, limiting damage to the brain and protecting it from further injury,” he added.

Caffeine’s ability to block adenosine receptors has been linked to cognitive improvement in certain neurodegenerative diseases and as a protectant against Alzheimer’s disease, he said.

“We feel that our foot is in the door now, and this research may lead to a way to reverse early cognitive impairment in the brain. We already have drugs that target certain adenosine receptors. Our work now is to determine which receptor is the most important and use a specific antagonist to that receptor,” he said.

The study appears in the Journal of Neuroscience and can be viewed online at http://www.jneurosci.org/content/32/40/13945.full 

McGill researchers link genetic mutation to psychiatric disease and obesity

Deletion of brain-derived neurotrophic factor leads to major depression, anxiety, and obesity

McGill researchers have identified a small region in the genome that conclusively plays a role in the development of psychiatric disease and obesity. The key lies in the genomic deletion of brain-derived neurotrophic factor, or BDNF, a nervous system growth factor that plays a critical role in brain development.

To determine the role of BDNF in humans, Prof. Carl Ernst, from McGill’s Department of Psychiatry, Faculty of Medicine, screened over 35,000 people referred for genetic screening at clinics and over 30,000 control subjects in Canada, the U.S., and Europe. Overall, five individuals were identified with BDNF deletions, all of whom were obese, had a mild-moderate intellectual impairment, and had a mood disorder. Children had anxiety disorders, aggressive disorders, or attention deficit-hyperactivity disorder (ADHD), while post-pubescent subjects had anxiety and major depressive disorders. Subjects gradually gained weight as they aged, suggesting that obesity is a long-term process when BDNF is deleted.

"Scientists have been trying to find a region of the genome which plays a role in human psychopathology, searching for answers anywhere in our DNA that may give us a clue to the genetic causes of these types of disorders," says Prof. Ernst, who is also a researcher at the Douglas Mental Health University Institute. "Our study conclusively links a single region of the genome to mood and anxiety."

The findings, published in the Archives of General Psychiatry, reveal for the first time the link between BDNF deletion, cognition, and weight gain in humans. BDNF has been suspected to have many functions in the brain based on animal studies, but no study had shown what happens when BDNF is missing from the human genome. This research provides a step toward better understanding human behaviour and mood by clearly identifying genes that may be involved in mental disorders.

"Mood and anxiety can be seen like a house of cards. In this case, the walls of the house represent the myriad of biological interactions that maintain the structure," says Ernst, "Studying these moving parts can be tricky, so teasing apart even a single event is important. Linking a deletion in BDNF conclusively to mood and anxiety really tells us that it is possible to dissect the biological pathways involved in determining how we feel and act.

We now have a molecular pathway we are confident is involved in psychopathology,” adds Ernst, “Because thousands of genes are involved in mood, anxiety, or obesity, it allows us to root our studies on a solid foundation. All of the participants in our study had mild-moderate intellectual disability, but most people with these cognitive problems do not have psychiatric problems – so what is it about deletion of BDNF that affects mood? My hope now is to test the hypothesis that boosting BDNF in people with anxiety or depression might improve brain health.”

How we manage to attend to multiple objects without being distracted by irrelevant information

The “tiki-taka”-style of the Spanish national football team is amazing to watch: Xavi passes to Andrès Iniesta, he just rebounds the ball once and it’s right at Xabi Alonso’s foot. The Spanish midfielders cross the field as if they run on rails, always maintaining attention on the ball and the teammates, the opponents chasing after them without a chance. An international team of scientists from the German Primate Center and McGill University in Canada, including Stefan Treue, head of the Cognitive Neuroscience Laboratory, has now uncovered how the human brain makes such excellence possible by dividing visual attention: The brain is capable of splitting its ‘attentional spotlight’ for an enhanced processing of multiple visual objects. (Neuron, doi: 10.1016/j.neuron.2011.10.013)

When we pay attention to an object, neurons responsible for this location in our field of view are more active then when they process unattended objects. But quite often we want to pay attention to multiple objects in different spatial positions, with interspersed irrelevant objects. Different theories have been proposed to account for this ability. One is, that the attentive focus is split spatially, excluding objects between the attentional spotlights. Another possibility is, that the attentional focus is zoomed out to cover all relevant objects, but including the interspersed irrelevant ones. A third possibility would be a single focus rapidly switching between the attended objects.

Studying rhesus macaques

In order to explain how such a complex ability is achieved, the neuroscientists measured the activity of individual neurons in areas of the brain involved in vision. They studied two rhesus macaques, which were trained in a visual attention task. The monkeys had learned to pay attention to two relevant objects on a screen, with an irrelevant object between them. The experiment showed, that the macaques’ neurons responded strongly to the two attended objects with only a weak response to the irrelevant stimulus in the middle. So the brain is able to spatially split visual attention and ignore the areas in between. “Our results show the enormous adaptiveness of the brain, which enables us to deal effectively with many different situations.

This multi-tasking allows us to simultaneously attend multiple objects”, Stefan Treue says. Such a powerful ability of our attentive system is one precondition for humans to become perfect football-artists but also to safely navigate in everyday traffic.

Groundbreaking research taking place at the University of York could lead to Alzheimer’s disease being diagnosed in minutes using a simple brain scan.

Scientists are working on new technology that could revolutionise the way in which Magnetic Resonance Imaging (MRI) scans are used to view the molecular events behind diseases like Alzheimer’s, without invasive procedure, by increasing the sensitivity of an average hospital scanner by 200,000 times.

The technology underpinning this project, SABRE (Signal Amplification by Reversible Exchange), has received a £3.6m Strategic Award from the Wellcome Trust to fund a team of seven post-doctoral researchers from this month.

The new grant brings the total support for SABRE from the Wellcome Trust, the Wolfson Foundation, Bruker Biospin, the University of York and the Engineering and Physical Sciences Research Council (EPSRC) to over £12.5m in the last three years.

A new Centre for Hyperpolarisation in Magnetic Resonance (CHyM) is being purpose-built at York to house the project. The building, which is nearing completion at York Science Park, includes a chemical laboratory, four high field nuclear magnetic resonance systems and space for 30 research scientists.

The SABRE project is led by Professor Simon Duckett, from the Department of Chemistry at York, Professor Gary Green, from the York Neuroimaging Centre (YNiC) and Professor Hugh Perry, from the Centre for Biological Sciences, University of Southampton.

Professor Duckett said: “While MRI has completely changed modern healthcare, its value is greatly limited by its low sensitivity. As well as tailoring treatments more accurately to the needs of individual patients, our hope is that in the future doctors will be able to accurately make diagnoses that currently take days, weeks and sometimes months, in just minutes.”

Professor Green added: “SABRE has the potential to revolutionise clinical MRI and related MR methods by providing a huge improvement in the sensitivity of scanners. This will ultimately produce a step change in the use and type of information available to scientists and clinicians through MRI, allowing the diagnosis, treatment and clinical monitoring of diverse neurodegenerative diseases.”