INTEGRATE · An integrated hypothesis for cognitive and positive symptoms in schizophrenia
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-12-01 → 2021-12-01
- EU contribution
- €208,400
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
An integrated hypothesis for cognitive and positive symptoms in schizophrenia
The overall objective of this project was to obtain a deeper understanding of the pathophysiology of schizophrenia, a prevalent yet poorly understood neurodevelopmental disorder. Specifically, our aim was to investigate the interplay between cognitive deficits and psychosis. Our original hypothesis was that genetic mutation leading to an imbalance between excitation and inhibition could lead to abnormal brain development widespread across multiple regions, including cortical and subcortical regions involved in cognition and motor representation. In addition, we were interested as to understand how brain codes would be affected in these conditions. A clearer understanding in the pathophysiology of schizophrenia could have helped us to develop new and better targeted therapeutics, still currently missing. While our preliminary results showed promising interplay between abnormal inhibition, cognitive dysfunctions and sign of psychosis (including increased motor activity and velocity), our examination was inconclusive as to the role of dopamine in this. Furthermore, our investigations were hampered by the COVID crisis that prevented us to import mutated mice in our animal facilities – or even work in said animal facilities. However, we were able to perform computational analyses to focus on a very interesting phenomenon that we observed during our initial recordings as to the neurophysiology of cortical and subcortical region supporting velocity coding, a possible bridge between abnormal cognitive representations and pathologic motor activity seen as a proxy for positives symptoms. The manuscript covering part of these results was just officially accepted by Nature Communication. Furthermore, the MSCA was essential in establishing new methods at the University of Oslo. These methods formed the cornerstone of successful grant proposals that allowed the MSCA recipient to become an independent group leader.
Data: CORDIS, © European Union
Project objective
An integrated hypothesis for cognitive and positive symptoms in schizophrenia:Schizophrenia is a complex developmental brain disorder with three main clusters of symptoms: (i) positive (psychosis, delusions and hallucinations), (ii) negative (reduced motivation and social withdrawal), and (iii) cognitive (memory and executive function deficits). For the last 50 years, the only effective treatment has consisted of antipsychotics targeting dopamine receptors. Yet, antipsychotics control mostly the positive symptoms and are largely ineffective at treating other deficits. It is frequently assumed that distinct pathophysiological mechanisms underlie different symptoms. Psychosis is associated with striatal hyperdopaminergia, probably due to abnormal activity of midbrain dopaminergic neurons. Yet cognitive deficits seem to arise from cortical excitation/inhibition unbalance. I propose to test, in a mice model, the hypothesis that striatal hyperdopaminergia results from dysfunctional cortical inhibition. If verified, this would suggest that normalizing cortical activity in schizophrenia might both restore cognitive function and prevent psychosis.
Original text from CORDIS.
Participants
- UNIVERSITETET I OSLO · OsloCoordinatorNorway
Links
Data: CORDIS, © European Union