Neuroscience

The switch works by regulating the activity of a handful of sleep-promoting nerve cells, or neurons, in the brain. The neurons fire when we’re tired and need sleep, and dampen down when we’re fully rested.

‘When you’re tired, these neurons in the brain shout loud and they send you to sleep,’ says Professor Gero Miesenböck of Oxford University, in whose laboratory the new research was performed.

Although the research was carried out in fruit flies, or Drosophila, the scientists say the sleep mechanism is likely to be relevant to humans.

Dr Jeffrey Donlea, one of the lead authors of the study, explains: ‘There is a similar group of neurons in a region of the human brain. These neurons are also electrically active during sleep and, like the flies’ cells, are the targets of general anaesthetics that put us to sleep. It’s therefore likely that a molecular mechanism similar to the one we have discovered in flies also operates in humans.’

The researchers say that pinpointing the sleep switch might help us identify new targets for novel drugs – potentially to improve treatments for sleep disorders.

But there is much still to find out, and further research could give insight into the big unanswered question of why we need to sleep at all, they say.

‘The big question now is to figure out what internal signal the sleep switch responds to,’ says Dr Diogo Pimentel of Oxford University, the other lead author of the study. ‘What do these sleep-promoting cells monitor while we are awake?

‘If we knew what happens in the brain during waking that requires sleep to reset, we might get closer to solving the mystery of why all animals need to sleep.’

The findings are reported in the journal Neuron. The work of the Centre for Neural Circuits and Behaviour is funded by the Wellcome Trust and the Gatsby Charitable Foundation. This study was also supported by the UK Medical Research Council, the US National Institutes of Health, and the Human Frontier Science Program.

The body uses two mechanisms to regulate sleep. One is the body clock, which attunes humans and animals to the 24 hour cycle of day and night. The other mechanism is the sleep ‘homeostat’: a device in the brain that keeps track of your waking hours and puts you to sleep when you need to reset. This mechanism represents an internal nodding off point that is separate from external factors. When it is turned off or out of use, sleep deficits build up.

What makes us go to sleep at night is probably a combination of the two mechanisms,’ says Professor Miesenböck. ‘The body clock says it’s the right time, and the sleep switch has built up pressure during a long waking day.’

The work in fruit flies allowed the critical part of the sleep switch to be discovered. ‘We discovered mutant flies that couldn’t catch up on their lost sleep after they had been kept awake all night,’ says Dr Jeffrey Donlea.

Flies stop moving when they go to sleep and require more disturbance to get them up. Sleep-deprived flies are prone to nodding off and are cognitively impaired – they have severe learning and memory deficits, much as sleep loss in humans leads to problems.

Professor Miesenböck says: ‘The sleep homeostat is similar to the thermostat in your home. A thermostat measures temperature and switches on the heating if it’s too cold. The sleep homeostat measures how long a fly has been awake and switches on a small group of specialized cells in the brain if necessary. It’s the electrical output of these nerve cells that puts the fly to sleep.’

In the mutant flies, the researchers were able to show a key molecular component of the electrical activity switch is broken and the sleep-inducing neurons are always off, causing insomnia.

An international group of researchers has identified a major new pathway thought to be involved in the development of Huntington disease. The findings, published in the Proceedings of the National Academy of Sciences journal, could eventually lead to new treatments for the disease, which currently has no cure.

Scientists at the BC Cancer Agency Research Centre and the Centre for Molecular Medicine and Therapeutics in Vancouver, Canada, and the MRC Toxicology Unit in Leicester, UK, studied mice and human tissue and found that the HACE1 gene is essential for mopping up toxic molecules during periods of oxidative stress, where harmful ‘reactive oxygen species’ build up in the cell.

Oxidative stress is thought to be involved in the development of a number of diseases including cancer and neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. Therefore finding out how this process occurs in the body is important for understanding the course of disease.

The body has evolved highly effective defence mechanisms that sense and respond to oxidative stress to protect the cells from damage. One of these protective mechanisms is controlled by a molecule called NRF2 which springs into action and switches on the production of proteins and enzymes that detoxify the cell.

In this study, scientists found that the HACE1 also plays a vital role in this detoxification process, by activating NRF2. The authors believe that this mechanism goes wrong in Huntington’s disease, leading to gradual destruction of nerve cells in the brain.

Lead author Dr Barak Rotblat, of the MRC Toxicology Unit, said:

“One of the early observations was that enhanced HACE1 expression rescued cells from mutant Huntingtin (the mutant protein that is responsible for Huntington disease) toxicity. We knew then that we had to figure out how HACE1 can protect these cells.

“Our evidence points towards a previously unknown role of HACE1 in Huntington disease and possibly other forms of neurodegeneration. It’s very early days, but if we were able to find a way to boost this pathway, we might be able to develop a treatment that halts, or even reverses progression of Huntington disease.”

HACE1 is already known to play a protective role against tumour formation, but its role in neurodegeneration has not been investigated before.

Dr Poul Sorensen, the senior author of the work from the BC Cancer Agency Research Centre and a Professor at the University of British Columbia, said:

“This is a glowing example of how work in one field, namely childhood cancers, where we first identified the HACE1 gene, has applications to a completely different disease, Huntington disease”.

In this study, researchers looked at mice with and without the HACE1 gene and found that those without the gene had more oxidative stress in the brain, and their response to this was impaired. Depleting HACE1 in cells also resulted in reduced NRF2 activity, leading to lower tolerance against oxidative stress triggers.

The scientists also looked at human brain samples from Huntington disease patients and found a striking reduction of HACE1 levels in the striatum – the area of the brain where the disease develops and is most damaged.

Finally, they looked at HACE1 in a cellular model of Huntington disease. They found that upping expression of the gene in nerve precursor cells protected them against oxidative stress.

A new Indiana University study that examines the brain activity of alcohol-dependent women compared to women who were not addicted found stark and surprising differences, leading to intriguing questions about brain network functions of addicted women as they make risky decisions about when and what to drink.

The study used functional magnetic resonance imaging, or fMRI, to study differences between patterns of brain network activation in the two groups of women. The findings indicate that the anterior insular region of the brain may be implicated in the process, suggesting a possible new target of treatment for alcohol-dependent women.

"We see that the network dynamics of alcohol-dependent women may be really different from that of healthy controls in a drinking-related task," said Lindsay Arcurio, a graduate student in the Department of Psychological and Brain Sciences. "We have evidence to suggest alcohol-dependent women have trouble switching between networks of the brain."

The research is part of a larger new effort to understand the differences between men and women with respect to alcohol. Arcurio said most of the research on alcohol dependence has been conducted with men or groups of men and women. Yet several factors make looking at women “really important.”

One such factor is that the physiological effects of drinking alcohol, which include liver damage, heart disease or breast cancer, set in much earlier in women than in men. For this reason, the suggested limit on the number of drinks per week that women can safely consume is eight, whereas for men, it is 14. Secondly, binge-drinking in women is on the rise. One in five adolescent girls is binge-drinking three times a month. In women between the ages of 18 and 54, that number is one in eight.

A ‘sledgehammer’ approach to defining differences in brain network activation

Research on decision-making mechanisms in alcohol-dependent individuals typically involves a general risk-taking situation in which money or points are at stake. In this study, participants were placed in the fMRI brain scanner and asked to consider low-risk and high-risk situations specifically related to alcohol — what the researchers describe as “ecological” tasks. Participants were then asked to make decisions regarding control stimuli — food as well as a presumably neutral stimuli, a stapler — to observe whether risky behavior was greater with respect to drinking than with these other items. The same picture cues were used to present high-risk and low-risk scenarios, and these two extremes were as follows:

For the low-risk situation, participants were told: Imagine you are at a bar. You are offered a drink, already paid for, with two shots of alcohol, and you have a safe ride home. For the high-risk, they were told: You are at a bar and are offered a drink already paid for, with six shots of alcohol, but you do not have a safe ride home.

The reason for such an extreme contrast between the two situations, Arcurio said, is that “as one of the first ecological tasks used in the scanner, we wanted to take a sledgehammer approach to really find the differences between cases that are definitely high-risk and those that are definitely low-risk.”

The findings, however, reflect an equally sharp contrast in differences between the brain network activation in alcohol-dependent women versus the controls.

For the control group, high-risk decisions to drink led to the deactivation of regions associated with “approach behavior,” deciding to take the drink in a risky situation. Conversely, women in the control group activate regions associated with the default mode network, a region traditionally thought to involve resting-state behavior or inactive or relaxed mental state, but which some now speculate plays a role in conceptualizing one’s future.

"It gets really interesting," Arcurio said, "comparing this pattern of activation to those in alcohol-dependent women, who behaviorally say they’re more likely to take the high-risk drink compared to the controls. They don’t deactivate anything. In contrast to the controls, alcohol-dependent women activate all three regions in question. They activate regions associated with reward (which release dopamine). They also activate frontal control regions involved in cognitive control and regions associated with the default mode network, involved in resting-state behavior. They are activating everything."

The investigators infer from these findings that alcohol-dependent women have trouble switching between networks. Being unable to activate one region and deactivate another in response to an alcohol-related situation means they are unable to use one strategy over another.

Furthermore, Arcurio said, “a lot of evidence suggests that switching between networks is influenced by the anterior insular and anterior cingulate regions of the brain, and we did find major differences in the insula between the alcohol-dependent women and controls. We’re thinking the issue is pinpointed to that region.”

The researchers are now running analyses to test the hypothesis that the insula helps in this process, which could offer new possibilities for intervention, with both behavioral therapy and medication.

The research is part of a whole research program, both planned and in the works, to further explore the questions about risky decision-making in alcohol-dependent women: studies of adolescent drinking, risky sexual behavior in alcohol-dependent women, the interaction of visual networks with decision-making networks, as well as the way music (or auditory networks) interacts with decision-making mechanisms in alcohol-dependent women. In the latter experiment, college-age participants choose a song that they associate with drinking and one with quiet reflection.

"There’s a lot of Miley Cyrus in the first category," Arcurio said.

Hyperactivity of our immune system can cause a state of chronic inflammation. If chronic, the inflammation will affect our body and result in disease. In the devastating disease multiple sclerosis, hyperactivity of immune cells called T-cells induce chronic inflammation and degeneration of the brain. Researchers at BRIC, the University of Copenhagen, have identified a new type of regulatory blood cells that can combat such hyperactive T-cells in blood from patients with multiple sclerosis. By stimulating the regulatory blood cells, the researchers significantly decreased the level of brain inflammation and disease in a biological model. The results are published in the journal Nature Medicine.

Molecule activate anti-inflammatory blood cells

The new blood cells belong to the group of our white blood cells called lymphocytes. The cells express a molecule called FoxA1 that the researchers found is responsible for the cells’ development and suppressive functions.

"We knew that some unidentified blood cells were able to inhibit multiple sclerosis-like disease in mice and through gene analysis we found out, that these cells are a subset of our lymphocytes expressing the gene FoxA1. Importantly, when inserting FoxA1 into normal lymphocytes with gene therapy, we could change them to actively regulate inflammation and inhibit multiple sclerosis", explains associated professor Yawei Liu leading the experimental studies.

Image caption: Tissue sections from an untreated diseased brain and a FoxA1-treated brain from the researchers biological model. (Photo: Yawei Liu)

Activating own blood cells for treatment of disease

FoxA1 expressing lymphocytes were not known until now, and this is the first documentation of their importance in controlling multiple sclerosis. The number of people living with this devastating disease around the world has increased by 10 percent in the past five years to 2.3 million. It affects women twice more than men and no curing treatment exists. The research group headed by professor Shohreh Issazadeh-Navikas from BRIC examined blood of patients with multiple sclerosis, before and after two years of treatment with the drug interferon-beta. They found that patients who benefit from the treatment increase the number of this new blood cell type, which fight disease.

Image caption: FoxA1-lymphocytes. (Photo: Yawei Liu)

“From a therapeutic viewpoint, our findings are really interesting and we hope that they can help finding new treatment options for patients not benefiting from existing drugs, especially more chronic and progressive multiple sclerosis patients. In our model, we could activate lymphocytes by chemical stimulation and gene therapy, and we are curios whether this can be a new treatment strategy”, says professor Shohreh Issazadeh-Navikas.

And this is exactly what the research group will focus on at next stage of their research. They have already started to test whether the new FoxA1-lymphocytes can prevent degradation of the nerve cell’s myelin layer and brain degeneration in a model of progressive multiple sclerosis. Besides multiple sclerosis, knowledge on how to prevent chronic inflammation will also be valuable for other autoimmune diseases like type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis, where inflammation is a major cause of the disease.

Boys are at greater risk for delayed language development than girls, according to a new study using data from the Norwegian Mother and Child Cohort Study. The researchers also found that reading and writing difficulties in the family gave an increased risk.

“We show for the first time that reading and writing difficulties in the family can be the main reason why a child has a speech delay that first begins between three to five years of age,” says Eivind Ystrøm, senior researcher at the Norwegian Institute of Public Health.

Ystrøm was supervisor of Imac Maria Zambrana, a former PhD student at the Norwegian Institute of Public Health who conducted the research in this study as part of her doctoral research.

The researchers used data from questionnaires completed by the mothers who are participating in the Norwegian Mother and Child Cohort Study (MoBa). The study included more than 10,000 children from week 17 of pregnancy up to five years of age.

“MoBa is a large study with a normal cross-section of the population. It gives us a unique opportunity to examine changes over time, the scope and any risk factors for delayed language development,” says Ystrøm.

Mostly boys

The researchers classified the language difficulties at three and five years of age in three groups: persistent delayed language development (present at both times), transient delayed language development (only present at three years) and delayed language development first identified at five years old.

Boys are in the majority for the groups with persistent and transient language difficulties. Ystrøm explains that boys are biologically at greater risk for developmental disorders in utero than girls. British scientists have measured the male sex hormone (testosterone) in amniotic fluid and they found that the levels were related to the development of both autism and language disorders. Ystrøm points out that boys are generally a little later in language development than girls, but that most catch up during the first year. Therefore, many boys could be at risk of persistent language impairment and increasingly have transient language difficulties that disappear before school age.

The researchers found that gender was irrelevant for the third group who have language difficulties that begin sometime between three and five years of age.

Hereditary factors

We have good knowledge about normal language development in children. Many genes are important for language development and research suggests that different genes are involved in different types of language difficulty.

“Reading and writing difficulties in the family are the predominant risk factors for late-onset language difficulties. We see no language problems when the child is between 18 months and three years old. They are latent” says Ystrøm.

The researchers believe that both specific genes and factors in the child’s external environment can lead to delays in language development at three to five years of age.

What can we do?

Ystrøm believes that children with delayed language development must be identified as early as possible. Parents, health care workers and child care staff should be aware of the language development of children and encourage an enabling language environment, in some cases with specially adapted measures. In particular, they must be aware of children who have sustained disabilities, or who have had normal language development up to three years and then unexpectedly began to have difficulties.

“Professionals and caregivers must be vigilant. It is difficult to detect language difficulties when language becomes more complex in older children. They must be trained so that they are confident in how to spot language difficulties and how to encourage a child’s language. We need more research into the needs of children with different trajectories”, says Ystrøm.

Parents who are concerned about their child’s language development should consult their doctor. They should also raise the issue at the regular check-ups at the health clinic when the child is between two and four years old.

“The checks must take place at the appropriate time. It is important that they are not delayed or not implemented at all,” says Ystrøm.

A few years ago, a survey by the Health and Welfare Department in Oslo showed that few of the health centres in Oslo met the required 14 consultations for each child from birth to school stipulated by the Norwegian Directorate of Health.

Further research

In addition to researchers at the Norwegian Institute of Public Health, researchers at the University of Oslo and the University of Melbourne in Australia participated in this study. The work is funded by the Extra Foundation for Health and Rehabilitation.

“We hope to continue this research and specifically look at the relationship between gender and language. We need more research into the needs of children with various types of language delay”, says Eivind Ystrøm.

Reference

Zambrana, IM, Pons, F., Eadie, P. and Ystrom, E. (2013). Trajectories of language delay from age 3 to 5: persistence, recovery and late onset. International Journal of Language & Communication

Researchers at the University of Bristol and University College London found that lactate – essentially lactic acid – causes cells in the brain to release more noradrenaline (norepinephrine in US English), a hormone and neurotransmitter which is fundamental for brain function. Without it people can hardly wake up or focus on anything.

Production of lactate can be triggered by muscle use, which reinforces the connection between exercise and positive mental wellbeing.

Lactate was first discovered in sour milk by Swedish chemist, Carl Wilhelm Scheele in 1780. It is produced naturally by the body, for example when muscles are at work. In the brain, it has always been regarded as an energy source which can be delivered to neurones as fuel to keep them working when brain activity increases.

This research, published today [11 February] in Nature Communications, identifies a secondary function for lactate as a signal between brain cells. It implies that there is an as yet unknown receptor for lactate in the brain which must be present on noradrenaline cells to make them sensitive to lactate.

Professor Sergey Kasparov, from Bristol University’s School of Physiology and Pharmacology, said: “Our findings suggest that lactate has more than one incarnation - in addition to its role as an energy source, it is also a signal to neurones to release more noradrenaline.”

Dr Anja Teschemacher, also from the University of Bristol, added: “The next big task is to identify the receptor which mediates this effect because this will help to design drugs to block or stimulate this response. If we can regulate the release of noradrenaline – which is absolutely fundamental for brain function - then this could have important implications for the treatment of major health problems such as stress, blood pressure, pain and depression.”

Astrocytes, small non-neuronal star-shaped cells in the brain and spinal cord, are the principle source of brain lactate. The discovery that astrocytes communicate directly with neurones opens up a whole new area of pharmacology which has been little explored.

For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment. 

The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified. 

An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence. 

Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”

She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.” 

The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate. 

To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.

The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder. 

Scientists from the School of Medicine at The University of Texas Health Science Center at San Antonio have found a clue as to why muscles weaken with age. In a study published today in The Journal of Neuroscience, they report the first evidence that “set points” in the nervous system are not inalterably determined during development but instead can be reset with age. They observed a change in set point that resulted in significantly diminished motor function in aging fruit flies.

“The body has a set point for temperature (98.6 degrees), a set point for salt level in the blood, and other homeostatic (steady-state) set points that are important for maintaining stable functions throughout life,” said study senior author Ben Eaton, Ph.D., assistant professor of physiology at the Health Science Center. “Evidence also points to the existence of set points in the nervous system, but it has never been observed that they change, until now.”

Dr. Eaton and lead author Rebekah Mahoney, a graduate student, recorded changes in the neuromuscular junction synapses of aging fruit flies. These synapses are spaces where neurons exchange electrical signals to enable motor functions such as walking and smiling. “We observed a change in the synapse, indicating that the homeostatic mechanism had adjusted to maintain a new set point in the older animal,” Mahoney said.

The change was nearly 200 percent, and the researchers predicted that it would leave muscles more vulnerable to exhaustion.

Aside from impairing movement in aging animals, a new functional set point in neuromuscular junctions could put the synapse at risk for developing neurodegeneration — the hallmark of disorders such as Alzheimer’s and Parkinson’s diseases, Mahoney said.

“Observing a change in the set point in synapses alters our paradigms about how we think age affects the function of the nervous system,” she said.

It appears that a similar change could lead to effects on learning and memory in old age. An understanding of this phenomenon would be invaluable and could lead to development of novel therapies for those issues, as well.

A genetic disorder that affects about 1 in every 2,500 births can cause a bewildering array of clinical problems, including brain tumors, impaired vision, learning disabilities, behavioral problems, heart defects and bone deformities. The symptoms and their severity vary among patients affected by this condition, known as neurofibromatosis type 1 (NF1).

Image caption: A mutation in the gene that causes a human condition, neurofibromatosis type 1 (NF1), leads to shorter nerve cell branches (right) in the back of the eyes of female mice. The shorter branches, not seen in male mice with the mutation, make the cells more vulnerable. This may explain why girls with NF1 are more at risk of vision loss from brain tumors. (Credit: David H. Gutmann)

Now, researchers at Washington University School of Medicine in St. Louis have identified a patient’s gender as a clear and simple guidepost to help health-care providers anticipate some of the effects of NF1. The scientists report that girls with NF1 are at greater risk of vision loss from brain tumors. They also identified gender-linked differences in male mice that may help explain why boys with NF1 are more vulnerable to learning disabilities.

“This information will help us adjust our strategies for predicting the potential outcomes in patients with NF1 and recommending appropriate treatments,” said David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology, who treats NF1 patients at St. Louis Children’s Hospital.

The findings appear online in the Annals of Neurology.

Kelly Diggs-Andrews, PhD, a postdoctoral research associate in Gutmann’s laboratory, reviewed NF1 patient data collected at the Washington University Neurofibromatosis (NF) Center. In her initial assessment, Diggs-Andrews found that the number of boys and girls was almost equal in  a group of nearly 100 NF1 patients who had developed brain tumors known as optic gliomas. But vision loss occurred three times more often in girls with these tumors.

With help from David Wozniak, PhD, research professor of psychiatry, the scientists looked for an explanation in Nf1 mice (which, like NF1 patients, have a mutation in their Nf1 gene). They found that more nerve cells died in the eyes of female mice, and they linked the increased cell death to low levels of cyclic AMP, a chemical messenger that plays important roles in nerve function and health in the brain. In addition, Wozniak discovered that only female Nf1 mice had reduced vision, paralleling what was observed in children with NF1.

Two previous studies have shown that boys with NF1 are at higher risk of learning disorders than girls, including spatial learning and memory problems. To look for the causes of this gender-related difference, the scientists first confirmed that Nf1 mice had learning problems by testing the ability of the mice to find a hidden platform after training. After multiple trials, female Nf1 mice quickly found the hidden platform. In striking contrast, the male Nf1 mice did not, revealing that they had deficits in spatial learning and memory.

When the researchers examined the brain regions involved in learning and memory in the Nf1 mice, they identified biochemical abnormalities in the males but not in the females.

“We’re currently working to determine whether differences in the sex hormones are responsible for these abnormalities in vision and memory,” Gutmann said. “We’re talking about a disorder in young kids and in mice, where we normally would not expect sex hormones to play a major role, but we can’t rule them out yet.”

If hormones are responsible for these gender-linked distinctions in NF1, treatments that block hormonal function may be an option for use in patients with NF1, Gutmann added. 

“Moreover, these studies identify sex as one important factor that helps to predict clinical outcomes, such as vision loss and problems in cognitive function, in children with NF1,” Gutmann said. “Further understanding of the interplay between sex and NF1 may change the way we manage individuals with this common brain tumor predisposition syndrome.”

While the function of eating is to nourish the body, this is not what actually compels us to seek out food. Instead, it is hunger, with its stomach-growling sensations and gnawing pangs that propels us to the refrigerator – or the deli or the vending machine. Although hunger is essential for survival, abnormal hunger can lead to obesity and eating disorders, widespread problems now reaching near-epidemic proportions around the world.

Over the past 20 years, Beth Israel Deaconess Medical Center (BIDMC) neuroendocrinologist Bradford Lowell, MD, PhD, has been untangling the complicated jumble of neurocircuits in the brain that underlie hunger, working to create a wiring diagram to explain the origins of this intense motivational state. Key among his findings has been the discovery that Agouti-peptide (AgRP) expressing neurons – a group of nerve cells in the brain’s hypothalamus – are activated by caloric deficiency, and when either naturally or artificially stimulated in animal models, will cause mice to eat voraciously after conducting a relentless search for food.

Now, in a new study published on-line this week in the journal Nature, Lowell’s lab has made the surprising discovery that the hunger-inducing neurons that activate these AgRP neurons are located in the paraventricular nucleus — a brain region long thought to cause satiety, or feelings of fullness. This unexpected finding not only provides a critical addition to the overall wiring diagram, but adds an important extension to our understanding of what drives appetite.

"Our goal is to understand how the brain controls hunger," explains Lowell, an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School. "Abnormal hunger can lead to obesity and eating disorders, but in order to understand what might be wrong – and how to treat it – you first need to know how it works. Otherwise, it’s like trying to fix a car without knowing how the engine operates."

Hunger is notoriously complicated and questions abound: Why do the fed and fasted states of your body increase or decrease hunger? And how do the brain’s reward pathways come into play – why, as we seek out food, especially after an otherwise complete meal, do we prefer ice cream to lettuce?

"Psychologists have explained how cues from the environment and from the body interact, demonstrating that food and stimuli linked with food [such as a McDonald’s sign] are rewarding and therefore promote hunger," explains Lowell. "It’s clear that fasting increases the gain on how rewarding we find food to be, while a full stomach decreases this reward. But while this model has been extremely important in understanding the general features of the ‘hunger system,’ it’s told us nothing about what’s inside the ‘black box’ – the brain’s neural circuits that actually control hunger."

To deal with this particularly complex brain region – a dense and daunting tangle of circuits resembling a wildly colorful Jackson Pollack painting – the Lowell team is taking a step-by-step approach to find out how the messages indicating whether the body is in a state of feeding or fasting enter this system. Their search has been aided by a number of extremely powerful technologies, including rabies circuit mapping and channelrhodopsin-assisted circuit mapping, which enable their highly specific, neuron-by-neuron analysis of the region.

"By making use of these new technologies, we are able to follow the synapses, follow the axons, and see how it all works," says Lowell. "While this sounds like a relatively straightforward concept, it’s actually been a huge challenge for the neuroscience field."

In this new paper, first authors Michael Krashes, PhD, and Bhavik Shah, PhD, postdoctoral fellows in the Lowell lab, employed rabies circuit mapping, a technology in which a modified version of the rabies virus is engineered to “infect” just one type of neuron – in this case, the AgRP neurons that drive hunger. The virus moves upstream one synapse and identifies all neurons that are providing input to AgRP starter neurons. Then, using a host of different neuron-specific cre-recombinase expressing mice (a group of genetically engineered animals originally developed in the Lowell lab) the investigators were able to map inputs to just these nerve cells, and then manipulate these upstream neurons so that they could be targeted for activation by an external stimulus.

"We wanted to know, of all the millions of neurons in a mouse brain, which provided input to the AgRP neurons," explains Lowell. "And the shocking result was that there were only two sites in the brain that were involved – the dorsal medial hypothalamus and the paraventricular nucleus, with the input from the paraventricular neurons shown to be extremely strong."

With this new information, the investigators now had a model to pursue. “We hypothesized that neurons in the paraventricular nucleus were communicating with and turning on the AgRP neurons. We developed mice that expressed cre-recombinase in many subsets of the paraventricular neurons and then, mapping the neurons one-by-one, we determined which was talking to which,” says Lowell. Their results revealed that subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cylcase-activating polypeptide (PACAP) were in on the neuronal chatter.

Finally, through a chemogenetic technique known as DREADDs – Designer Receptor Exclusively Activated by Designer Drug – the authors used chemicals to specifically and selectively stimulate or inhibit these upstream neurons in the animal models. The fed mice, which had already consumed their daily meal and otherwise had no interest in food, proceeded to search out and voraciously eat after DREADD stimulation. Conversely, the fasting mice – which should have been hungry after a period of no food – ate very little when these upstream neurons were turned off.

"This has led us to the discovery of a novel, previously unknown means of activating AgRP neurons and producing hunger," explains Lowell. "Surprisingly, these hunger-inducing neurons were found in a region of the brain which has long been thought to have the opposite effect – causing satiety. This unexpected discovery, made possible only through the use of the new wiring diagram-elucidating technologies, highlights the importance of following the labeled neuronal lines of information flow. We are getting closer and closer to completing our wiring diagram, and the nearer we come to understanding how it all works, the better our chances of being able to treat obesity and eating disorders, the consequences of abnormal hunger."

Scientists have discovered a link between a largely unstudied gene and schizophrenia.

They also found a link between the same gene and bipolar disorder, depression and autism.

The University of Aberdeen-led research - published in the Journal of Cell Science - set out to look for genes that might be important for schizophrenia.

During analysis of five major patient cohorts, scientists picked out the poorly-understood gene ULK4 which has previously been associated with hypertension but never before with mental health disorders.

They discovered that a mutation of the gene ULK4 was found far more frequently in patients with schizophrenia.

Researchers also found mutation of ULK4 in some people with bipolar disorder, depression and autism.

First author Dr Bing Lang, Research Fellow at the University of Aberdeen, said: “Schizophrenia is a severe psychiatric disorder affecting about 1% of the population. Genetics are estimated to be between 60 and 80% responsible for the condition, but very few specific susceptibility genes for schizophrenia have been firmly confirmed in humans.

“However our results suggest that mutation of the gene UKL4 can be a rare genetic risk factor for schizophrenia as well as other psychiatric disorders.” 

The researchers found evidence that ULK4 regulates many important signalling pathways within nerve cells involved in schizophrenia and stress.

They also discovered that mutation of the gene reduced communication between brain cells.

Professor Colin McCaig, one of the researchers and Head of the University’s School of Medical Sciences, added: “This is an important discovery of a gene involved in major mental health disorders which affects basic nerve cell growth and nerve to nerve communication. We expect it will form another important piece of the jigsaw that will produce a fuller understanding of what goes wrong in the brain in conditions such as schizophrenia.”

Dr Lang added: “We are very excited by our findings. We still need to do much more work to understand the mechanisms underlying the role of UKL4 in schizophrenia in the hope that this may lead to the discovery of new drug targets for a condition that deprives some sufferers of the ability to lead normal, independent lives.”