Key Points: Neurons in the hypothalamus that regulate appetite may also be linked to depression, according to new animal research. Targeting those neurons may offer new treatment options for serious depression.
Medical College of Georgia (MCG) at Augusta University scientists and their colleagues have discovered that unpredictable chronic stress causes changes in a small population of neurons in the hypothalamus that contribute to depression.
In the January 11 issue of Molecular Psychiatry, the researchers report that, in an animal model of depression involving chronic exposure to unpredictable stress, certain hypothalamic cells exhibit maladaptive synaptic and intrinsic plasticity, leading to neuronal hypoactivity.
These cells are located exclusively in the arcuate nucleus in the bottom of the hypothalamus and are identified by their expression of agouti-related protein (AgRP). The investigators found that chemical activation of AgRP cells completely reversed despair and anhedonic behaviors induced by chronic unpredictable stress. Conversely, chemical inhibition of AgRP neurons increased susceptibility to unpredictable stress.
Normally these neurons are stimulated by hunger signals and inhibited by satiety. In fact, just the presence of food normally increases the firing of these cells, which have been dubbed “hangry” neurons.
The findings are the first to show that maladaptive synaptic and intrinsic plasticity of AgRP neurons may contribute to the development of depression and suggest a novel and effective treatment for depression by increasing AgRP neuronal activity.
Looking Beyond the Prefrontal Cortex and Hippocampus for Causes of Depression
According to the National Institute of Mental Health, an estimated 17.3 million adults in the United States experience at least one episode of major depression. The prefrontal cortex and hippocampus have attracted major attention as locations for the neural substrates underlying depression. However, only about a third of patients achieve full remission.
The high incidence of treatment-resistant depression has highlighted the need for a better understanding of the pathogenesis of depression and the development of new treatments.
"We want to find better ways to treat it, including more targeted treatments that may reduce side effects, which often are significant enough to prompt patients to stop taking them," said Dr. Xin-Yun Lu, the corresponding author of the study and chair of the Department of Neuroscience and Regenerative Medicine at MCG at Augusta University.
"It is clear that when we manipulate these neurons, it changes behavioral reactions," Lu said. "We can remotely stimulate those neurons and reverse depression."
Lu and colleagues induced expression of synthetic chemogenetic receptors in the AgRP neurons through the use of a viral vector, then stimulated the AgRP neurons with synthetic small molecule agonists. Such stimulation increased susceptibility to chronic, unpredictable stress and induced depression-like behavior like a reduced desire for sucrose rewards and sex. When researchers activated the neurons, classic depressive behaviors like despair and the inability to experience pleasure were reversed.
New Possibilities for Treating Depression
Although more research is needed before it is known how stress-related changes in AgRP neurons contribute to depression, the new research suggests that chronic stress causes AgRP dysfunction and that AgRP neurons are a key component in the neural circuitry underlying depression-like behavior.
Lu and colleagues suspect that one reason for the reduced excitability of these neurons may be due to increased sensitivity to the inhibitory neurotransmitter GABA.
Future research will assess whether removal of the chronic stressors alone can eventually result in the AgRP neurons returning to more normal activity. The researchers will also further investigate the fact that the stress-related decrease in AgRP neuron activity seemed to produce an increase in the activity of other types of nearby neurons in the arcuate nucleus.
It is not known whether existing antidepressants happen to affect AgRP neurons. In addition, Lu cautions that due to the cells’ role in feeding behavior and metabolism, new therapies designed to target these neurons may produce the same unwanted weight gain side effects as some traditional antidepressants.
Fang, X, Jiang, S., Wang, J., Bai, Y., et al. (2021). Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity. Molecular Psychiatry; DOI: 10.1038/s41380-020-01004-x.