A small population of neurons can play a major role in depression

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

These AgRP neurons are called exclusively in the lower part of the hypothalamus, the arch nucleus, or ARC, and are known to be important for the energy homeostasis in the body, and also cause us to pick up a fork if we are hungry and see food.

Now, scientists from Georgia Medical College and their colleagues are reporting the first evidence that, not short-term stress, such as a series of difficult college exams, rather chronic, unpredictable stresses such as those that erupt in our personal and professional lives, changes in function cause. of 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 the MCG at Augusta University and Georgia Research Alliance, a leading translator in Translational Neuroscience.

Although it is too early to say whether the shift in neuronal activity caused by chronic stress and associated with depression begins in these neurons, it is a definite and likely key piece in the puzzle, says Lu, corresponding author of the study in the magazine. Molecular psychiatry.

“Obviously, when we manipulate these neurons, it changes behavioral responses,” she says, but there are still many questions, such as how these AgRP neurons in the human brain help us cope over time and adapt to unpredictable chronic stress.

They have shown that this type of stress, which leads to an animal model of depression, reduces the activity of AgRP, or agouti-related proteins, neurons, which reduces the neurons’ ability to fire spontaneously, increases the irregularities of the fire and otherwise the usual shooting characteristics change. of AgRP neurons in both their male and female mouse model of depression.

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

“We can stimulate the neurons remotely and reverse depression,” says Lu. He uses a synthetic small-molecule agonist that binds to a man-made chemogenetic receptor in their target neurons – a common method to study the relationship between behavior and specific neurons. directly to the neurons via a viral vector.

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

The scientists found that the stress-related decrease in AgRP neuronal activity apparently causes an increase in the activity of other nearby neuron types in the ARC, and they further strive for the observation. They also look at adaptations that may occur with other neurons that respond to stress and reward in other subregions of the hypothalamus, as well as other parts of the brain to define the circuits involved.

They are also already looking at the more time-consuming process of determining whether the removal of the chronic stressors will eventually also lead to the AgRP neurons resuming more normal activity.

According to the National Institute of Mental Health, major depression is one of the most common mental health disorders in the United States, with approximately 17.3 million adults experiencing at least one episode. The incidence is highest among 18-25 year olds, women have about twice the risk for men and depression can occur in families.

Only about a third of patients achieve full remission with existing treatments and anhedonia, the inability to experience pleasure, which increases the risk of suicide, is usually the last symptom to be resolved. However, the scientists say that the mechanisms behind the effects of depression are poorly understood.

“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 it,” says Lu. Side effects can include weight gain and insomnia.

For example, Prozac 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 serotonin reuptake inhibitors.

Although it is unknown whether some of the existing antidepressants affect AgRP neurons, it is possible that new therapies targeting the neurons may also cause weight gain due to the role of the neurons in nutritional behavior and metabolism, Lu says.

Lu was one of the scientists who previously characterized the network of AgRP neurons in the brain, and was the first to show fluency in the production of AgRP during the course of the day and that a surge of glucocorticoid stress hormones preceded the expression of AgRP and nutrition.

The new study shows that AgRP neurons are an important component of the neural circuits under depression-like behavior, and it writes, and chronic stress causes AgRP dysfunction. They suspect one of the reasons for the decreased excitation of the neurons is the increased sensitivity to the inhibitory neurotransmitter GABA.

AgRP neurons are stimulated by hunger signals and saturated by satiety. Previous studies have shown that AgRP neurons, when activated, can cause significant increases in eating which can result in significant weight gain. Activating these neurons in mice increases food and food search. Only the presence of food increases the firing of AgRP neurons, which intensifies your hunger and moves you to pick up the fork, Lu says about the neuron sometimes called the hangar neuron.

The elimination of AgRP neurons suppresses nutrition inversely and appears to increase anorexia.

###

The first author of the new study is dr. Xing Fang, who completed postgraduate studies in neuroscience at MCG and The Graduate School at the AU 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 that is involved in essentials 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.