Posts Tagged ‘stress’
Inherited variations in the amount of an innate anxiety-reducing molecule help explain why some people can withstand stress better than others, according to a new study led by researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH).
“Stress response is an important variable in vulnerability to alcohol dependence and other addictions, as well as other psychiatric disorders,” noted NIAAA Director Ting-Kai Li, M.D. “This finding could help us understand individuals’ initial vulnerability to these disorders.”
Scientists led by David Goldman, M. D., chief of the NIAAA Laboratory of Neurogenetics, identified gene variants that affect the expression of a signaling molecule called neuropeptide Y (NPY). Found in brain and many other tissues, NPY regulates diverse functions, including appetite, weight, and emotional responses.
“NPY is induced by stress and its release reduces anxiety,” said Dr. Goldman. “Previous studies have shown that genetic factors play an important role in mood and anxiety disorders. In this study, we sought to determine if genetic variants of NPY might contribute to the maladaptive stress responses that often underlie these disorders.” A report of the findings appears online today in Nature.
Analyses of human tissue samples led by researchers at NIAAA identified several NPY gene variants. Collaborations with NIH-supported scientists at the University of Michigan, University of Pittsburgh, University of Helsinki, University of Miami, University of Maryland, the University of California at San Diego, and Yale University, showed that these variants result in a range of different effects including altered levels of NPY in brain and other tissues, and differences in emotion and emotion-induced responses of the brain.
The researchers evaluated the NPY gene variants’ effects on brain responses to stress and emotion. Using functional brain imaging, they found that individuals with the variant that yielded the lowest level of NPY reacted with heightened emotionality to images of threatening facial expressions. “Metabolic activity in brain regions involved in emotional processing increased when these individuals were presented with the threatening images,” explained Dr. Goldman.
In another brain imaging experiment, people with the low level NPY variant were found to have a diminished ability to tolerate moderate levels of sustained muscular pain. Previous studies had shown that NPY’s behavioral effects are mediated through interactions with opioid compounds produced by the body to help suppress pain, stress, and anxiety. “As shown by brain imaging of opioid function, these individuals released less opioid neurotransmitter in response to muscle discomfort than did individuals with higher levels of NPY,” said Dr. Goldman. “Their emotional response to pain was also higher, showing the close tie between emotionality and resilience to pain and other negative stimuli.”
In a preliminary finding, the low level NPY gene variant was found to be more common than other variants among a small sample of individuals with anxiety disorders. The researchers also found that low level NPY expression was linked to high levels of trait anxiety. “Trait anxiety is an indication of an individual’s level of emotionality or worry under ordinary circumstances,” explained Dr. Goldman.
The researchers conclude that these converging findings are consistent with NPY’s role as an anxiety-reducing peptide and help explain inter-individual variation in resiliency to stress. “This inherited functional variation could also open up new avenues of research for other human characteristics, such as appetite and metabolism, which are also modulated by NPY,” said Dr. Goldman.
 Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, Maryland 20892, USA  These authors contributed equally to this work.
Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.
Bach is better than sex – applies to the composer rather than the inventor of the same named flowers. One of the most comprehensive investigations done to date on aromatherapy failed to show any improvement in either immune status, wound healing or pain control among people exposed to two often-touted scents.
While one of two popular aromas touted by alternative medicine practitioners – lemon – did appear to enhance moods positively among study subjects, the other – lavender – had no effect on reported mood, based on three psychological tests.
Neither lemon nor lavender showed any enhancement of the subjects’ immune status, nor did the compounds mitigate either pain or stress, based on a host of biochemical markers. In some cases, even distilled water showed a more positive effect than lavender.
The study, published online in the journal Psychoneuroendocrinology, looked for evidence that such aromas go beyond increasing pleasure and actually have a positive medical impact on a person’s health. While a massive commercial industry has embraced this notion in recent decades, little, if any, scientific proof has been offered supporting the products’ health claims.
“We all know that the placebo effect can have a very strong impact on a person’s health but beyond that, we wanted to see if these aromatic essential oils actually improved human health in some measurable way,” explained Janice Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State University and lead author of the study.
The researchers chose lemon and lavender since they were two of the most popular scents tied to aromatherapy. Recently, two other studies focused on these same two scents.
For the study, Kiecolt-Glaser; Ronald Glaser, a professor of molecular virology, immunology and medical genetics, and William Malarkey, professor of internal medicine, assembled a group of 56 healthy volunteers. These men and women were screened beforehand to confirm their ability to detect standard odors. Some were proponents of the merits of aromatherapy while others expressed no opinion on its use.
Each person took part in three half-day sessions where they were exposed to both scents. Participants were monitored for blood pressure and heart rate during the experiments, and the researchers took regular blood samples from each volunteer.
Researchers taped cotton balls laced with either lemon oil, lavender oil or distilled water below the volunteers’ noses for the duration of the tests.
The researchers tested volunteers’ ability to heal by using a standard test where tape is applied and removed repeatedly on a specific skin site. The scientists also tested volunteers’ reaction to pain by immersing their feet in 32-degree F water.
Lastly, volunteers were asked to fill out three standard psychological tests to gauge mood and stress three times during each session. They also were asked to record a two-minute reaction to the experience which was later analyzed to gauge positive or negative emotional-word use.
The blood samples were later analyzed for changes in several distinct biochemical markers that would signal affects on both the immune and endocrine system. Levels of both Interleukin-6 and Interleukin-10 – two cytokines – were checked, as were stress hormones such as cortisol, norepinephrine and other catacholomines.
While lemon oil showed a clear mood enhancement, lavender oil did not, the researchers said. Neither smell had any positive impact on any of the biochemical markers for stress, pain control or wound healing.
“This is probably the most comprehensive study ever done in this area, but the human body is infinitely complex,” explained Malarkey. “If an individual patient uses these oils and feels better, there’s no way we can prove it doesn’t improve that person’s health.
“But we still failed to find any quantitative indication that these oils provide any physiological effect for people in general.”
The wound healing experiments measured how fast the skin could repair itself, Glaser said. “Keep in mind that a lot of things have to take place for that healing process to succeed. We measured a lot of complex physiological interactions instead of just a single marker, and still we saw no positive effect,” he said.
The project was supported in part by the National Center for Complementary and Alternative Medicine at the National Institutes of Health. Kiecolt-Glaser, Glaser and Malarkey are all members of Ohio State’s Institute for Behavioral Medicine Research.Psychoneuroendocrinology. 2008 Apr;33(3):328-39.
Department of Psychiatry, The Ohio State University, 1670 Upham Drive, Columbus, OH 43210, USA; The Ohio State Institute for Behavioral Medicine Research, 2175 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210, USA.
Despite aromatherapy’s popularity, efficacy data are scant, and potential mechanisms are controversial. This randomized controlled trial examined the psychological, autonomic, endocrine, and immune consequences of one purported relaxant odor (lavender), one stimulant odor (lemon), and a no-odor control (water), before and after a stressor (cold pressor); 56 healthy men and women were exposed to each of the odors during three separate visits. To assess the effects of expectancies, participants randomized to the “blind” condition were given no information about the odors they would smell; “primed” individuals were told what odors they would smell during the session, and what changes to expect. Experimenters were blind. Self-report and unobtrusive mood measures provided robust evidence that lemon oil reliably enhances positive mood compared to water and lavender regardless of expectancies or previous use of aromatherapy. Moreover, norepinephrine levels following the cold pressor remained elevated when subjects smelled lemon, compared to water or lavender. DTH responses to Candida were larger following inhalation of water than lemon or lavender. Odors did not reliably alter IL-6 and IL-10 production, salivary cortisol, heart rate or blood pressure, skin barrier repair following tape stripping, or pain ratings following the cold pressor.
One way to alleviate the pain of banging your shin while on a hike is to encounter a grizzly bear–a well-known phenomenon called stress-induced analgesia. Now, researchers have elucidated a key mechanism by which the stress hormone noradrenaline — which floods the bloodstream during grizzly encounters and other stressful events — affects the brain’s pain-processing pathway to produce such analgesia.
In their experiments, Sah and colleagues studied a region of the amygdala, the brain’s emotion-processing region known to mediate the emotional and stress-related aspects of pain. Researchers had long known that these amygdala-based processes were controlled by neurons that originated in the brainstem and that were regulated by noradrenaline.
Sah and colleagues sought in their studies to understand the mechanism by which noradrenaline influences neuronal transmission of pain inputs from the brainstem region known as the pontine parabrachial (PB).
In their experiments with rats, the researchers analyzed the effects of noradrenaline on electrical stimulation of the pathway between the PB and amygdala. They found that noradrenaline acted as a powerful suppressor of that stimulation. The researchers’ studies also revealed that noradrenaline suppression acted on the “transmission” side of the connections between neurons, called synapses. Their analyses revealed how noradrenaline causes such suppression: by activating specific receptors, called adrenocreceptors, on the PB neurons.
The researchers’ studies showed that noradrenaline’s action appears to reduce the number of sites that launch the chemical signals called neurotransmitters by which one neuron triggers a nerve impulse in another, reported the researchers.
They concluded that “Our results show that an important mediator of stress-induced analgesia could be the potent modulation by noradrenaline of [pain] PB inputs in the central amygdala.”
In an accompanying perspective article on the research, Harvard Medical School researchers Keith Tully, Yan Li, and Vadim Bolshakov wrote that “The impressive new study… provides important mechanistic clues helping to explain this phenomenon.”
Neuron, Vol 56, 880-892, 06 December 2007
Noradrenaline Modulates Transmission at a Central Synapse by a Presynaptic Mechanism
The lateral division of the central amygdala (CeAL) is the target of ascending fibers from the pain-responsive and stress-responsive nuclei in the brainstem. We show that single fiber inputs from the nociceptive pontine parabrachial nucleus onto CeAL neurons form suprathreshold glutamatergic synapses with multiple release sites. Noradrenaline, acting at presynaptic α2 receptors, potently inhibits this synapse. This inhibition results from a decrease in the number of active release sites with no change in release probability. Introduction of a presynaptic scavenger of Gβγ subunits blocked the effects of noradrenaline, and botulinum toxin A reduced its effects, showing a direct action of βγ subunits on the release machinery. These data illustrate a mechanism of presynaptic modulation where the output of a large multiple-release-site synapse is potently regulated by endogenously released noradrenaline and suggests that the CeA may be a target for the central nociceptive actions of noradrenaline.
When faced with adversity, some people succumb to debilitating psychological diseases including posttraumatic stress disorder and depression, while others are able to remain remarkably optimistic. The difference may depend in part on the chemistry of the brains’ reward circuits.
Results of a new study may one day help scientists learn how to enhance a naturally occurring mechanism in the brain that promotes resilience to psychological stress.The findings could point to new psychiatric drugs, and perhaps even new ways to encourage resilience for people in high-stress circumstances, including soldiers in combat, disaster relief workers, and disaster victims, according to the researchers.
Researchers found that, in a mouse model, the ability to adapt to stress is driven by a distinctly different molecular mechanism than is the tendency to be overwhelmed by stress. The researchers mapped out the mechanisms — components of which also are present in the human brain — that govern both kinds of responses.
In humans, stress can play a major role in the development of several mental illnesses, including post-traumatic stress disorder and depression. A key question in mental health research is: Why are some people resilient to stress, while others are not” This research indicates that resistance is not simply a passive absence of vulnerability mechanisms, as was previously thought; it is a biologically active process that results in specific adaptations in the brain’s response to stress.
Vulnerability was measured through behaviors such as social withdrawal after stress was induced in mice by putting them in cages with bigger, more aggressive mice. Even a month after the encounter, some mice were still avoiding social interactions with other mice — an indication that stress had overwhelmed them — but most adapted and continued to interact, giving researchers the opportunity to examine the biological underpinnings of the protective adaptations.
“We now know that the mammalian brain can launch molecular machinery that promotes resilience to stress, and we know what several major components are. This is an excellent indicator that there are similar mechanisms in the human brain,” said NIMH Director Thomas R. Insel, MD.
Looking at a specific part of the brain, the researchers found differences in the rate of impulse-firing by cells that make the chemical messenger dopamine. Vulnerable mice had excessive rates of impulse-firing during stressful situations. But adaptive mice maintained normal rates of firing because of a protective mechanism — a boost in activity of channels that allow the mineral potassium to flow into the cells, dampening their firing rates.
Higher rates of impulse-firing in the vulnerable mice led to more activity of a protein called BDNF, which had been linked to vulnerability in previous studies by the same researchers. With their comparatively lower rates of impulse-firing, the resistant mice did not have this increase in BDNF activity, another factor that contributed to resistance.
The scientists found that these mechanisms occurred in the reward area of the brain, which promotes repetition of acts that ensure survival. The areas involved were the VTA (ventral tegmental area) and the NAc (nucleus accumbens).
In a series of experiments, the scientists extended their findings to provide a progressively larger picture of the vulnerability and resistance mechanisms. They used a variety of approaches to test the findings, strengthening their validity.
“The extensiveness and thoroughness of their research enabled these investigators to make a very strong case for their hypothesis,” Insel said.
For example, the researchers showed that the excess BDNF protein in vulnerable mice originated in the VTA, rather than in the NAc. Chemical signals the protein sent from the VTA to the NAc played an essential role in making the mice vulnerable. Blocking the signals with experimental compounds turned vulnerable mice into resistant mice.
The scientists also conducted a genetic experiment which showed that, in resistant mice, many more genes in the VTA than in the NAc went into action in stressful situations, compared with vulnerable mice. Gene activity governs a host of biochemical events in the brain, and the results of this experiment suggest that genes in the VTA of resilient mice are working hard to offset mechanisms that promote vulnerability.
Another component of the study revealed that mice with a naturally occurring variation in part of the gene that produces the BDNF protein are resistant to stress. The variation results in lower production of BDNF, consistent with the finding that low BDNF activity promotes resilience.
The scientists also examined brain tissue of deceased people with a history of depression, and compared it with brain tissue of mice that showed vulnerability to stress. In both cases, the researchers found higher-than-average BDNF protein in the brain’s reward areas, offering a potential biological explanation of the link between stress and depression.
“The fact that we could increase these animals’ ability to adapt to stress by blocking BDNF and its signals means that it may be possible to develop compounds that improve resilience. This is a great opportunity to explore potential ways of increasing stress-resistance in people faced with situations that might otherwise result in post-traumatic stress disorder, for example,” said Nestler.
“But it doesn’t happen in a vacuum. Blocking BDNF at certain stages in the process could perturb other systems in negative ways. The key is to identify safe ways of enhancing this protective resilience machinery,” Nestler added.
Cell, Vol 131, 391-404, 19 October 2007
Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions
1 Departments of Psychiatry and Basic Neuroscience, The University of Texas Southwestern Medical Center (UTSWMC), 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA
2 Department of Molecular Biology, The University of Texas Southwestern Medical Center (UTSWMC), 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA
3 Department of Genetics and McLean Hospital, Harvard University, Cambridge, MA 02478, USA
4 Departments of Psychiatry and Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA
Eric J. Nestler
While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain’s reward circuits in actively maintaining an emotional homeostasis.
Neuron. 2007 Jul 19;55(2):289-300.
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
We analyzed the influence of the transcription factor DeltaFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces DeltaFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual’s subsequent behavorial deficit-with the strongest DeltaFosB induction observed in the most resilient animals. Induction of DeltaFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for DeltaFosB, is downregulated upon DeltaFosB induction. Local overexpression of DeltaFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.