Summary: p11, a protein implicated in serotonin function, affects the initial release of cortisol in mice by modulating the activity of specific neurons in the hypothalamus. Previous studies found people with depression lave lower levels of p11 in their brains. The findings could help in the development of new treatments for depression and stress.
Source: Karolinska Institute
Researchers at Karolinska Institutet in Sweden have identified a protein in the brain that is important both for the function of the mood-regulating substance serotonin and for the release of stress hormones, at least in mice. The findings, which are published in the journal Molecular Psychiatry, may have implications for the development of new drugs for depression and anxiety.
After experiencing trauma or severe stress, some people develop an abnormal stress response or chronic stress. This increases the risk of developing other diseases such as depression and anxiety, but it remains unknown what mechanisms are behind it or how the stress response is regulated.
The research group at Karolinska Institutet has previously shown that a protein called p11 plays an important role in the function of serotonin, a neurotransmitter in the brain that regulates mood. Depressed patients and suicide victims have lower levels of the p11 protein in their brain, and laboratory mice with reduced p11 levels show depression- and anxiety-like behaviour. The p11 levels in mice can also be raised by some antidepressants.
The new study shows that p11 affects the initial release of the stress hormone cortisol in mice by modulating the activity of specific neurons in the brain area hypothalamus. Through a completely different signalling pathway originating in the brainstem, p11 also affects the release of two other stress hormones, adrenaline and noradrenaline. In addition, the tests showed that mice with p11 deficiency react more strongly to stress, with a higher heart rate and more signs of anxiety, compared to mice with normal p11 levels.
“We know that an abnormal stress response can precipitate or worsen a depression and cause anxiety disorder and cardiovascular disease,” says first author Vasco Sousa, researcher at the Department of Clinical Neuroscience, Karolinska Institutet.
“Therefore, it is important to find out whether the link between p11 deficiency and stress response that we see in mice can also be seen in patients.”
The researchers believe that the findings may have implications for the development of new, more effective drugs. There is a great need for new treatments because current antidepressants are not effective enough in many patients.
“One promising approach involves administration of agents that enhance localised p11 expression, and several experiments are already being conducted in animal models of depression,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, who led the study. “Another interesting approach which needs further investigation involves developing drugs that block the initiation of the stress hormone response in the brain.”
Funding: The study was done in collaboration with researchers at the Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands, and was supported by the Swedish Research Council, the Söderberg Foundation, the Swedish Brain Foundation, the Wenner-Gren Foundation and the European Union Seventh Framework Programme (BrainTrain).
P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness
Patients suffering from mood disorders and anxiety commonly exhibit hypothalamic–pituitary–adrenocortical (HPA) axis and autonomic hyperresponsiveness. A wealth of data using preclinical animal models and human patient samples indicate that p11 deficiency is implicated in depression-like phenotypes. In the present study, we used p11-deficient (p11KO) mice to study potential roles of p11 in stress responsiveness. We measured stress response using behavioral, endocrine, and physiological readouts across early postnatal and adult life. Our data show that p11KO pups respond more strongly to maternal separation than wild-type pups, even though their mothers show no deficits in maternal behavior. Adult p11KO mice display hyperactivity of the HPA axis, which is paralleled by depression- and anxiety-like behaviors. p11 was found to be highly enriched in vasopressinergic cells of the paraventricular nucleus and regulates HPA hyperactivity in a V1B receptor-dependent manner. Moreover, p11KO mice display sympathetic–adrenal–medullary (SAM) axis hyperactivity, with elevated adrenal norepinephrine and epinephrine levels. Using conditional p11KO mice, we demonstrate that this SAM hyperactivity is partially regulated by the loss of p11 in serotonergic neurons of the raphe nuclei. Telemetric electrocardiogram measurements show delayed heart rate recovery in p11KO mice in response to novelty exposure and during expression of fear following auditory trace fear conditioning. Furthermore, p11KO mice have elevated basal heart rate in fear conditioning tests indicating increased autonomic responsiveness. This set of experiments provide strong and versatile evidence that p11 deficiency leads to HPA and SAM axes hyperresponsiveness along with increased stress reactivity.