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

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.