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An integrated hypothesis for cognitive and positive symptoms in schizophrenia

Periodic Reporting for period 1 - INTEGRATE (An integrated hypothesis for cognitive and positive symptoms in schizophrenia)

Reporting period: 2018-12-01 to 2020-11-30

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.
I Technical set up and procedures refinement inherent to specific research, as well as further exploitation for future research (see details in technical report)
1. Engineering of targeted deletion in space and developmental time
2. Set up of behavior room and positive symptoms test procedures and analyses (including self-motion analyses)
3. Refinement of specific immunohistochemistry procedures

II Overview of the research results (see details in technical report)
Our first result was to verify that conditional mutant presented a significant increase in positive symptoms at postnatal day P30 (such as exemplify by hyperlocomotion) compared to control mice. Once this established, we went on to test two different focal mutants resulting from targeted injection either the (1) frontal cortex or (2) the striatum. We then used immunohistochemistry methods with the goal to establish the accuracy of the erbb4 deletion in targeted cells, as well as their effect on the local network. However, we encounter strong caveats with this method and had to spend a considerable amount of time to refine our primary and secondary antigen combination, as well microscopy procedures. While we confirm accurate deletion at P30, we did not observe any further impact of the deletion on either the local network or the behavioral phenotype of either mutant, thus invalidating our original hypothesis. We then moved on to test local dopamine levels with microdyalisis. While we observed a significant increase in dopamine levels in conditional mutant, we did not replicate this result in focal mutants. Because of the covid crisis our access to animal facilities was strongly reduce, therefore prevented us to explore further these discrepancies with PET-scan and investigate whether our original hypothesis was truly invalidated and why. However, this situation provided us with extra-time to develop new computational methods to further investigate our behavioral results, specifically representations of velocity. This research revealed itself to be fertile and led us to discover a new type of velocity conjunctive coding, combining representation of both angular and linear velocity in normal subjects. We further tested this type of coding in other data set that we had access to, specifically a data set that the grant recipient had collected during her PhD. This discovery led to a very fruitful collaboration with the International School for Advanced Studies (SISSA) in Trieste.

III Exploitation and dissemination of the research results
As mentioned above, 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 at the University of Oslo. Intermediate results were regularly presented at internal labmeeting, seminars and institute retreat, where they were discussed with scientific assemblies of diverse size ranging from the core group (5-10 researchers) to >150 researchers belonging to the institute. Some of the results were also presented at the bi-annual meeting of the Federation of European neuroscience societies (FENS) regrouping over 5000 participants, as well as to the COSYNE meeting in Colorado (US). The recipient of the grant was also invited to present these results to multiple talks, including talks given to Queens Mary College (London, UK), The Technion (Haifa, Israel), SISSA (Trieste, Italy), NCMM (Oslo, Norway) and the university of Tsukuba (Japan). Most of these talks were given online because of the COVID restrictions. The manuscript covering part of the results obtain thanks to the MSCA funding was just officially accepted by Nature Communication.
The action allowed us to establish new experimental and computational methods at the host university. These methods will allow to advance the technical state of the art to study neurodevelopmental disorders in animal models. These technical advancements are now integrated in the new independent research developed by the MSCA recipient and funded by successful grant application that would not have been granted without the results obtains with the MSCA. When it comes to the invalidation of the original hypothesis, further experiments will be necessary to determine their cause. However, we were able to apply our newly discovered computational methods to an additional data set of in vivo multiunit recordings. This led us to discover a nee type of velocity conjunctive coding. This discovery will have a significant impact in the leading consensus and theories about self-motion and path integration, notably the continuous attractor network theory. Further studies will be necessary to understand how neurodevelopmental diseases such as schizophrenia, but also autism may impact self-motion and association with so-called positive symptoms.
Summary of the workflow to test original hypothesis