Role of perisomatic inhibition on prefrontal cortex neurons in gamma oscillations and cognitive flexibility

Project Information

CCKinPFC

Grant agreement ID: 101029791

DOI

10.3030/101029791

Project closed

EC signature date 26 April 2021

Start date 1 June 2021

End date 31 May 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 196 707,84

EU contribution

€ 196 707,84

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - CCKinPFC (Role of perisomatic inhibition on prefrontal cortex neurons in gamma oscillations and cognitive flexibility)

Reporting period: 2021-06-01 to 2023-05-31

Summary of the context and overall objectives of the project

Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates and humans to update their behavior to adapt to changes in the environment – for example, during cognitive tasks. Parvalbumin-expressing inhibitory neurons in the medial prefrontal cortex are important for learning new strategies during a rule-shift task, but the circuit interactions that switch prefrontal network dynamics from maintaining to updating task-related patterns of activity remain unknown. Here we describe a mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations. Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts or disrupt the evolution of activity patterns, selectively inhibiting only callosal projections of parvalbumin-expressing neurons impairs rule-shift learning, desynchronizes the gamma-frequency activity that is necessary for learning and suppresses the reorganization of prefrontal activity patterns that normally accompanies rule-shift learning. This dissociation reveals how callosal parvalbumin-expressing projections switch the operating mode of prefrontal circuits from maintenance to updating by transmitting gamma synchrony and gating the ability of other callosal inputs to maintain previously established neural representations. Thus, callosal projections originating from parvalbumin-expressing neurons represent a key circuit locus for understanding and correcting the deficits in behavioral flexibility and gamma synchrony that have been implicated in schizophrenia and related conditions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Here, we discovered a new type of inhibitory connection between the left and right prefrontal cortex that helps switch the brain from maintaining to updating previously learned behavioral strategies. We found that this connection synchronizes the two hemispheres and gates the ability of other connections between the hemispheres to maintain previously-learned patterns of brain activity. We have used a multidisciplinary approach, combining in vitro and in vivo physiology, viral and transgenics strategies, pharmacology, a combination of microendoscopic calcium imaging with optogenetics, and a combination of voltage indicator imaging and optogenetics to describe this mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations in the prefrontal cortex during a task that tests cognitive flexibility. Targeting this connection can lead to persistent deficits or improvements in cognitive flexibility, which may be relevant to conditions such as schizophrenia. The results are published in bioRxiv (April 2022) and Nature (April 2023).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our results show how a novel connection switches the prefrontal cortex from maintaining to updating behavioural strategies by gating the ability of callosal communication to maintain previously established activity patterns. Furthermore, this connection can trigger a novel bi-directional form of network plasticity. Thus, callosal connections originating from prefrontal PV neurons represent a critical circuit locus for understanding and potentially correcting deficits in gamma synchrony and behavioural flexibility that are major features of schizophrenia.

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