GABAergic INterneurons signaling ImbalancE; A promising target underlying PFC-dependent cognitive flexibility defects.

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.