SPPIN’s webinar winter-spring 2021, 29 JUNE at 10h00 – UNUSUAL TIME -, online – Ask link to a SPPIN member.
Laetitia CHAUVIÈRE – Radboud University Medical Centre Nijmegen, the Netherlands
Early cognitive comorbidities in related brain diseases
Brain diseases are a societal, economic, and health challenge, with ~1 in 3 European citizens’ lives being affected each year, and cost Europe an estimated €798 billion in 2010 (Gustavsson et al., 2010; Wittchen et al., 2010). There is a paucity of disease-modifying therapies for brain diseases and so preventive measures are a health priority. Neurodevelopmental disorders (NDD) such as autism, epilepsy, and schizophrenia are clinically heterogenous but i) epidemiology shows high rates of co-occurrence; ii) there are similar genetic risk factors such as copy number variants; iii) cognitive and mood comorbidities are common. I aim to study NDD as a cross-diagnostic spectrum by focusing on the shared cognitive comorbidities. Commonly cognitive or affective symptoms precede the core disease symptoms. My hypothesis is that these could constitute a broad biomarker of brain diseases and reveal common endophenotypes. In this research project, I will investigate early cognitive comorbidities in related brain diseases, taking the example of schizophrenia and temporal lobe epilepsy (TLE) using rodent models. The main question I want to investigate is whether restoring abnormal network dynamics underlying those early comorbidities could prevent disease onset?
To achieve this, I will first identify abnormal network dynamics associated with cognitive deficits ahead of disease onset. The focus will be on the highly interconnected septal-entorhinal-hippocampal-prefrontal network involved in theta rhythm generation and in cognition, with theta coordinating those brain areas during cognition. We will use state-of-the-art chronic extracellular recordings in vivo using Neuropixels probes in adult rats performing cognitive tasks.
Secondly, I will investigate whether restoring those dynamics to control levels can suppress or delay disease onset. Preliminary data showed that temporal lobe interareal coherence in the theta range was impaired during sleep ahead of TLE onset. I thus expect theta dynamics to be altered within our network of interest associated with early cognitive comorbidities. Such abnormalities will be restored in real-time using closed-loop optogenetics (Krook-Magnuson et al., 2013; Amstrong et al., 2013; Zaaimi et al., 2021). As the integrity of theta rhythm requires an intact input from specific inhibitory and excitatory cells in the medial septum, entorhinal cortex, and hippocampus, we will express opsins in specifically targeted neurons to study which expression restores best theta dynamics, such as interareal coherence. Using the stabilized step-function opsin which operates for 30 minutes after being activated by a single one-second light pulse, I plan to study theta dynamics during cognitive tasks. I will then investigate whether the recovery of these dynamics at different intervals during the period prior to the respective disease onset (i) restores the cognitive performances, (ii) is transient or persistent, and (iii) under which conditions it offers the optimal window of intervention to suppress or delay the respective disease onset.