Research

Research

Whilst various neurotransmitter systems (e.g. serotonin, glutamate) have been targeted for anti-depressant treatments with some limited efficacy, the actual aetio-pathophysiology of depression remains to be identified. Controlled animal studies can provide critical evidence. Our approach is to study the effects of chronic social stress (CSS) on depression-relevant neurobehavioural states in mice. Uncontrollable psychosocial life events are major aetiological factors for human depression. With respect to neurobehavioural states, our approach is consistent with the NIH research domain criteria (RDoC) framework, focussing on the neurobiology of specific psychopathologies rather than the complex disorder. Neurobehavioural states induced by CSS and of particular translational interest are reduced reward salience and amotivation under effortful conditions, increased aversion salience, helplessness, and fatigue. These states are of direct relevance to major symptoms and daily functioning in depression as well as other major disorders.  

With respect to aetio-pathophysiology, we are particularly interested in the processing of reward salience and aversion salience in the amygdala, and whether and how CSS impacts on this. At the level of the amygdala as an entire (heterogeneous) region, we have demonstrated that CSS leads to altered functional connectivity (fMRI), increased inflammatory markers (MRS, LC-MS/MS), altered gene expression at the transcriptome level (RNA-seq), and reduced reward salience and increased aversion salience (automated tests). Now we are focussing at the sub-regional and cellular levels of the amygdala, to identify the amygdala microcircuitry mediating CSS effects on depression-relevant behaviours. It is anticpated that this approach will identify pathophysiological mechanisms as well as molecular targets for the treatment of specific psychopathologies. 

In parallel to this preclinical target discovery and validation approach, we also conduct mouse studies that complement the experimental psychopharmacology research being conducted in human studies.  

Keywords

Stress

Immune system

Reward

Amotivation

Aversion

Helplessness

Fatigue

Amygdala

Nucleus accumbens

Research collaborations

Swiss Federal Institute of Technology Zurich, CH

Animal Imaging Center

Prof. Markus Rudin

 

University of Zurich, Zurich, CH

Institute of Pharmacology

Prof. Bruno Weber

 

University of Zurich, Zurich, CH

Brain Research Institute

Prof. Fritjof Helmchen

 

University of Roehampton, London, UK

Department of Life Sciences

Prof. Jolanta Opacka-Juffry, Dr. Michael Patterson

 

Max Planck Institute of Experimental Medicine, Göttingen, Germany

Department of Neurogenetics

Dr. Sandra Goebbels, Prof. Klaus-Armin Nave

 

Boehringer Ingelheim Pharma, Biberach, Germany

CNS Diseases Research

Prof. Bastian Hengerer, Prof. Boris Ferger, Dr. Angelo Ceci

 

Roche Innovation Center Basel, CH

NeuroImmunology Section

Dr. Irene Knuesel