Deletion ofCrtc1leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

Abstract

Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models, can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying the underlying molecular/physiological origin, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point towards the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential.

Quercetin reshapes gut microbiota homeostasis and modulates brain metabolic profile to regulate depression-like behaviors induced by CUMS in rats

“…Increasing evidence suggests a close association between carbohydrate metabolism and depression, with abnormalities in carbohydrate metabolism being observed in the PFC (Baxter et al, 1989;Kennedy et al, 2001;Hennings et al, 2012;Li et al, 2015;Yao et al, 2023), HIP (Cherix et al, 2022), andHYP (Al-Massadi et al, 2021) of depression patients or depression-like animal models. This study found that quercetin may ameliorate depression-like behaviors in CUMS rats by modulating glycolysis/ gluconeogenesis and the pentose phosphate pathway.…”

New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity

“…Deletion of Crtc1 gene in mice induces insulin resistance and obesity, together with a depressive-like phenotype ( Altarejos et al, 2008 ; Breuillaud et al, 2009 , 2012 ; Rossetti et al, 2017 ). Using in vivo MRS at high field, we have observed that this phenotype translates into measurable neurochemical alterations in the hippocampus of Crtc1 –/– mice ( Cherix et al, 2020 ). Noteworthy, we identified lower levels of phosphocreatine relative to creatine, an indication that ATP production or consumption is impaired.…”