A small population of neurons may play an important role in depression

A small population of neurons known to be important for appetite appear to also play an important role in depression resulting from chronic and unpredictable stress, scientists say.

These AgRP neurons reside exclusively in the lower part of the hypothalamus called the arched nucleus (ARC), and are known to be important for the body’s energy homeostasis, which also causes us to trigger a fork when we are hungry and see food.

Now scientists at the Medical College of Georgia and colleagues report from the first evidence that, not short-term stress, as a series of difficult college exams, but chronic and unpredictable stress like the one that erupts in our personal and professional life, induces changes in function. of AgRP neurons that may contribute to depression, they write.

Xin-Yun Lu, chair of MCG’s Department of Neuroscience and Regenerative Medicine at Augusta University and Georgia Research Alliance Eminent Scholar in Translational Neurosciences, says the small number of AgRP neurons are logical targets for treating depression.

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, lead author of the study. in the magazine Molecular psychiatry.

“It’s clear that when we manipulate these neurons, it changes behavioral reactions,” she says, but many questions remain, such as how these human brain’s AgRP neurons help us cope and adapt to unpredictable chronic stress with the passage of time.

They have shown this type of stress, which results in an animal model of depression, which decreases the activity of AgRP neurons, or agouti-related protein, decreasing the ability of neurons to shoot spontaneously, increasing the irregularities of cooking and altering the usual properties of cooking. of AgRP neurons in the male and female mouse depression model.

In addition, when they used a small molecule to directly inhibit neurons, it increased their susceptibility to chronic and unpredictable stress, inducing depression-like behavior in mice, including reducing the usual desire for rewards such as consuming sucrose. and sex. When they activated the neurons, he reversed classic depressive behaviors such as despair and the inability to experience pleasure.

“We can remotely stimulate these neurons and reverse depression,” says Lu, using a synthetic small-molecule agonist that binds to a man-made chemogenetic receptor also made in target neurons, a common method for studying the relationship between behavior and specific neurons. directly to these neurons using a viral vector.

As in life, unpredictability can increase the impact of stress, Lu says, so they also used this approach in their studies, using techniques such as social isolation and changing light and dark cycles. , and found that mice began to show depressive behavior for 10 days.

The scientists found that the stress-related decrease in the activity of AgRP neurons appears to produce an increase in the activity of other types of neurons close to the CRA and they continue this observation. They also study adjustments that can be made to other neurons that respond to stress and reward in other subregions of the hypothalamus, as well as in other parts of the brain, to help define the circuits involved.

They are also studying the process that requires more time to assess whether the removal of chronic stressors will only end up causing AgRP neurons to regain more normal activity.

Major depression is one of the most common mental health disorders in the United States, according to the National Institute of Mental Health, with approximately 17.3 million adults experiencing at least one episode. Prevalence rates are highest among young people aged 18 to 25, women are about twice as likely as men and depression can pass on to families.

Only about a third of patients achieve complete remission with existing treatments and anedonia, the inability to experience pleasure, which increases the risk of suicide, is usually the last symptom to be resolved. However, the mechanisms behind the effects of depression remain little known, according to scientists.

“We want to find better ways to treat it, including more specific treatments that can reduce side effects, which are often significant enough for patients to stop taking them,” Lu says. Undesirable effects may 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 disturbances are an established side effect. of selective serotonin reuptake inhibitors.

While it is unknown whether some of the existing antidepressants affect AgRP neurons, it is possible that new therapies designed to target neurons may also produce weight gain due to the role of neurons in eating behavior and metabolism, he notes. Lu.

Lu was one of 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 rise in glucocorticoid stress hormones comes before the maximum AgRP expression and feeding.

The new study demonstrates that AgRP neurons are a key component of the neural circuits underlying behavior similar to depression, they write, and chronic stress causes AgRP dysfunction. They suspect that one of the reasons for the reduced excitability of neurons is 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 lead to significant weight gain. Activation of these neurons in mice, in fact, increases their feeding and food search. Only the presence of food increases the firing of AgRP neurons, which reinforces that you are hungry and leads you to pick up this fork, Lu says about the neuron sometimes called the hanging neuron.

Elimination of AgRP neurons suppresses feeding and has been shown to increase anorexia.

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The first author of the new study is Dr. Xing Fang, who completed graduate studies in neuroscience at MCG and The Graduate School of the UA and is now a postdoctoral fellow at the University of Southern California.

The hypothalamus is a small region, about the size of an almond, located just above the brainstem and involved in basic elements such as body temperature, blood pressure and heart rate, emotion and sleep cycles. , as well as appetite and weight control.

The research was supported by the National Institutes of Health.

Read the full study.