Stress hormone helps control the circadian rhythm of brain cells
November 8, 2019
Science Daily/University of Copenhagen The Faculty of Health and Medical Sciences
Researchers have shown how the brain's circadian rhythm in rats is, among other things, controlled by the stress hormone corticosterone -- in humans called cortisol. This has been shown by means of a completely new method in the form of implanted micropumps.
As day turns into night, and night turns into day, the vast majority of living organisms follow a fixed circadian rhythm that controls everything from sleep needs to body temperature.
This internal clock is found in everything from bacteria to humans and is controlled by some very distinct hereditary genes, known as clock genes.
In the brain, clock genes are particularly active in the so-called suprachiasmatic nucleus. It sits just above the point where the optic nerves cross and sends signals to the brain about the surrounding light level. From here, the suprachiasmatic nucleus regulates the rhythm of a number of other areas of the body, including the cerebellum and the cerebral cortex.
However, these three areas of the brain are not directly linked by neurons, and this made researchers at the University of Copenhagen curious. Using test rats, they have now demonstrated that the circadian rhythm is controlled by means of signalling agents in the blood, such as the stress hormone corticosterone.
'In humans, the hormone is known as cortisol, and although the sleep rhythm in rats is the opposite of ours, we basically have the same hormonal system', says Associate Professor Martin Fredensborg Rath of the Department of Neuroscience.
He explains that recent years have seen an increasing, scientific focus on research on clock genes, one reason being that previous research on clock genes have found a correlation between depression and irregularities in the body's circadian rhythms.
New Method with Medical Micropumps
In the study with the stress hormone corticosterone, the researchers removed the suprachiasmatic nucleus in a number of rats. As expected, this removed the circadian rhythm of the animals.
Among other things, the body temperature and activity level of the rats went from circadian oscillations to a more constant state. The same was true of the otherwise rhythmic hormone production.
However, the circadian rhythm of the cerebellum was restored when the rats were subsequently implanted with a special programmable micropump, normally used to dose medication in specific quantities.
In this case, however, the researchers used the pump to emit carefully metered doses of corticosterone at different times of the day and night, similar to the animals' natural rhythm.
'Nobody has used these pumps for anything like this before. So technically, we were onto something completely new', says Martin Fredensborg Rath.
For that reason, the researchers spent the best part of a year carrying out a large number of control tests to ensure that the new method was valid.
Interaction Between Neurons and Hormones
As mentioned, the new method paid off. With the artificial corticosterone supplement, researchers were again able to read a rhythmic activity of clock genes in the cerebellum of the rats, even though their suprachiasmatic nucleus had been removed.
'This is hugely interesting from a scientific point of view, because it means that we have two systems -- the nervous system and the hormonal system -- that communicate perfectly and influence one another. All in the course of a reasonably tight 24-hour programme', says Martin Fredensborg Rath.
With the test results and the new method in the toolbox, the researchers' next step is to study other rhythmic hormones in a similar manner, including hormones from the thyroid gland.
https://www.sciencedaily.com/releases/2019/11/191108102850.htm
Compound found in red wine opens door for new treatments for depression, anxiety
Resveratrol, found in grape skin, shuts down depression-causing enzyme in brain
July 29, 2019
Science Daily/University at Buffalo
Like to unwind with a glass of red wine after a stressful day? Don't give alcohol all the credit.
New research has revealed that the plant compound resveratrol, which is found in red wine, displays anti-stress effects by blocking the expression of an enzyme related to the control of stress in the brain, according to a University at Buffalo-led study.
The findings shed light onto how resveratrol impacts neurological processes. According to the Anxiety and Depression Association of America, depression and anxiety disorders affect 16 and 40 million people respectively in the United States.
"Resveratrol may be an effective alternative to drugs for treating patients suffering from depression and anxiety disorders," says Ying Xu, MD, PhD, co-lead author and research associate professor in the UB School of Pharmacy and Pharmaceutical Sciences.
The study, published on July 15 in the journal Neuropharmacology, was also led by Xiaoxing Yin, PhD, professor at Xuzhou Medical University in China.
Protection Against Extreme Stress
Resveratrol, which has been linked to a number of health benefits, is a compound found in the skin and seeds of grapes and berries. While research has identified resveratrol to have antidepressant effects, the compound's relationship to phosphodiesterase 4 (PDE4), an enzyme influenced by the stress hormone corticosterone, was unknown.
Corticosterone regulates the body's response to stress. Too much stress, however, can lead to excessive amounts of the hormone circulating in the brain and, ultimately, the development of depression or other mental disorders.
These unknown physiological relationships make drug therapy complex. Current antidepressants instead focus on serotonin or noradrenaline function in the brain, but only one-third of patients with depression enter full remission in response to these medications, says Xu.
In a study on mice, researchers revealed that PDE4, induced by excessive amounts of corticosterone, causes depression- and anxiety-like behavior.
The enzyme lowers cyclic adenosine monophosphate -- a messenger molecule that signals physiological changes such as cell division, change, migration and death -- in the body, leading to physical alterations in the brain.
Resveratrol displayed neuroprotective effects against corticosterone by inhibiting the expression of PDE4. The research lays the groundwork for the use of the compound in novel antidepressants.
Although red wine contains resveratrol, consumption of alcohol carries various health risks, including addiction.
https://www.sciencedaily.com/releases/2019/07/190729094553.htm
Stress in early life could make people more likely to develop depression
May 8, 2019
Science Daily/University of Bristol
New research by the University of Bristol has found that early life adversity could make an individual more at risk of developing negative thinking, which could lead to major depressive disorder (MDD). The findings provide biological and psychological evidence to support work first proposed in the 1960s.
The study, published in Neuropsychopharmacology and funded by the MRC and BBSRC, using a rodent model of early life adversity, has shown that offspring are much more sensitive to negative biases in their cognition when treated with the stress hormone, corticosterone.
The research has shown a dose of corticosterone had no effect in normal rats but caused a negative bias in the early life adversity animals. The study also found that the early life adversity rats were less likely to anticipate positive events and failed to properly learn about reward value. These impairments in reward-related cognition are particularly interesting as one of the main features of depression is a loss of interest in previously enjoyable activities.
The findings support the idea that those at risk of developing mood disorders may have impairments in the way they learn about and use their memories about how rewarding an experience has been to then guide and motivate them to repeat the activity. The researchers suggest that these neuropsychological effects might explain why early life adversity can make people more likely to develop depression.
Emma Robinson, Professor of Psychopharmacology, School of Physiology, Pharmacology & Neuroscience and lead author on the paper, said: "This study supports a wider body of literature which suggests that depression may develop from an interesting yet complex interaction between biological and psychological processes. As we start to understand these better we hope that the knowledge we generate can be used to better guide current and future treatments.
"Our larger body of work suggests that the effectiveness of current antidepressant treatments might be linked to how much a person is able to re-engage with their environment and their level of social support.
"The findings also add further evidence to support the validity of this relatively new area of research into mood disorders, particularly studies using animals to understand the neurobiology of affective biases and how they contribute to normal and pathological behaviour."
Studies in patients have shown that depression is linked to changes in how the person processes information particularly emotional information. People with depression have a negative view of the world which can be measured by looking at how they process information such as emotional faces and words. However, whether this causes the illness or are a consequence is not known.
The researchers developed a method to use in rodents where similar neuropsychological processes were measured. One of the tasks, the affective bias test, looked at how simple associations between a specific cue, a bowl with a specific digging substrate in it, and a reward, a food pellet, could be biased by the animal's affective state when they learn about it.
When animals learn the association in a negative affective state they remember it in a more pessimistic way whilst memories formed in a positive affective state are remembered in a more positive way. The biases the study was able to measure in rodents correlated exactly with how these same treatments affect peoples' mood in the long-term, something which no other animal test in psychiatry has been able to achieve.
The next step in the research will be to understand how these processes and the deficits seen in the animals respond to current antidepressant treatments including the recently licensed, rapid onset antidepressant ketamine. The researchers already have some evidence about how ketamine interacts with these neuropsychological processes and this latest work will help them bring these findings together with an important disease model and risk factor for depression.
https://www.sciencedaily.com/releases/2019/05/190508113326.htm