hypothalamus,

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.

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Scientists Tinker with Neurons to Turn Lovers into Fighters

It would be nice to know how and why aggression occurs. It would give us better insight into everything from international war to schoolyard bullying. New research in mice suggests that estrogen may be more important than testosterone in modulating aggressive behavior, and that sex and aggression may be intimately connected.

A Caltech research group led by David J. Anderson (who also studies aggression in fruit flies) started by identifying a set of neurons in the hypothalamus of mouse brains that are active during social behaviors. Specifically, those neurons are found in the ventromedial hypothalamus, which means they’re near the bottom (ventral) and interior (medial) surfaces of the hypothalamus.

The hypothalamus, which is contained in the brains of all vertebrate species, is involved in a wide variety of functions, from regulating circadian rhythms and thirst to modulating anti-predator defense and parenting behaviors. It’s therefore not surprising that the mouse hypothalamus is active during social encounters, both between two males and between males and females.

But rather than be content that this cluster of neurons was affiliated with social behavior the researchers, led by research fellow Hyosang Lee, wanted to see whether there was a direct causal relationship between those brain cells and visible social behavior. After all, one important “unsolved problem in neuroscience,” according to Anderson, is how the selection of overt behaviors is encoded in the brain.

Using a technique called optogenetics, the group used pulses of light directed through an electrode implanted in the brains of the mice to activate or inhibit those particular neurons. Indeed, they found that when they artificially activated hypothalamic brain cells, the male mice became more aggressive, even attacking females and toy mice. On the other hand, if they temporarily stopped the activity of those neurons, they could eliminate all aggression, even in the middle of a fight.

When they tried to activate those same cells in the brains of female mice, they weren’t able to induce attack-related behaviors, but they did increase “social investigation.” It isn’t that female mice aren’t capable of aggression, or that those cells aren’t used for social behaviors in females, just that other cells must be somehow more important for female aggression.

What the researchers identified a cluster of cells directly responsible for aggression in males is interesting to be sure, but what’s more interesting is just how those cells work.

For one thing, the neurons – which initiate attack behaviors in males but not females – have specialized receptors for binding to estrogen. While the nuances of the relationship between the hormone estrogen and the neurobiology of those cells are still not entirely understood, the finding adds to a growing pile of evidence that estrogen plays a key role in guiding male aggression.

If that wasn’t enough to make you sit up and take notice, the estrogen-sensitive neurons of the male hypothalamus have another curious feature. It’s not as if these cells act as an on-off switch, such that when activated they promote aggression, and when inhibited they stop attacks from occurring. Instead, they’re more like volume control knobs.

When the researchers used their optogenetic techniques to create a high level of activation, as if they were turning the volume all the way up to 11, the mice launched their attack behaviors. But when they activated those cells only weakly, if the volume knob was set to just 1 or 2 or 3, the males instead initiated mating-related behaviors. By fiddling with the knobs, the researchers could provoke their male mice to mount not just females, but also males, both intact and castrated.

By slowly increasing the strength of neural stimulation, the researchers were even able to switch the behavior of individual mice from sexual mounting to attack! Kissing becomes killing, humping becomes homicide (well, muricide, technically).

There were two important differences between the way these neurons responded to artificial stimulation for aggression and for mating. First, even though the researchers could invoke the males to attempt to mate with other males, the pair never actually proceeded to pelvic thrusting or ejaculation. Second, if the researchers inhibited those cells while male and female mice were already having sex, they didn’t stop. That’s contrary to the findings for aggression, since the researchers were able to artificially disrupt a fight.

What does it all mean? At the neurobiological level, it tells us that the level of activity in those neurons determines, at least in part, just what sort of social behavior is elicited.

It’s easy to run away with endless speculations based on these findings, but it’s worth taking a step back. For one thing, this work was done in mice, and there are plenty of reasons to suspect that mice are fairly unreliable as a model species when it comes to gaining better insight into our own. For another, the brain is perhaps the most complicated system in the known universe, and even the simplest behavior is the consequence of dizzying complexity.

Still, the finding further erodes the common views that aggression is controlled primarily by testosterone, and that estrogen is associated with more stereotypically feminine behaviors. Rather, estrogen is important both for males and for females, and is implicated in different types of social behavior. Could the same be true for humans? At least one thing is for certain: neurobiology is simply more complicated than the prevailing assumptions would lead you to believe.

Deep within the brain’s hypothalamus, there is a collection of neurons that serve as the central regulators of appetite, metabolism and fat storage. Called the arcuate nucleus, these neurons respond to circulating hunger and satiety signals in blood, increasing or decreasing our food intake accordingly.

It’s no wonder then, that the arcuate nucleus is one of the main focus areas when looking into the neurological influences of obesity. In a recent study, researchers at Children’s Hospital Los Angeles (CHLA) found that the presence of the “hunger hormone” ghrelin—which initiates our urge to eat—in early infancy can cause changes to the arcuate nucleus that may link to an increased risk of obesity later in life.

Read more about how ghrelin levels affect the brain and influence obesity risk

Image Caption: Immunofluorescent staining of neuronal culture derived from the arcuate nucleus

Image Credit: Richard Simerly, PhD, director of the Developmental Neuroscience Program and deputy director of The Saban Research Institute of CHLA

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.”

The neural basis of ‘being in the mood’

What determines receptivity or rejection towards potential sexual partners? For people, there are many factors that play a part, appearance, culture, age, are all taken into account. But what part does the internal state of the individual play? The functioning of our bodies is maintained through a complicated system of hormonal signals. Some of these signals vary along different physiological rhythms, such as the menstrual cycle. How do changes in hormone-levels affect the activity of individuals’ brains and their behaviour?

“It is well known that the behaviour of female mice changes dramatically during the different phases of their reproductive cycle, called the Estrous cycle”, says Susana Lima, a principal investigator at the Champalimaud Centre for the Unknown in Lisbon. “Responses to brief social interactions with males can result in radically different outcomes ranging from receptivity to aggression. In this study, we investigated the question - what is the neural basis that underlies these polar behaviours?”

The researchers chose to focus their research on the hypothalamus. “The hypothalamus regulates many instinctive behaviours, including feeding, sleep and sexual behaviour”, says Kensaku Nomoto, a postdoctoral researcher in the lab of Susana Lima. “We recorded the activity of neurons in an area within the hypothalamus dedicated to socio-sexual behaviour. The activity of the neurons was observed while the females interacted with males or with other females.”

The researchers found that the activity of these neurons changed dramatically depending on the reproductive state of the female. “When the female was not in a receptive state, the activity of the neurons was similar for social encounters with males and females. However, when the female was in the receptive state, the activity of the neurons was enhanced only when interacting with males”, says Dr. Nomoto.

“This is the first time that the activity of these neurons is recorded in naturally cycling females, where we investigated the effect of the reproductive cycle on neuronal physiology. It establishes that there is in fact a brain region where hormonal state and social interaction are integrated. In humans, the effect of hormonal state on attraction and rejection is quite controversial, studies such as this one, may help shed light on the neural circuits that mediate these behaviours.” Concludes Dr. Lima.

Image credit: Gil Costa

Fat signals control energy levels in the brain

An enzyme secreted by the body’s fat tissue controls energy levels in the brain, according to new research at Washington University School of Medicine in St. Louis. The findings, in mice, underscore a role for the body’s fat tissue in controlling the brain’s response to food scarcity, and suggest there is an optimal amount of body fat for maximizing health and longevity.

The study appears April 23 in the journal Cell Metabolism.

“We showed that fat tissue controls brain function in a really interesting way,” said senior author Shin-ichiro Imai, MD, PhD, professor of developmental biology and of medicine. “The results suggest that there is an optimal amount of fat tissue that maximizes the function of the control center of aging and longevity in the brain. We still don’t know what that amount is or how it might vary by individual. But at least in mice, we know that if they don’t have enough of a key enzyme produced by fat, an important part of the brain can’t maintain its energy levels.”

The findings may help explain the many studies that show a survival benefit to having a body mass index toward the low end of what is considered overweight.

“As we age, people who are slightly overweight tend to have fewer problems,” Imai said. “No one knows why people categorized as being slightly overweight tend to have a lower mortality rate. But our study suggests that if you don’t have an optimal amount of fat, you are affecting a part of the brain that is particularly important for controlling metabolism and aging.”

Imai and his colleagues study how cells produce and utilize energy and how that affects aging. Past work of theirs and others demonstrated the importance of an enzyme called NAMPT in producing a vital cellular fuel called NAD. Traditionally, NAMPT is thought to be important for making this fuel inside cells. But Imai and members of his team noticed that fat tissue churned out a lot of NAMPT that ended up outside cells, circulating in the bloodstream.

“There’s been a lot of controversy in the field about whether extracellular NAMPT has any function in the body,” Imai said. “Some researchers have said it’s just a result of leakage from dead cells. But our data indicate it is a highly active enzyme that is highly regulated.”

Such fine-tuned regulation suggests secreted NAMPT is doing something important somewhere in the body. To find out what that is, the researchers raised mice that lacked the ability to produce NAMPT only in the fat tissue.

“We were not surprised to see that energy levels in the fat tissue plummeted when fat tissue lacked this key enzyme,” Imai said. “Other tissues such as the liver and muscles were unaffected. But there was one distant location that was affected, and that was the hypothalamus.”

The hypothalamus is a part of the brain known to have important roles in maintaining the body’s physiology, including regulating body temperature, sleep cycles, heart rate, blood pressure, thirst and appetite. Mice with low NAMPT in fat tissue had low fuel levels in the hypothalamus. These mice also showed lower measures of physical activity than mice without this defect.

Their findings suggest that fat tissue communicates specifically with the hypothalamus, influencing the way the brain controls the body’s physiologic set points. Indeed, past work from Imai’s group also supported an important role for the hypothalamus in whole body metabolism. They showed that increasing the expression of a protein called SIRT1 in the mouse hypothalamus increased the mouse lifespan, mimicking the effects of a calorie-restricted diet.  

Imai suspects that all these processes influence one another. Their past work on the hypothalamus also had shown that SIRT1 function is dependent on energy levels in cells. And the new paper links energy levels in the hypothalamus to the fat tissue’s newly identified function.

After examining what happens to mice with fat tissue that doesn’t make NAMPT, they performed the opposite experiment, studying mice that produced more NAMPT in fat tissue than is typical.

Mice that expressed high levels of NAMPT in the fat tissue were very physically active. Their activity levels were especially pronounced after fasting. The mice with low NAMPT in the fat tissue became even more lethargic after the fasting period. The mice with an overabundance of NAMPT in the fat tissue appeared unaffected by the period of time without food, remaining at activity levels similar to normal mice without food restriction. In fact, the mice with a lot of NAMPT produced in their fat behaved very similarly to the mice with a lot of SIRT1 in the brain.

Imai said they are now studying whether an overabundance of NAMPT in the fat increases lifespan, as they showed in the mice with an overabundance of SIRT1 in the brain.

The researchers also found they could temporarily boost the physical activity of the mice with low NAMPT in the fat tissue by injecting NMN, the compound that the enzyme NAMPT produces. Imai is investigating NMN as a possible intervention in diseases associated with aging.

Imai speculated that this NAMPT signal from the fat tissue, especially in response to fasting, may serve as a survival mechanism.

“This phenomenon makes sense in the wild,” Imai said. “If you can’t get food and you just sit around and wait, you won’t survive. So the brain, working in conjunction with the fat tissue, has a way to kick in and let you move to survive, even when food is scarce.”

Researchers: Eating too much fat can injure parts of your brain

C is for Uh-Oh: Medical researchers have found that within 24 hours of a high-fat diet, there is measurable damage in the brains of rodents and humans. “Obese individuals are biologically defending their elevated body weight,” said Dr. Michael Schwartz, a professor at the University of Washington. The study indicates that eating fat leads to changes in the brain, and in the body, because it affects the hypothalamus, which regulates weight. source

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Scientists Uncover Unique Role of Nerve Cells in the Body’s Use of Energy

While it is well-known that weight gain results from an imbalance between what we eat and our energy expenditure, what is not obvious is the role that the nervous system plays in controlling that energy balance. Now scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed light on that question.

“Our new study has identified novel populations of nerve cells that regulate appetite, thermogenesis and physical activity,” said TSRI Professor Baoji Xu, who led the research. “We think these neurons could be targets for drug development.”

The findings were published by the journal Cell Metabolism online ahead of print on June 11.

In the new study, Xu and his colleagues examined several groups of neurons that express a substance called “brain-derived neurotrophic factor” (BDNF) within a small brain region called the paraventricular hypothalamus.

BDNF is an extremely important protein in the brain and is involved in a number of functions. It has been shown that deleting the BDNF gene causes significant problems, among them, dramatically increased appetite (hyperphagia) and severe obesity.

The new study shows that deleting the BDNF gene also impairs thermogenesis—the ability of cells to burn fat to produce heat. The study further reveals two distinct types of BDNF neurons—those that control appetite or satiety and those that control thermogenesis. Not only do these two groups play different biological roles, they are located in two separate sections of the paraventricular hypothalamus brain region.

This “geographical” split raises some interesting questions. “We don’t yet know what the distinctive placement means to the control of body weight, nor do we know if these two clusters of neurons communicate with each other as yet,” said Juanji An, the first author of the study and a member of the Xu lab. “But given the fact that mice and humans with mutations in the BDNF gene or its receptor develop severe obesity, a better understanding of the mechanism underlying the effect BDNF has on body weight could provide great insights into the regulation of energy balance.”

Xu is also hopeful about the potential of BDNF as a drug target. “Our findings suggest that activation of each of these two populations of neurons should powerfully suppress appetite or promote energy expenditure,” he said. However, he cautions that because BDNF’s functions are so widespread, a good drug candidate would need to closely target only BDNF-expressing neurons in the paraventricular hypothalamus, thus limiting potential side effects.

In the hypothalamus we take small chain proteins called "peptides" and we assemble them into certain neural peptides, or neural horomones that match the emotional states we experience on a daily basis.

The cells are yelling up to the brain saying, we haven’t gotten our fix today, and it’s going to start sending impressions to the brain, and the brain is going to start formulating imagery. It’s going to sound like voices in our head, to think of a reason why we should be depressed, think of a reason why we should be confused, think of a reason for our own suffering. And the body is going to be telling the brain that it’s not getting its chemical needs met. And so the brain will then activate and start going to our past situations and flashing pictures to our frontal lobe. But my definition of an addiction is something really simple; something that you can’t stop. We bring to ourselves situations that will fulfill the biochemical craving of our body, by creating situations that create our chemical need. So my definition really means that if you can’t control your emotional state, you must be addicted to it.