Somatostatin Neurons Growth Hormone Activity Helps Regulate Anxiety

growth hormone

Growth hormone (GH) operates on various tissues throughout the body, including the bones and muscles. It is also an effective anxiolytic.

Researchers from the University of São Paulo (USP) in Brazil recently conducted a study that deepened our understanding of the role of growth hormone in reducing anxiety and, for the first time, identified the population of neurons responsible for modulating the influence of GH on the development of neuropsychiatric disorders involving anxiety, depression, and post-traumatic stress.

“Our discovery of the mechanism involving anxiolytic effects of GH offers a possible, merely chemical, explanation for these disorders, suggesting why patients with more or less GH secretion are more or less susceptible to them,”

said José Donato Júnior, professor at the university’s Biomedical Sciences Institute (ICB-USP) and the last author of the article.

Exploring Growth Hormone’s Anxiety Role

The researchers reported that male mice lacking the GH receptor in a subset of somatostatin-expressing neurons demonstrated higher anxiety in the study. Somatostatin is a peptide that affects a variety of physiological processes, including the release of growth hormone and other hormones such as insulin.

On the other hand, they found that in both males and females, the deletion of the GH receptor in somatostatin-expressing neurons reduced fear memory, a crucial component of post-traumatic stress disorder. The discovery could aid in the creation of new kinds of anxiolytic medications in the future.

In the study, the researchers conducted three types of experiments involving mice (open field, elevated plus maze, and light/dark box) to test the animals’ capacity to explore the environment and take risks.

“These are well-established experiments to analyze behavior similar to anxiety and memory of fear, which is an element in post-traumatic stress. As a result, we were able to explore the role of GH in these animals,”

Donato explained.

The findings of the study revealed no explanations for the lack of increased anxiety-like behavior in female mice.

“We believe it may be related to sexual dimorphism. We know the brain region containing the neurons we studied is a bit different in males and females. Some neurological disorders are also different in men and women, probably not by chance,”

he said.

Neuropsychiatric Illness Factors

Neuropsychiatric illnesses affect thousands of people worldwide. Although anxiety and depression are the most common, their origins are yet unknown.

Scientists think a variety of factors, such as stress, genetics, social pressures, economic difficulties, and/or gender issues, are to blame for them.

There is now mounting evidence that hormones play a role in the regulation of many brain processes and the susceptibility to neuropsychiatric illnesses. Changes in sex hormone levels, such as estradiol, influence anxiety, sadness, and fear memory in mice and humans, for example.

Preliminary results of other studies suggest that glucocorticoids (steroid hormones such as cortisol as well as synthetic forms such as prednisone and dexamethasone) may be involved in the development of neuropsychiatric disorders. The regulatory mechanism in neurons associated with such disorders had not yet been identified in the case of GH.

“We demonstrated that GH changes the synapses and structurally alters the neurons that secrete somatostatin,”

Donato said.

Different Reactions, Same Neuronal Circuit

The study also revealed that anxiety, post-traumatic stress disorder, and fear memory are all different aspects of the same neuronal circuit.

Anxiety, according to Donato, is defined as excessive fear or distrust, whereas fear memory refers to a negative previous event that causes a brain modification that causes an intensified response anytime the individual is subjected to a comparable stimulus. This reaction might range from tears to tremors and even paralysis.

“All this happens in the same neuron population expressing the GH receptor. In our experiment, fear memory was reduced in mice when we switched the GH receptor off. This means the capacity to form fear memory is impaired. It may be the case that GH contributes to the development of post-traumatic stress,”

he said.

Another piece of evidence is that chronic stress raises the hormone ghrelin, which is a powerful trigger of GH secretion.

“The role of ghrelin in post-traumatic stress has been studied for some time. Research has shown that ghrelin-induced GH secretion increases in chronic stress, favoring the development of fear memory and post-traumatic stress in the animal’s brain,”

he said.

Growth Hormone Deficiency

In humans, the pituitary gland secretes GH into the bloodstream, encouraging tissue growth throughout the body through protein production, cell multiplication, and cell differentiation.

Growth hormone is essential during childhood, adolescence, and pregnancy, when its secretion is at its greatest. It naturally lowers with age.

GH deficiency can lead to dwarfism, which is mostly manifested from 2 years of age, preventing growth during childhood and adolescence.

“Previous research involving patients with GH deficiency showed a higher prevalence of anxiety and depression in these individuals, but the cause hadn’t yet been established. Some authors blame it on problems of self-image and bullying due to short stature,”

Donato said.

The mouse study demonstrated the importance of GH in these disorders in the absence of potential confounders, such as body image issues.

“We were able to find out how much is due directly to the effects of GH or the indirect effects of growth deficit. Because we were able to identify the mechanism involving GH, we know it’s a direct cause of anxiety disorder, and this knowledge can facilitate the development of therapies,”

Donato said.

The research team’s next steps include looking into the role of growth hormone during pregnancy.

“We know one of the peaks in GH production occurs during pregnancy. We also know that the prevalence of depression rises in this period owing to post-partum depression. Of course, these disorders also reflect social, economic, and other kinds of pressure, but we mustn’t forget that the rise in hormone secretion during and after pregnancy can dysregulate brain functioning, also leading to this kind of mental illness,”

he said.


Dysfunctions in growth hormone (GH) secretion increase the prevalence of anxiety and other neuropsychiatric diseases. GH receptor (GHR) signaling in the amygdala has been associated with fear memory, a key feature of posttraumatic stress disorder. However, it is currently unknown which neuronal population is targeted by GH action to influence the development of neuropsychiatric diseases. Here, we showed that approximately 60% of somatostatin (SST)-expressing neurons in the extended amygdala are directly responsive to GH. GHR ablation in SST-expressing cells (SSTΔGHR mice) caused no alterations in energy or glucose metabolism. Notably, SSTΔGHR male mice exhibited increased anxiety-like behavior in the light-dark box and elevated plus maze tests, whereas SSTΔGHR females showed no changes in anxiety. Using auditory Pavlovian fear conditioning, both male and female SSTΔGHR mice exhibited a significant reduction in fear memory. Conversely, GHR ablation in SST neurons did not affect memory in the novel object recognition test. Gene expression was analyzed in a micro punch comprising the central nucleus of the amygdala (CEA) and basolateral (BLA) complex. GHR ablation in SST neurons caused sex-dependent changes in the expression of factors involved in synaptic plasticity and function. In conclusion, GHR expression in SST neurons is necessary to regulate anxiety in males, but not female mice. GHR ablation in SST neurons also decreases fear memory and affects gene expression in the amygdala, although marked sex differences were observed. Our findings identified for the first time a neurochemically-defined neuronal population responsible for mediating the effects of GH on behavioral aspects associated with neuropsychiatric diseases.

  1. Willian O. dos Santos, Vitor A. L. Juliano, Fernanda M. Chaves, Henrique R. Vieira, Renata Frazao, Edward O. List, John J. Kopchick, Carolina D. Munhoz, Jose Donato Jr. Growth Hormone Action in Somatostatin Neurons Regulates Anxiety and Fear Memory. Journal of Neuroscience 4 October 2023, 43 (40) 6816-6829; DOI:10.1523/JNEUROSCI.0254-23.2023