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

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

These AgRP neurons live 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 causing us to lift a fork when we are hungry and see food.

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

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

Although 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 lead author. Molecular psychiatry.

“Clearly, 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. time.

They showed this type of stress, which results in an animal model of depression, decreases the activity of AgRP or proteins associated with agouti, neurons, decreasing the ability of neurons to shoot spontaneously, increasing burning irregularities and otherwise altering the usual burning properties of AgRP neurons in both their depression model and the female mouse.

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

“We can remotely stimulate those neurons and reverse depression,” says Lu, using a small-molecule synthetic agonist that binds to a human-created chemogenetic receptor in target neurons – a common method for studying the relationship between behavior and neurons. certain – delivered directly to these neurons through a viral vector.

As in life, unpredictability can increase the impact of stress, says Lu, so they used this approach in their studies, with techniques such as social isolation and changing light and dark cycles, and found that mice began to exhibit depressive behavior with 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 nearby neurons in the ARC, and they are following this observation further. It also looks at 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 already looking at the process that takes longer to assess whether the removal of chronic stressors alone will eventually lead to the resumption of the activity of AgRP neurons.

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 suffering from at least one episode. Prevalence rates are highest among young people aged 18 to 25, with women at about twice the risk of men, and depression running in families.

Only about a third of patients get 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 poorly understood, scientists say.

“We want to find better ways to treat it, including better targeted treatments that can reduce side effects, which are often significant enough to cause patients to stop taking them,” says Lu. Undesirable effects may include weight gain and insomnia.

Prozac, for example, reduces the absorption of serotonin, a neurotransmitter involved in regulating mood, but serotonin also has important functions such as regulating the sleep cycle, and sleep disorders are an established side effect of selective serotonin reuptake inhibitors.

Although it is not known whether some of the existing antidepressants have an impact on AgRP neurons, it is possible that new therapies designed to target neurons will also cause weight gain due to the role of neurons in feeding and metabolism behavior, notes Lu.

Lu was among the scientists who first characterized the network of AgRP neurons in the brain and was the first to show fluctuations in AgRP production during the day and that an increase in glucocorticoid stress hormones comes before the maximum expression of AgRP and feeding.

The new study shows that AgRP neurons are a key component of the neural circuits that underlie depression-like behavior, they write, and chronic stress causes AgRP dysfunction. They suspect that one reason for the low 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 diet, which can lead to significant weight gain. Activation of these neurons in mice, in fact, increases their consumption and search for food. Only the presence of food increases the triggering of AgRP neurons, reinforcing the fact that you are hungry and causes you to lift the fork, says Lu about the neuron sometimes called the hanging neuron.

Elimination of AgRP neurons inversely 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 graduated with a graduate degree in neuroscience from MCG and the AU Graduate School and is now a postdoctoral researcher at the University of Southern California.

The hypothalamus is a small region – the size of an almond – located just above the brainstem and involved in essential 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.