„Metabolic Chronopathology in Depression: Functional Astrocyte-Neuron
Interactions in the Cellular Model of Glucocorticoid Resistance”

(acronym: MiChroFAN)

The research leading to project results has been funded from Norwegian Financial Mechanism for 2014-2021, Program „POLS” no 2020/37/K/NZ3/02783

Total cost: 873 750,00 PLN – € 198 982
Norwegian Financial Mechanism for 2014-2021: 742 687,50 PLN – € 169 134,73
Duration: 2021/09/01 – 2023/11/30

TEAM MEMBERS:

• • Michał Ślęzak, PhD, PI & Head of Laboratory of Astrocyte Biology

• • Tansu Gover, MSc, Process Engineer

Glucocorticoids are major hormones engages in stress response, while in physiological conditions they act as the main regulators of circadian metabolism across the body. Under conditions of glucocorticoid resistance, the response of various tissues to this physiological signal is blunted. A large body of evidence has shown the relationship between deficient glucocorticoid signaling and metabolic impairment in peripheral tissues, as this interaction occurs in several other disorders, for example diabetes. However, the impact of glucocorticoid resistance on the brain remains unknown. This ignorance is calling for resolution, since it is plausible that the impairment of glucocorticoid signaling will disrupt energy metabolism in the brain, ultimately leading to synaptic deficits, as observed for example in depression. We started to fill this knowledge gap by showing that astrocytes mediate many effects of glucocorticoids in the brain. Furthermore, we shown that chronic stress, a major risk factor in depression, has dramatic effect on gene expression profile in astrocytes. We therefore hypothesize that impaired glucocorticoid signaling accompanying depression negatively affects astrocytes metabolism. In this project, my group will employ state-of-the-art genetic and imaging tools to explore this hypothesis.

Several mechanisms were proposed to mediate cellular glucocorticoid resistance, but all of them focus on impaired function of glucocorticoid receptor, a molecule mediating effects of glucocorticoids on gene expression. It has been shown that this activity is negatively regulated by another protein which binds to GR, namely FKBP5. Interestingly, FKBP5 exists in several variants across the population studies shown that some of these variants are more frequent in the population of patients suffering from depression. To understand how these variants affect cell biology, we will use novel genetic models to examine the role of FKBP5 variants in the regulation of metabolism in two major brain cell types, neurons and astrocytes. Our goal is to shed new light on the metabolic relationship in a cellular model of depression-related phenotypes. We believe that our approach will lead to deeper understanding of neuropathology accompanying psychiatric symptoms, so much needed for accelerating the development of efficient therapeutic strategies.