Foetal exposure to excessive stress hormones in the womb linked to adult mood disorders

Exposure of the developing foetus to excessive levels of stress hormones in the womb can cause mood disorders in later life and now, for the first time, researchers have found a mechanism that may underpin this process, according to research presented today (Sunday) at the British Neuroscience Association Festival of Neuroscience (BNA2013) in London.

The concept of foetal programming of adult disease, whereby the environment experienced in the womb can have profound long-lasting consequences on health and risk of disease in later life, is well known; however, the process that drives this is unclear. Professor Megan Holmes, a neuroendocrinologist from the University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science in Scotland (UK), will say: “During our research we have identified the enzyme 11ß-HSD2 which we believe plays a key role in the process of foetal programming.”

Adverse environments experienced while in the womb, such as in cases of stress, bereavement or abuse, will increase levels of glucocorticoids in the mother, which may harm the growing baby. Glucocorticoids are naturally produced hormones and they are also known as stress hormones because of their role in the stress response.

“The stress hormone cortisol may be a key factor in programming the foetus, baby or child to be at risk of disease in later life. Cortisol causes reduced growth and modifies the timing of tissue development as well as having long lasting effects on gene expression,” she will say.

Prof Holmes will describe how her research has identified an enzyme called 11ß-HSD2 (11beta-hydroxysteroid dehydrogenase type 2) that breaks down the stress hormone cortisol to an inactive form, before it can cause any harm to the developing foetus. The enzyme 11ß-HSD2 is present in the placenta and the developing foetal brain where it is thought to act as a shield to protect against the harmful actions of cortisol.

Prof Holmes and her colleagues developed genetically modified mice that lacked 11ß-HSD2 in order to determine the role of the enzyme in the placenta and foetal brain. “In mice lacking the enzyme 11ß-HSD2, foetuses were exposed to high levels of stress hormones and, as a consequence, these mice exhibited reduced foetal growth and went on to show programmed mood disorders in later life. We also found that the placentas from these mice were smaller and did not transport nutrients efficiently across to the developing foetus. This too could contribute to the harmful consequences of increased stress hormone exposure on the foetus and suggests that the placental 11ß-HSD2 shield is the most important barrier.

“However, preliminary new data show that with the loss of the 11ß-HSD2 protective barrier solely in the brain, programming of the developing foetus still occurs, and, therefore, this raises questions about how dominant a role is played by the placental 11ß-HSD2 barrier. This research is currently ongoing and we cannot draw any firm conclusions yet.

“Determining the exact molecular and cellular mechanisms that drive foetal programming will help us identify potential therapeutic targets that can be used to reverse the deleterious consequences on mood disorders. In the future, we hope to explore the potential of these targets in studies in humans,” she will say.

Prof Holmes hopes that her research will make healthcare workers more aware of the fact that children exposed to an adverse environment, be it abuse, malnutrition, or bereavement, are at an increased risk of mood disorders in later life and the children should be carefully monitored and supported to prevent this from happening.

In addition, the potential effects of excessive levels of stress hormones on the developing foetus are also of relevance to individuals involved in antenatal care. Within the past 20 years, the majority of women at risk of premature delivery have been given synthetic glucocorticoids to accelerate foetal lung development to allow the premature babies to survive early birth.

“While this glucocorticoid treatment is essential, the dose, number of treatments and the drug used, have to be carefully monitored to ensure that the minimum effective therapy is used, as it may set the stage for effects later in the child’s life,” Prof Holmes will say.

Puberty is another sensitive time of development and stress experienced at this time can also be involved in programming adult mood disorders. Prof Holmes and her colleagues have found evidence from imaging studies in rats that stress in early teenage years could affect mood and emotional behaviour via changes in the brain’s neural networks associated with emotional processing.

The researchers used fMRI (Functional Magnetic Resonance Imaging) to see which pathways in the brain were affected when stressed, peripubertal rats responded to a specific learned task.

Prof Holmes will say: “We showed that in stressed ‘teenage’ rats, the part of the brain region involved in emotion and fear (known as amygdala) was activated in an exaggerated fashion when compared to controls. The results from this study clearly showed that altered emotional processing occurs in the amygdala in response to stress during this crucial period of development.”

(Image: iStockphoto)

Researchers shine light on how stress circuits learn

Researchers at the University of Calgary’s Hotchkiss Brain Institute have discovered that stress circuits in the brain undergo profound learning early in life. Using a number of cutting edge approaches, including optogenetics, Jaideep Bains, PhD, and colleagues have shown stress circuits are capable of self-tuning following a single stress. These findings demonstrate that the brain uses stress experience during early life to prepare and optimize for subsequent challenges.

The team was able to show the existence of unique time windows following brief stress challenges during which learning is either increased or decreased. By manipulating specific cellular pathways, they uncovered the key players responsible for learning in stress circuits in an animal model. These discoveries culminated in the publication of two back-to-back studies in the April 7 online edition of Nature Neuroscience [1, 2], one of the world’s top neuroscience journals.

"These new findings demonstrate that systems thought to be ‘hardwired’ in the brain, are in fact flexible, particularly early in life," says Bains, a professor in the Department of Physiology and Pharmacology. "Using this information, researchers can now ask questions about the precise cellular and molecular links between early life stress and stress vulnerability or resilience later in life."

Stress vulnerability, or increased sensitivity to stress, has been implicated in numerous health conditions including cardiovascular disease, obesity, diabetes and depression. Although these studies used animal models, similar mechanisms mediate disease progression in humans.

"Our observations provide an important foundation for designing more effective preventative and therapeutic strategies that mitigate the effects of stress and meet society’s health challenges," he says.

Study stops stress-based drug relapse in rats

All too often, stress turns addiction recovery into relapse, but years of basic brain research have provided scientists with insight that might allow them develop a medicine to help. A new study in the journal Neuron pinpoints the neural basis for stress-related relapse in rat models to an unprecedented degree. The advance could accelerate progress toward a medicine that prevents stress from undermining addiction recovery.

In the paper published March 6, researchers at Brown University and the University of Pennsylvania demonstrated specific steps in the sequence of neural events underlying stress-related drug relapse and showed that they take place within a brain region called the ventral tegmental area (VTA), which helps reinforce behaviors related to fulfilling basic needs. They also showed that a closely related neural process believed to be crucial to stress-related relapse may not be involved after all.

Moreover, this new understanding allowed the researchers to prevent relapse to drug seeking in the animal model. When they treated rats that had recovered from cocaine addiction with a chemical that blocks the “kappa opioid receptors” that stress activates in the VTA, the rats did not relapse to cocaine use under stress. Untreated rats who had also recovered from addiction did relapse after the same stress.

The chemical that helped the rats, “nor-BNI,” may be one that would someday be tried in humans, said study senior author Julie Kauer, professor of biology in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. By deepening scientists’ understanding of the stress-related relapse mechanism, she and her co-authors hope to identify multiple possible targets for eventual patient treatments.

“If we understand how kappa opioid receptor antagonists are interfering with the reinstatement of drug seeking we can target that process,” Kauer said. “We’re at the point of coming to understand the processes and possible therapeutic targets. Remarkably, this has worked.”

The neural crux of relapse

Exactly how stress acts in the brain to trigger relapse is a complicated sequence that is still not fully understood, but the new study focuses on and elucidates three key players at the crux of the phenomenon in the VTA: GABA-releasing neurons, dopamine-releasing neurons, and the kappa opioid receptors that affect their connections.

Fulfilling natural needs such as hunger or thirst results in a rewarding release of dopamine from the VTA’s dopamine neurons, Kauer said. Unfortunately, so does using drugs of abuse.

In normal brain function, GABA applies the brakes on the rewarding dopamine release, slowing it back to a normal level. It achieves this by forging and then strengthening the connections, called synapses, with the dopamine neuron. The strengthening process is called long-term potentiation (LTP).

In the first of their experiments, the team at Brown, including lead author Nicholas Graziane, showed that stress interrupts the LTP process, hindering GABA’s ability to slam the brakes on dopamine release.

Previous research implicated kappa opioid receptors as one of many neural entities that could have a role in stress-related relapse. Kauer, Graziane, and co-author Abigail Polter investigated that directly by blocking the receptors in some rats with a treatment of nor-BNI in the VTA and leaving others untreated. Then they subjected the rats to a standardized five-minute stress exercise. After 24 hours they looked at the cells in the VTA and found that LTP was hindered in the untreated rats but still present and underway in the rats whose receptors had been blocked with nor-BNI.

With the role of stress and the receptors in the GABA-dopamine dynamic both confirmed and then mitigated, the question remained: Could this knowledge be used to prevent relapse?

To answer that, Penn co-authors Lisa Briand and Christopher Pierce performed the experiment demonstrating that nor-BNI delivered directly to the VTA prevented stressed rats from relapsing to cocaine seeking, while untreated rats subjected to the same stress did relapse.

“Our results indicate that the kappa receptors within the VTA critically control stress-induced drug seeking in animals,” the authors wrote in Neuron.

Along the way, the team also discovered evidence that another stress-affected synapse in the VTA – one that excites dopamine release rather than inhibits it – does not play a role in the stress-related relapse as many researchers have thought. The nor-BNI treatment that prevented stress-related relapse, for example, did not affect those synapses.

Kauer emphasized that her lab’s findings of therapeutic potential are the product of more than a decade of essential basic research on the importance of how changes in synapses relate to behaviors including addiction.

“If we can figure out how not only stress, but the whole system works, then we’ll potentially have a way to tune it down in a person who needs that,” she said.

Researchers look to breath to identify stress

According to a new pilot study, published in IOP Publishing’s Journal of Breath Research, there are six markers in the breath that could be candidates for use as indicators of stress.

The researchers hope that findings such as these could lead to a quick, simple and non-invasive test for measuring stress; however, the study, which involved just 22 subjects, would need to be scaled-up to include more people, over a wider range of ages and in more “normal” settings, before any concrete conclusions can be made, they state.

Lead-author of the study, Professor Paul Thomas, said: “If we can measure stress objectively in a non-invasive way, then it may benefit patients and vulnerable people in long-term care who find it difficult to disclose stress responses to their carers, such as those suffering from Alzheimer’s.”

The study, undertaken by researchers at Loughborough University and Imperial College London, involved 22 young adults (10 male and 12 female) who each took part in two sessions: in the first, they were asked to sit comfortably and listen to non-stressful music; in the second, they were asked to perform a common mental arithmetic test that has been designed to induce stress.

A breath test was taken before and after each session, whilst heart-rates and blood pressures were recorded throughout. The breath samples were examined using a technique known as gas chromatography-mass spectrometry, and then statistically analysed and compared to a library of compounds.

Two compounds in the breath – 2-methyl, pentadecane and indole – increased following the stress exercise which, if confirmed, the researchers believe could form the basis of a rapid test.

A further four compounds were shown to decrease with stress, which could be due to changes in breathing patterns.

“What is clear from this study is that we were not able to discount stress. It seems sensible and prudent to test this work with more people over a range of ages in more normal settings.

“We will need to think carefully about experimental design in order to explore this potential relationship further as there are ethical issues to consider when deliberately placing volunteers under stress. Any follow up study would need to be led by experts in stress,” Professor Thomas continued.

Breath profiling has become an attractive diagnostic method for clinicians, and recently researchers have found biomarkers associated with tuberculosis, multiple cancers, pulmonary disease and asthma. It is still unclear how to best manage external factors, such as diet, environment and exercise, which can affect a person’s breath sample.

“It is possible that stress markers in the breath could mask or confound other key compounds that are used to diagnose a certain disease or condition, so it is important that these are accounted for,” said Professor Thomas.

The researcher’s initial assumptions are that stressed people breathe faster and have increased pulse rates and an elevated blood-pressure, which is likely to change their breath profile. They emphasise, however, that it is too soon to postulate the biological origins and the roles of the compounds as part of a stress-sensitive response.

Stressed-Out Tadpoles Grow Larger Tails to Escape Predators

When people or animals are thrust into threatening situations such as combat or attack by a predator, stress hormones are released to help prepare the organism to defend itself or to rapidly escape from danger—the so-called fight-or-flight response.

Now University of Michigan researchers have demonstrated for the first time that stress hormones are also responsible for altering the body shape of developing animals, in this case the humble tadpole, so they are better equipped to survive predator attacks.

Through a series of experiments conducted at field sites and in the laboratory, U-M researchers demonstrated that prolonged exposure to a stress hormone enabled tadpoles to increase the size of their tails, which improved their ability to avoid lethal predator attacks.

"This is the first clear demonstration that a stress hormone produced by the animal can actually cause a morphological change, a change in body shape, that improves their survival in the presence of lethal predators. It’s a survival response," said Robert Denver, a professor of molecular, cellular and developmental biology and of ecology and evolutionary biology.

The team’s surprising findings are detailed in a paper to be published online March 5 in the journal Proceedings of the Royal Society B. First author of the paper is Jessica Middlemis Maher, a former U-M doctoral student, now at Michigan State University, who conducted the work for her dissertation.

Scientists have long known that environmental changes can prompt animals and plants to alter their morphology and physiology, as well as the timing of developmental events. For example, tadpoles can accelerate metamorphosis into frogs in response to a drying pond, a high density of predators or a lack of food.

The term “phenotypic plasticity” is used to describe modifications by animals and plants in response to a changing environment.

"There’s been a lot of interest in phenotypic plasticity among developmental biologists and evolutionary ecologists for more than 70 years, but there’s been relatively little focus on the mechanisms by which the environmental signal is translated into a functional response," Denver said.

"We’ve known, for example, that tadpoles can change their body shape in response to predation risk. But until now, nobody knew the basic physiological mechanisms mediating that response. That’s what’s novel about this study."

(Image: Wikimedia Commons)

Mom’s Placenta Reflects Her Exposure to Stress

The mammalian placenta is more than just a filter through which nutrition and oxygen are passed from a mother to her unborn child. According to a new study by a research group from the University of Pennsylvania School of Veterinary Medicine, if a mother is exposed to stress during pregnancy, her placenta translates that experience to her fetus by altering levels of a protein that affects the developing brains of male and female offspring differently.

These findings suggest one way in which maternal-stress exposure may be linked to neurodevelopmental diseases such as autism and schizophrenia, which affect males more frequently or more severely than females.

“Most everything experienced by a woman during a pregnancy has to interact with the placenta in order to transmit to the fetus,” said Tracy L. Bale, senior author on the paper and an associate professor in the Department of Animal Biology at Penn Vet. “Now we have a marker that appears to signal to the fetus that its mother has experienced stress.”

Bale also holds an appointment in the Department of Psychiatry in Penn’s Perelman School of Medicine. Her coauthors include lead author and postdoctoral researcher Christopher L. Howerton, graduate student Christopher Morgan and former technician David B. Fischer, all of Penn Vet.

Published in the Proceedings of the National Academy of Sciences, the study builds on previous work by Bale and her colleagues which found that female mice exposed to stress during pregnancy gave birth to males who had heightened reactions to stress. Further research showed that the effect extended to the second generation: The sons of those male mice also had abnormal stress reactions.

Meanwhile, human studies conducted by other researchers have shown that males born to women who experience stress in the first trimester of pregnancy are at an increased risk of developing schizophrenia.

The Penn team hoped to find a biomarker that could account for these changes and risk factors. To be an effective signal of maternal stress, the researchers reasoned, a biomarker would need to show differences in expression between male and female offspring and would need to be different between stressed and unstressed mothers. They also wanted to find a marker that behaved similarly in humans.

Malign environmental combination favours schizophrenia

The interplay between an infection during pregnancy and stress in puberty plays a key role in the development of schizophrenia, as behaviourists from ETH Zurich demonstrate in a mouse model. However, there is no need to panic.

Around one per cent of the population suffers from schizophrenia, a serious mental disorder that usually does not develop until adulthood and is incurable. Psychiatrists and neuroscientists have long suspected that adverse enviromental factors may play an important role in the development of schizophrenia. Prenatal infections such as toxoplasmosis or influenza, psychological, stress or family history have all come into question as risk factors. Nevertheless, until now researchers were unable to identify the interplay of the individual factors linked to this serious mental disease.

However, a research group headed by Urs Meyer, a senior scientist at the Laboratory of Physiology & Behaviour at ETH Zurich, has now made a breakthrough: for the first time, they were able to find clear evidence that the combination of two environmental factors contributes significantly to the development of schizophrenia-relevant brain changes and at which stages in a person’s life they need to come into play for the disorder to break out. The researchers developed a special mouse model, with which they were able to simulate the processes in humans virtually in fast forward. The study has just been published in the journal Science.