GinieEffect · GABAergic INterneurons signaling ImbalancE; A promising target underlying PFC-dependent cognitive flexibility defects.
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-07-01 → 2024-06-30
- EU contribution
- €153,487
- Participants
- 2
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
GABAergic INterneurons signaling ImbalancE; A promising target underlying PFC-dependent cognitive flexibility defects.
The Covid-19 outbreak has highlighted the significance of adapting our decision-making and behavior in response to unforeseen changes in our surroundings. In vertebrates, prefrontal cortex (PFC) has the cognitive control to modify the animal behavior when the rules change, but the exact mechanisms underlying PFC function at the neuronal level are still largely unknown. Inhibitory GABAergic interneurons (INs) regulate the overall excitability of the prefrontal cortex by reducing the firing rate of the major excitatory pyramidal neurons and thereby fine-tuning the balance between excitation and inhibition. GenieEffect aimed to combine behavioural studies in freely moving mice with neuronal circuit modeling to long-term dysregulate the INs function and investigate their role on the PFC circuit function, with respect to flexible behaviour. A deeper understanding of the role of INs at the neuronal level is important in order to better understand complex behaviors such as decision making. In addition, it can help us better understand traumatic brain injuries, diseases and disorders that involve the PFC region and impact decision-making such as: frontal lobe disorders, executive function disorders, substance use disorders and neurodegenerative diseases. Enriching our basic scientific knowledge on the PFC can help healthcare providers in the future to better understand, diagnose and treat the PFC-dependent psychiatric and neurological disorders.
Data: CORDIS, © European Union
Project objective
Covid-19 pandemic has highlighted the importance of making decisions and adjusting our behavioural strategy to tackle unexpected changes in our environment. The cognitive flexibility required to modify behaviour when the rules change is ascribed primarily to the prefrontal cortex (PFC), but the exact mechanisms underlying this phenomenon remain unknown. Inhibitory GABAergic interneurons (INs) seem to play a key role in this process by modulating the primary excitatory pyramidal neurons activity in the PFC. Indeed, individuals who have deficits in these INs, a common feature in many mental disorders, often fail to adjust their behaviour to a rule change, even though their ability to learn an initial rule remains intact. The two, main IN subsets, Parvalbumin-positive (PV) and Somatostatin-positive (SST) have different anatomical and physiological characteristics suggesting distinct functions. We, thus, hypothesize distinct roles for each subtype: PV cells may control the gain in pyramidal neuron activity, thereby affecting behaviour. SST cells, however, may control the ability to learn a new rule via plasticity in dendrites, thereby affecting behaviour, but leaving pyramidal neurons activity intact. Combining genetic, imaging and behavioural techniques in freely moving mice with in silico studies, we will dissect the effects of of long-term dysregulation of PV and SST INs on the PFC circuit function, with respect to flexible behaviour. Our experimental results will be fed to a computational model of the PFC circuit to further investigate how interneuronal control of information affects cognitive flexibility and to explore mechanisms that can reverse cognitive flexibility defects. Unravelling the mechanistic role of cognitive flexibility in the PFC will not only further our understanding of a complex brain function. It will also open new avenues for developing therapeutic approaches for numerous mental disorders, thus ameliorating a large societal and economic burden.
Original text from CORDIS.
Participants
Links
- View on CORDIS
- DOI: 10.3030/101067655
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e51120adcb&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5f5cd086f&appId=PPGMS
Data: CORDIS, © European Union