Uncovering antidepressive mechanisms of glutamatergic antagonism through neurocircuit, metabolic and morphological brain changes in a genetical rat model of depression

• Applicant: Dr. Natalia Gass
• Subject Area: Biological Psychiatry ; Human Cognitive and Systems Neuroscience
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266329777

Major depression remains a pressing clinical problem responsible for long-term disability and poses a considerable therapeutic challenge since only about two thirds of patients respond to standard antidepressants. Optimizing treatment requires better definition of the function and specificity of the brain circuits involved. There is a growing body of evidence implicating a role for the glutamatergic system. A randomized clinical trial in treatment-resistant depressed (TRD) patients revealed that glutamatergic NmethylDaspartate receptor antagonist ketamine elicits rapid antidepressant effects. This rapid response contrasts markedly with the clinical time course of conventional antidepressants, which takes weeks, and offer the hope for significant therapeutic improvements. We will use the congenital learned helpless strain (cLH) as a validated genetic animal model of TRD to answer the following questions: 1.What functional, morphological and metabolic changes occur in the brain after ketamine challenge and which of these changes could explain its antidepressant effect? 2.What is the difference in the effects of high versus low dose of ketamine on brain functional connectivity, morphology and metabolism? 3.What is the optimum ketamine dose to elicit a rapid antidepressant response? 4.Does acute and long-term (chronic) ketamine elicit a sustained antidepressant effect? 5.What is the difference in ketamine effects when administered acutely or chronically?Brain functional changes will be detected by resting state functional magnetic resonance imaging, and metabolic and morphological alterations by magnetic resonance spectroscopy and voxel based morphometry. Rats will be tested for learned helplessness, and their behavior in this paradigm will be correlated with brain functional changes.

• DFG Programme: Research Grants