Posts tagged hypothalamus
Articles and news from the latest research reports.
Research helps explain why elderly have trouble sleeping
As people grow older, they often have difficulty falling asleep and staying asleep, and tend to awaken too early in the morning. In individuals with Alzheimer’s disease, this common and troubling symptom of aging tends to be especially pronounced, often leading to nighttime confusion and wandering.
Now, a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the University of Toronto/Sunnybrook Health Sciences Center helps explain why sleep becomes more fragmented with age. Reported online today in the journal Brain, the new findings demonstrate for the first time that a group of inhibitory neurons, whose loss leads to sleep disruption in experimental animals, are substantially diminished among the elderly and individuals with Alzheimer’s disease, and that this, in turn, is accompanied by sleep disruption.
"On average, a person in his 70s has about one hour less sleep per night than a person in his 20s," explains senior author Clifford B. Saper, MD, PhD, Chairman of Neurology at BIDMC and James Jackson Putnam Professor of Neurology at Harvard Medical School. "Sleep loss and sleep fragmentation is associated with a number of health issues, including cognitive dysfunction, increased blood pressure and vascular disease, and a tendency to develop type 2 diabetes. It now appears that loss of these neurons may be contributing to these various disorders as people age."
In 1996, the Saper lab first discovered that the ventrolateral preoptic nucleus, a key cell group of inhibitory neurons, was functioning as a “sleep switch” in rats, turning off the brain’s arousal systems to enable animals to fall asleep. “Our experiments in animals showed that loss of these neurons produced profound insomnia, with animals sleeping only about 50 percent as much as normal and their remaining sleep being fragmented and disrupted,” he explains.
A group of cells in the human brain, the intermediate nucleus, is located in a similar location and has the same inhibitory neurotransmitter, galanin, as the vetrolateral preoptic nucleus in rats. The authors hypothesized that if the intermediate nucleus was important for human sleep and was homologous to the animal’s ventrolateral preoptic nucleus, then it may also similarly regulate humans’ sleep-wake cycles.
In order to test this hypothesis, the investigators analyzed data from the Rush Memory and Aging Project, a community-based study of aging and dementia which began in 1997 and has been following a group of almost 1,000 subjects who entered the study as healthy 65-year-olds and are followed until their deaths, at which point their brains are donated for research.
"Since 2005, most of the subjects in the Memory and Aging Project have been undergoing actigraphic recording every two years. This consists of their wearing a small wristwatch-type device on their non-dominant arm for seven to 10 days," explains first author Andrew S. P. Lim, MD, of the University of Toronto and Sunnybrook Health Sciences Center and formerly a member of the Saper lab. The actigraphy device, which is waterproof, is worn 24 hours a day and thereby monitors all movements, large and small, divided into 15-second intervals. "Our previous work had determined that these actigraphic recordings are a good measure of the amount and quality of sleep," adds Lim.
The authors examined the brains of 45 study subjects (median age at death, 89.2), identifying ventrolateral preoptic neurons by staining the brains for the neurotransmitter galanin. They then correlated the actigraphic rest-activity behavior of the 45 individuals in the year prior to their deaths with the number of remaining ventrolateral preoptic neurons at autopsy.
"We found that in the older patients who did not have Alzheimer’s disease, the number of ventrolateral preoptic neurons correlated inversely with the amount of sleep fragmentation," says Saper. "The fewer the neurons, the more fragmented the sleep became." The subjects with the largest amount of neurons (greater than 6,000) spent 50 percent or more of total rest time in the prolonged periods of non-movement most likely to represent sleep while subjects with the fewest ventrolateral preoptic neurons (less than 3,000) spent less than 40 percent of total rest time in extended periods of rest. The results further showed that among Alzheimer’s patients, most sleep impairment seemed to be related to the number of ventrolateral preoptic neurons that had been lost.
"These findings provide the first evidence that the ventrolateral preoptic nucleus in humans probably plays a key role in causing sleep, and functions in a similar way to other species that have been studied," says Saper. "The loss of these neurons with aging and with Alzheimer’s disease may be an important reason why older individuals often face sleep disruptions. These results may, therefore, lead to new methods to diminish sleep problems in the elderly and prevent sleep-deprivation-related cognitive decline in people with dementia."
Clues to curbing obesity found in neuronal ‘sweet spot’
Preventing weight gain, obesity, and ultimately diabetes could be as simple as keeping a nuclear receptor from being activated in a small part of the brain, according to a new study by Yale School of Medicine researchers.
Published in the Aug. 1 issue of The Journal of Clinical Investigation (JCI), the study showed that when the researchers blocked the effects of the nuclear receptor PPARgamma in a small number of brain cells in mice, the animals ate less and became resistant to a high-fat diet.
“These animals ate fat and sugar, and did not gain weight, while their control littermates did,” said lead author Sabrina Diano, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine. “We showed that the PPARgamma receptor in neurons that produce POMC could control responses to a high-fat diet without resulting in obesity.”
POMC neurons are found in the hypothalamus and regulate food intake. They are the neurons that when activated make you feel full and curb appetite. PPARgamma regulates the activation of these neurons.
Diano and her team studied transgenic mice that were genetically engineered to delete the PPARgamma receptor from POMC neurons. They wanted to see if they could prevent the obesity associated with a high-fat, high-sugar diet.
“When we blocked PPARgamma in these hypothalamic cells, we found an increased level of free radical formation in POMC neurons, and they were more active,” said Diano, who is also professor of comparative medicine and neurobiology at Yale and director of the Reproductive Neurosciences Group.
The findings also have key implications in diabetes. PPARgamma is a target of thiazolidinedione (TZD), a class of drugs used to treat type 2 diabetes. They lower blood-glucose levels, however, patients gain weight on these medications.
“Our study suggests that the increased weight gain in diabetic patients treated with TZD could be due to the effect of this drug in the brain, therefore, targeting peripheral PPARgamma to treat type 2 diabetes should be done by developing TZD compounds that can’t penetrate the brain,” said Diano. “We could keep the benefits of TZD without the side-effects of weight gain. Our next steps in this research are to test this theory in diabetes mouse models.”
Vitamin D Can Lower Weight, Blood Sugar via the Brain
Vitamin D treatment acts in the brain to improve weight and blood glucose (sugar) control in obese rats, according to a new study being presented Saturday at the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 in Chicago.
“Vitamin D deficiency occurs often in obese people and in patients with Type 2 diabetes, yet no one understands if it contributes to these diseases,” said Stephanie Sisley, MD, the study’s principal investigator and an assistant professor at Baylor College of Medicine, Houston. “Our results suggest that vitamin D may play a role in the onset of both obesity and Type 2 diabetes by its action in the brain.”
“The brain is the master regulator of weight,” Sisley said. A region of the brain called the hypothalamus controls both weight and glucose, and has vitamin D receptors there.
In this study funded by the National Institutes of Health, Sisley and partners at the University of Cincinnati delivered vitamin D directly to the hypothalamus. The investigators administered the active, potent form of vitamin D—called 1,25-dihydroxyvitamin D3—to obese male rats through a cannula (thin tube) surgically inserted using anesthesia into the brain’s third ventricle. This narrow cavity lies within the hypothalamus. Rats recovered their presurgery body weight, and the researchers verified the correct cannula placement.
The animals received nothing to eat for four hours, so they could have a fasting blood sugar measurement. Afterward, 12 rats received vitamin D dissolved in a solution acting as a vehicle for drug delivery. Another 14 rats, matched in body weight to the first group, received only the vehicle, thus serving as controls. One hour later, all rats had a glucose tolerance test, in which they received an injection of dextrose, a sugar, in their abdomen, followed by measurement of their blood sugar levels again.
Compared with the control rats, animals that received vitamin D had improved glucose tolerance, which is how the body responds to sugar. In a separate experiment, these treated rats also had greatly improved insulin sensitivity, the body’s ability to successfully respond to glucose. When this ability decreases—called insulin resistance—it eventually leads to high blood sugar levels. Two of insulin’s main effects are to clear glucose from the bloodstream and decrease glucose production in the liver. In this study, vitamin D in the brain decreased the glucose created by the liver.
In a separate experiment of long-term vitamin D treatment, the researchers gave three rats vitamin D and four rats vehicle alone for four weeks. They observed a large decrease in food intake and weight in rats receiving vitamin D compared with the group that did not get vitamin D. Over 28 days, the treated group ate nearly three times less food and lost 24 percent of their weight despite not changing the way they burned calories, study data showed. The control group did not lose any weight.
“Vitamin D is never going to be the silver bullet for weight loss, but it may work in combination with strategies we know work, like diet and exercise,” Sisley commented.
She said more research is necessary to determine if obesity alters vitamin D transport into the brain or its action in the brain.
(Source: newswise.com)
Study Links Placental Marker of Prenatal Stress to Brain Mitochondrial Dysfunction
When a woman experiences a stressful event early in pregnancy, the risk of her child developing autism spectrum disorders or schizophrenia increases. Yet how maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood.
New findings by University of Pennsylvania School of Veterinary Medicine scientists suggest that an enzyme found in the placenta is likely playing an important role. This enzyme, O-linked-N-acetylglucosamine transferase, or OGT, translates maternal stress into a reprogramming signal for the brain before birth.
(Image caption: Mice with reduced OGT in their placenta were shorter and leaner than their normal counterparts.)
“By manipulating this one gene, we were able to recapitulate many aspects of early prenatal stress,” said Tracy L. Bale, senior author on the paper and a professor in the Department of Animal Biology at Penn Vet. “OGT seems to be serving a role as the ‘canary in the coal mine,’ offering a readout of mom’s stress to change the baby’s developing brain.”
Bale also holds an appointment in the Department of Psychiatry in Penn’s Perelman School of Medicine. Her co-author is postdoctoral researcher Christopher L. Howerton. The paper was published online in PNAS this week.
OGT is known to play a role in gene expression through chromatin remodeling, a process that makes some genes more or less available to be converted into proteins. In a study published last year in PNAS, Bale’s lab found that placentas from male mice pups had lower levels of OGT than those from female pups, and placentas from mothers that had been exposed to stress early in gestation had lower overall levels of OGT than placentas from the mothers’ unstressed counterparts.
“People think that the placenta only serves to promote blood flow between a mom and her baby, but that’s really not all it’s doing,” Bale said. “It’s a very dynamic endocrine tissue and it’s sex-specific, and we’ve shown that tampering with it can dramatically affect a baby’s developing brain.”
To elucidate how reduced levels of OGT might be transmitting signals through the placenta to a fetus, Bale and Howerton bred mice that partially or fully lacked OGT in the placenta. They then compared these transgenic mice to animals that had been subjected to mild stressors during early gestation, such as predator odor, unfamiliar objects or unusual noises, during the first week of their pregnancies.
The researchers performed a genome-wide search for genes that were affected by the altered levels of OGT and were also affected by exposure to early prenatal stress using a specific activational histone mark and found a broad swath of common gene expression patterns.
They chose to focus on one particular differentially regulated gene called Hsd17b3, which encodes an enzyme that converts androstenedione, a steroid hormone, to testosterone. The researchers found this gene to be particularly interesting in part because neurodevelopmental disorders such as autism and schizophrenia have strong gender biases, where they either predominantly affect males or present earlier in males.
Placentas associated with male mice pups born to stressed mothers had reduced levels of the enzyme Hsd17b3, and, as a result, had higher levels of androstenedione and lower levels of testosterone than normal mice.
“This could mean that, with early prenatal stress, males have less masculinization,” Bale said. “This is important because autism tends to be thought of as the brain in a hypermasculinized state, and schizophrenia is thought of as a hypomasculinized state. It makes sense that there is something about this process of testosterone synthesis that is being disrupted.”
Furthermore, the mice born to mothers with disrupted OGT looked like the offspring of stressed mothers in other ways. Although they were born at a normal weight, their growth slowed at weaning. Their body weight as adults was 10-20 percent lower than control mice.
Because of the key role that that the hypothalamus plays in controlling growth and many other critical survival functions, the Penn Vet researchers then screened the mouse genome for genes with differential expression in the hypothalamus, comparing normal mice, mice with reduced OGT and mice born to stressed mothers.
They identified several gene sets related to the structure and function of mitochrondria, the powerhouses of cells that are responsible for producing energy. And indeed, when compared by an enzymatic assay that examines mitochondria biogenesis, both the mice born to stressed mothers and mice born to mothers with reduced OGT had dramatically reduced mitochondrial function in their hypothalamus compared to normal mice. These studies were done in collaboration with Narayan Avadhani’s lab at Penn Vet.
Such reduced function could explain why the growth patterns of mice appeared similar until weaning, at which point energy demands go up.
“If you have a really bad furnace you might be okay if temperatures are mild,” Bale said. “But, if it’s very cold, it can’t meet demand. It could be the same for these mice. If you’re in a litter close to your siblings and mom, you don’t need to produce a lot of heat, but once you wean you have an extra demand for producing heat. They’re just not keeping up.”
Bale points out that mitochondrial dysfunction in the brain has been reported in both schizophrenia and autism patients.
In future work, Bale hopes to identify a suite of maternal plasma stress biomarkers that could signal an increased risk of neurodevelopmental disease for the baby.
“With that kind of a signature, we’d have a way to detect at-risk pregnancies and think about ways to intervene much earlier than waiting to look at the term placenta,” she said.
Leptin also influences brain cells that control appetite
Twenty years after the hormone leptin was found to regulate metabolism, appetite, and weight through brain cells called neurons, Yale School of Medicine researchers have found that the hormone also acts on other types of cells to control appetite.
Published in the June 1 issue of Nature Neuroscience, the findings could lead to development of treatments for metabolic disorders such as obesity and diabetes.
"Up until now, the scientific community thought that leptin acts exclusively in neurons to modulate behavior and body weight," said senior author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine. "This work is now changing that paradigm."
Leptin, a naturally occurring hormone, is known for its hunger-blocking effect on the hypothalamus, a region in the brain. Food intake is influenced by signals that travel from the body to the brain. Leptin is one of the molecules that signal the brain to modulate food intake. It is produced in fat cells and informs the brain of the metabolic state. If animals are missing leptin, or the leptin receptor, they eat too much and become severely obese.
Leptin’s effect on metabolism has been found to control the brain’s neuronal circuits, but no previous studies have definitively found that leptin could control the behavior of cells other than neurons.
To test the theory, Horvath and his team selectively knocked out leptin receptors in the adult non-neuronal glial cells of mice. The team then recorded the water and food intake, as well as physical activity every five days. They found that animals responded less to feeding reducing effects of leptin but had heightened feeding responses to the hunger hormone ghrelin.
"Glial cells provide the main barrier between the periphery and the brain," said Horvath. "Thus glial cells could be targeted for drugs that treat metabolic disorders, including obesity and diabetes."
(Source: eurekalert.org)
The brain’s reaction to male odor shifts at puberty in children with gender dysphoria
The brains of children with gender dysphoria react to androstadienone, a musky-smelling steroid produced by men, in a way typical of their biological sex, but after puberty according to their experienced gender, finds a study for the first time in the open-access journal Frontiers in Endocrinology.
Around puberty, the testes of men start to produce androstadienone, a breakdown product of testosterone. Men release it in their sweat, especially from the armpits. Its only known function is to work like a pheromone: when women smell androstadienone, their mood tends to improve, their blood pressure, heart rate, and breathing go up, and they may become aroused.
Previous studies have shown that, in heterosexual women, the brain region that responds most to androstadienone is the hypothalamus, which lies just above the brainstem and links the nervous system to the hormonal system. In men with gender dysphoria (formerly called gender identity disorder) – who are born as males, but behave as and identify with women, and want to change sex – the hypothalamus also reacts strongly to its odor. In contrast, the hypothalamus of heterosexual men hardly responds to it.
Girls without gender dysphoria before puberty already show a stronger reaction in the hypothalamus to androstadienone than boys, finds a new study by Sarah Burke and colleagues from the VU University Medical Center of Amsterdam, the Netherlands, and the University of Liège, Belgium.
The researchers used neuroimaging to also show for the first time that in prepubescent children with gender dysphoria, the hypothalamus reacts to the smell of androstadienone in a way typical of their biological sex. Around puberty, its response shifts, and becomes typical of their experienced gender.
The reaction to the smell of androstadienone in the hypothalamus of 154 children and adolescents, including girls and boys, both before (7 to 11-year-old) and after puberty (15 to 16-year-old), of whom 74 had been diagnosed with gender dysphoria.
Results showed that the hypothalamus was more responsive to androstadienone in 7 to 11-year-old girls than in boys, both without gender dysphoria, although not yet as much as in adolescent girls. This means that the greater receptiveness of women to its odor already exists before puberty, either as an inborn difference or one that arises during early childhood.
Before puberty, the hypothalamus of boys with gender dysphoria hardly reacted to the odor, just as in other boys. But this changed in the 15 to 16-year-olds: the hypothalamus of adolescent boys with gender dysphoria now lit up as much as in heterosexual women, while the other adolescent boys still did not show any reaction. Adolescent girls with gender dysphoria showed the same reaction to androstadienone in their hypothalamus as is typical for heterosexual men.
These results suggest that as children with gender dysphoria grow up, their brain naturally undergoes a partial rewiring, to become more similar to the brain of the opposite sex – so corresponding to their experienced gender.
Researchers Discover the Seat of Sex and Violence in the Brain
As reported in a paper published online today in the journal Nature, Caltech biologist David J. Anderson and his colleagues have genetically identified neurons that control aggressive behavior in the mouse hypothalamus, a structure that lies deep in the brain (orange circle in the image). Researchers have long known that innate social behaviors like mating and aggression are closely related, but the specific neurons in the brain that control these behaviors had not been identified until now.
The interdisciplinary team of graduate students and postdocs, led by Caltech senior research fellow Hyosang Lee, found that if these neurons are strongly activated by pulses of light, using a method called optogenetics, a male mouse will attack another male or even a female. However, weaker activation of the same neurons will trigger sniffing and mounting: mating behaviors. In fact, the researchers could switch the behavior of a single animal from mounting to attack by gradually increasing the strength of neuronal stimulation during a social encounter (inhibiting the neurons, in contrast, stops these behaviors dead in their tracks).
These results suggest that the level of activity within the population of neurons may control the decision between mating and fighting.
The neurons initially were identified because they express a protein receptor for the hormone estrogen, reinforcing the view that estrogen plays an important role in the control of male aggression, contrary to popular opinion. Because the human brain contains a hypothalamus that is structurally similar to that in the mouse, these results may be relevant to human behavior as well.
Can ‘love hormone’ protect against addiction?
Researchers at the University of Adelaide say addictive behaviour such as drug and alcohol abuse could be associated with poor development of the so-called “love hormone” system in our bodies during early childhood.
The groundbreaking idea has resulted from a review of worldwide research into oxytocin, known as the “love hormone” or “bonding drug” because of its important role in enhancing social interactions, maternal behaviour and partnership.
This month’s special edition of the international journal Pharmacology, Biochemistry and Behavior deals with the current state of research linking oxytocin and addiction, and has been guest edited by Dr Femke Buisman-Pijlman from the University of Adelaide’s School of Medical Sciences.
Dr Buisman-Pijlman, who has a background in both addiction studies and family studies, says some people’s lack of resilience to addictive behaviours may be linked to poor development of their oxytocin systems.
"We know that newborn babies already have levels of oxytocin in their bodies, and this helps to create the all-important bond between a mother and her child. But our oxytocin systems aren’t fully developed when we’re born - they don’t finish developing until the age of three, which means our systems are potentially subject to a range of influences both external and internal," Dr Buisman-Pijlman says.
She says the oxytocin system develops mainly based on experiences.
"The main factors that affect our oxytocin systems are genetics, gender and environment. You can’t change the genes you’re born with, but environmental factors play a substantial role in the development of the oxytocin system until our systems are fully developed," Dr Buisman-Pijlman says.
"Previous research has shown that there is a high degree of variability in people’s oxytocin levels. We’re interested in how and why people have such differences in oxytocin, and what we can do about it to have a beneficial impact on people’s health and wellbeing," she says.
She says studies show that some risk factors for drug addiction already exist at four years of age. “And because the hardware of the oxytocin system finishes developing in our bodies at around age three, this could be a critical window to study. Oxytocin can reduce the pleasure of drugs and feeling of stress, but only if the system develops well.”
Her theory is that adversity in early life is key to the impaired development of the oxytocin system. “This adversity could take the form of a difficult birth, disturbed bonding or abuse, deprivation, or severe infection, to name just a few factors,” Dr Buisman-Pijlman says.
"Understanding what occurs with the oxytocin system during the first few years of life could help us to unravel this aspect of addictive behaviour and use that knowledge for treatment and prevention."
Study provides surprising new clue to the roots of hunger
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."
(Source: eurekalert.org)
According to the National Institute of Mental Health, over 18 percent of American adults suffer from anxiety disorders, characterized as excessive worry or tension that often leads to other physical symptoms. Previous studies of anxiety in the brain have focused on the amygdala, an area known to play a role in fear. But a team of researchers led by biologists at the California Institute of Technology (Caltech) had a hunch that understanding a different brain area, the lateral septum (LS), could provide more clues into how the brain processes anxiety. Their instincts paid off—using mouse models, the team has found a neural circuit that connects the LS with other brain structures in a manner that directly influences anxiety.
"Our study has identified a new neural circuit that plays a causal role in promoting anxiety states," says David Anderson, the Seymour Benzer Professor of Biology at Caltech, and corresponding author of the study. "Part of the reason we lack more effective and specific drugs for anxiety is that we don’t know enough about how the brain processes anxiety. This study opens up a new line of investigation into the brain circuitry that controls anxiety."
The team’s findings are described in the January 30 version of the journal Cell.
Led by Todd Anthony, a senior research fellow at Caltech, the researchers decided to investigate the so-called septohippocampal axis because previous studies had implicated this circuit in anxiety, and had also shown that neurons in a structure located within this axis—the LS—lit up, or were activated, when anxious behavior was induced by stress in mouse models. But does the fact that the LS is active in response to stressors mean that this structure promotes anxiety, or does it mean that this structure acts to limit anxiety responses following stress? The prevailing view in the field was that the nerve pathways that connect the LS with different brain regions function as a brake on anxiety, to dampen a response to stressors. But the team’s experiments showed that the exact opposite was true in their system.
In the new study, the team used optogenetics—a technique that uses light to control neural activity—to artificially activate a set of specific, genetically identified neurons in the LS of mice. During this activation, the mice became more anxious. Moreover, the researchers found that even a brief, transient activation of those neurons could produce a state of anxiety lasting for at least half an hour. This indicates that not only are these cells involved in the initial activation of an anxious state, but also that an anxious state persists even after the neurons are no longer being activated.
"The counterintuitive feature of these neurons is that even though activating them causes more anxiety, the neurons are actually inhibitory neurons, meaning that we would expect them to shut off other neurons in the brain," says Anderson, who is also an investigator with the Howard Hughes Medical Institute (HHMI).
So, if these neurons are shutting off other neurons in the brain, then how can they increase anxiety? The team hypothesized that the process might involve a double-inhibitory mechanism: two negatives make a positive. When they took a closer look at exactly where the LS neurons were making connections in the brain, they saw that they were inhibiting other neurons in a nearby area called the hypothalamus. Importantly, most of those hypothalamic neurons were, themselves, inhibitory neurons. Moreover, those hypothalamic inhibitory neurons, in turn, connected with a third brain structure called the paraventricular nucleus, or PVN. The PVN is well known to control the release of hormones like cortisol in response to stress and has been implicated in anxiety.
This anatomical circuit seemed to provide a potential double-inhibitory pathway through which activation of the inhibitory LS neurons could lead to an increase in stress and anxiety. The team reasoned that if this hypothesis were true, then artificial activation of LS neurons would be expected to cause an increase in stress hormone levels, as if the animal were stressed. Indeed, optogenetic activation of the LS neurons increased the level of circulating stress hormones, consistent with the idea that the PVN was being activated. Moreover, inhibition of LS projections to the hypothalamus actually reduced the rise in cortisol when the animals were exposed to stress. Together these results strongly supported the double-negative hypothesis.
"The most surprising part of these findings is that the outputs from the LS, which were believed primarily to act as a brake on anxiety, actually increase anxiety," says Anderson.
Knowing the sign—positive or negative—of the effect of these cells on anxiety, he says, is a critical first step to understanding what kind of drug one might want to develop to manipulate these cells or their molecular constituents. If the cells had been found to inhibit anxiety, as originally thought, then one would want to find drugs that activate these LS neurons, to reduce anxiety. However, since the group found that these neurons instead promote anxiety, then to reduce anxiety a drug would have to inhibit these neurons.
"We are still probably a decade away from translating this very basic research into any kind of therapy for humans, but we hope that the information that this type of study yields about the brain will put the field and medicine in a much better position to develop new, rational therapies for psychiatric disorders," says Anderson. "There have been very few new psychiatric drugs developed in the last 40 to 50 years, and that’s because we know so little about the brain circuitry that controls the emotions that go wrong in a psychiatric disorder like depression or anxiety."
The team will continue to map out this area of the brain in greater detail to understand more about its role in controlling stress-induced anxiety.
"There is no shortage of new questions that have been raised by these findings," Anderson says. "It may seem like all that we’ve done here is dissect a tiny little piece of brain circuitry, but it’s a foothold onto a very big mountain. You have to start climbing someplace."