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

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

Located exclusively in the lower portion of the hypothalamus, called the arcuate nucleus or ARC, these AgRP neurons are known to be important for energy homeostasis in the body and prompting us to pick up a fork when we are hungry and see food.

Now scientists at the Medical College of Georgia and their colleagues report the first evidence that, not short-term stress, such as a series of arduous college exams, rather chronic, unpredictable stress such as that erupting in our personal and professional lives, is triggering changes in function . of AgRP neurons that can contribute to depression, they write.

The small number of AgRP neurons are likely logical treatment goals 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.

While it is too early to say whether the shift in neuron activity caused by chronic stress and associated with depression begins with these neurons, they are clearly and likely key to the puzzle, says Lu, the study’s corresponding author in the journal. Molecular Psychiatry.

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

They have demonstrated this type of stress resulting in an animal model of depression, the activity of AgRP or agouti-related protein, decreases neurons, decreases the ability of the neurons to fire spontaneously, increasing firing irregularities and otherwise the usual subject properties 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 sensitivity to chronic, unpredictable stress, inducing depressive behaviors in the mice, including reducing the usual cravings for rewards such as consuming 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 remotely stimulate those neurons and reverse depression,” says Lu, using a synthetic small molecule agonist that binds to an also man-made chemogenetic receptor in their target neurons – a widely used method to explore the relationship between behavior and study particular neurons – delivered directly to those neurons via a viral vector.

As in life, unpredictability can increase the impact of stress, Lu says, so they used that approach in their studies too, using techniques such as social isolation and switching light and dark cycles, and found that mice started depressed behavior after 10 days. to show.

The scientists found that the stress-related decrease in AgRP neuron activity appears to cause an increase in the activity of other nearby neuron types in the ARC, and they are further following that observation. They also look at adaptations that can happen with other neurons that respond to stress and reward in other subregions of the hypothalamus and in other parts of the brain to help define the circuits involved.

They are also looking at the more time-consuming process of assessing whether removing the chronic stressors alone will ultimately cause the AgRP neurons to resume normal activity.

Major depression is one of the most common mental illnesses in the United States, with an estimated 17.3 million adults going through at least one episode, according to the National Institute of Mental Health. Prevalence rates are highest among 18-25 year olds, women are about twice as much at risk as men, and depression can run in families.

Only about a third of patients achieve complete remission with existing treatments and anhedonia, the inability to experience 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, the scientists say.

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

For example, Prozac decreases 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 the neurons could also cause weight gain due to the neurons’ role in feeding behavior and metabolism, Lu notes.

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 over the day and that a surge of glucocorticoid stress hormones before peak expression of AgRP and nutrition.

The new study shows that AgRP neurons are a key component of the neural circuitry that underlies depression-like behavior, they write, and chronic stress causes AgRP dysfunction. They suspect that one reason for the reduced excitability of the 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 a significant increase in eating, which can result in significant weight gain. Activating these neurons in mice actually increases their eating and foraging for food. The mere presence of food increases the firing of AgRP neurons, reinforcing that you are hungry and prompting you to pick up that fork, Lu says of the neuron sometimes referred to as the pendant neuron.

Eliminating AgRP neurons inversely suppresses nutrition and has been shown to enhance anorexia.

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

The hypothalamus is a small area – about the size of an almond – located just above the brain stem and involved in essential things 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.