IMAGE: Dr. Xin-Yun Lu’s Vision most
Credit: Phil Jones, freelance photographer
A tiny population of neurons known to be important for appetite also appears to play a significant role in depression that results from chronic and unpredictable stress, say the scientists.
These AgRP neurons reside exclusively in the lower part of the hypothalamus, called the arcuate nucleus, or ARC, and are known to be important for energy homeostasis in the body, also leading us to pick up a fork when we are hungry and see food.
Now, scientists at the Medical College of Georgia and colleagues report the first evidence that, not short-term stress, like a series of difficult exams in college, but chronic and unpredictable stress like the one that breaks out in our personal and professionals, induces changes in the function of AgRP neurons that can contribute to depression, they write.
The small number of AgRP neurons are likely to be logical targets for treating depression, says Dr. Xin-Yun Lu, chairman of the MCG’s Department of Neuroscience and Regenerative Medicine at Augusta University and Georgia Research Alliance Eminent Scholar in Translational Neuroscience.
While it is too early to say whether the change in neuronal activity caused by chronic stress and associated with depression begins with these neurons, they are a definite and likely key piece of the puzzle, says Lu, the study’s corresponding author in the newspaper Molecular Psychiatry.
“Of course, when we manipulate these neurons, it changes behavioral reactions,” she says, but many questions remain, such as how these AgRP neurons in the human brain help us cope and adapt to unpredictable chronic stress over time. .
They showed this type of stress, which results in an animal model of depression, decreases the activity of AgRP, or agouti-related protein, neurons, decreasing the ability of neurons to fire spontaneously, increasing the triggering irregularities and changing the usual properties of firing AgRP neurons in both male and female mouse depression models.
In addition, when they used a small molecule to directly inhibit neurons, they increased their susceptibility to chronic and unpredictable stress, inducing depression-like behavior in rats, including reducing the usual cravings for rewards like consuming tasty sucrose and sex. When they activated neurons, they reversed classic depressive behaviors, such as despair and an inability to feel pleasure.
“We can remotely stimulate these neurons and reverse depression,” says Lu, using a small synthetic molecule agonist that binds to a chemogenetic receptor that is also synthetic in its target neurons – a common method for studying the relationship between specific neurons and behavior – delivered directly to these neurons via a viral vector.
As in life, unpredictability can increase the impact of stress, says Lu, so they also used this approach in their studies, with techniques like social isolation and changing light and dark cycles, and found that mice started to exhibit depressive behavior in 10 days.
The scientists found that the stress-related decrease in the activity of the AgRP neuron appears to produce an increase in the activity of other types of nearby neurons in the ARC, and are pursuing that observation even more. They are also looking for adjustments that can happen to other neurons that respond to stress and reward in other sub-regions of the hypothalamus, as well as in other parts of the brain, to help define the circuits involved.
They are also already looking at the longer process of assessing whether removing chronic stressors on their own will also result in the resumption of normal activity by AgRP neurons.
Major depression is one of the most common mental disorders in the United States, according to the National Institute of Mental Health, with about 17.3 million adults experiencing at least one episode. Prevalence rates are highest between 18-25 years, women are about twice the risk of men and depression can occur in families.
Only about a third of patients achieve complete remission with existing treatments and anhedonia, the inability to feel pleasure, which increases the risk of suicide, is usually the last symptom to resolve. However, the mechanisms behind the effects of depression remain poorly understood, say the scientists.
“We want to find better ways to treat it, including more targeted treatments that can reduce side effects, which are often significant enough to make patients stop taking them,” said Lu. Undesirable effects can include weight gain and insomnia.
Prozac, for example, reduces the uptake of serotonin, a neurotransmitter involved in mood regulation, but serotonin also has important functions, such as regulating the sleep cycle, and sleep disorders are an established side effect of selective reuptake inhibitors. of serotonin.
While it is not known whether any of the existing antidepressants affect AgRP neurons, it is possible that new therapies designed to target neurons may also produce weight gain because of the role of neurons in eating behavior and metabolism, notes Lu.
Lu was among the scientists who previously characterized the network of AgRP neurons in the brain, and was the first to show fluctuations in AgRP production throughout the day and that a peak in glucocorticoid stress hormones comes before the peak of AgRP expression and feeding .
The new study shows that AgRP neurons are a key component of the neural circuitry underlying depression-like behavior, they write, and chronic stress causes AgRP dysfunction. They suspect that one reason for the reduced excitability of neurons is the increased sensitivity to the inhibitory neurotransmitter GABA.
AgRP neurons are stimulated by hunger signals and inhibited by satiety. Previous studies have shown that, when activated, AgRP neurons can produce significant increases in food that can result in significant weight gain. The activation of these neurons in mice, in fact, increases their food and search for food. Only the presence of food increases the firing of the AgRP neurons, reinforcing that you are hungry and causing you to pick up that fork, Lu says of the neuron sometimes called the hanger neuron.
The elimination of AgRP neurons, on the other hand, suppresses food and has been shown to increase anorexia.
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The first author of the new study is Dr. Xing Fang, who completed his postgraduate studies in neuroscience at MCG and the AU Postdoctoral School and is now a postdoctoral fellow at the University of Southern California.
The hypothalamus is a small region – the size of an almond – located just above the brain stem and involved in essential items such as body temperature, blood pressure and heart rate, emotions and sleep cycles, as well as appetite and weight control.
The research was supported by the National Institutes of Health.
Read the full study.