CCKinPFC · Role of perisomatic inhibition on prefrontal cortex neurons in gamma oscillations and cognitive flexibility
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-06-01 → 2023-05-31
- EU contribution
- €196,708
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Role of perisomatic inhibition on prefrontal cortex neurons in gamma oscillations and cognitive flexibility
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.
Data: CORDIS, © European Union
Project objective
Dysfunction of the prefrontal cortex (PFC) contributes to cognitive deficits that represent the primary cause of disability associated with schizophrenia. However, currently available antipsychotic medications are only minimally effective for cognitive symptoms, demonstrating the need for better therapeutic targets. Treatments for cognitive deficits in schizophrenia remain underdeveloped in large part because the relevant physiological mechanisms remain unclear.A major hypothesis is that in schizophrenia, GABAergic interneuron abnormalities, notably fast-spiking interneurons that express parvalbumin (PV) and generate gamma oscillations, disrupt PFC-dependent cognition in schizophrenia. PV interneurons are critical for synchronization of neural activity, but exactly how these oscillations are regulated remain unknown. Perisomatic inhibition from cholecystokinin (CCK) interneurons can alter properties of PV networks by regulating the likelihood to generate oscillations or to affect the frequency, duration, synchrony, spatial extent, or other properties of these oscillations. Yet their role in PFC is elusive and surprisingly little is known about their functional role in the emergence of gamma activity and cognition despite their structural control over their postsynaptic partners. My research plan has two aims: to characterize the circuit-specific activity dynamics of CCK interneurons in 1) PFC gamma oscillations and 2) cognition. I will use a multidisciplinary approach, combining in vitro and in vivo physiology, viral and transgenics strategies, pharmacology, fiber photometry, 2-photon imaging, and optogenetics to provide a more specific mechanistic framework for therapeutic intervention. I hypothesize that CCK interneurons significantly control the perisomatic region of pyramidal as well as PV neurons, thus contributing to the spiking properties that underlie gamma oscillations and ultimately, cognition.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union