Hagopian, L. L. | Search bioRxiv

bioRxiv2025

Synaptic plasticity of prefrontal long-range inhibition regulates cognitive flexibility

While glutamatergic synaptic plasticity is believed to be a fundamental mechanism mediating learning, the behavioral significance of plasticity at cortical GABAergic synapses remains less well understood. Furthermore, despite recent discoveries of long-range projections from neocortical GABAergic neurons, details about how they function are also sparse. Here we combine behavioral optogenetics with patch-clamp electrophysiology to link plasticity at long-range GABAergic synapses with higher-order cognitive functions. Specifically, learning extradimensional rule shifts potentiates callosal GABAergic synapses from prefrontal parvalbumin-expressing (PV) neurons onto corticothalamic neurons. Disrupting this potentiation by inhibiting callosal PV terminals during rule shifts induces perseveration, whereas reinstating this potentiation with subsequent gamma-frequency callosal PV terminal stimulation restores flexible behavior. This shows how a novel plasticity locus can regulate brain circuits underlying normal cognition and pathological states.

neuroscience↗

bioRxiv2024

Cell type-specific dynamics of prefrontal gamma synchrony during flexible behavior

Cognitive dysfunction in conditions such as schizophrenia involves disrupted communication between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). Parvalbumin interneurons (PVI) are known to regulate PFC microcircuits and generate gamma-frequency ([~]40Hz) oscillations - fast, synchronized neural rhythms that are recruited during many executive functions, necessary for cognitive flexibility, and deficient in schizophrenia. While targeting PVI-mediated gamma oscillations holds great therapeutic promise, their nature and specific functions, e.g., for regulating PFC[->]MD communication, remain elusive. Using dual-color voltage indicators and optogenetics, we reveal that PVIs dynamically entrain MD-projecting PFC neurons both locally and contralaterally, giving rise to multiple distinct circuit-specific patterns of distributed synchronization that are recruited in a behaviorally-specific manner to support particular aspects of flexible behavior. Thus, gamma oscillations are not unitary phenomena characterized by one microcircuit-wide pattern of entrainment. Rather, they comprise diverse motifs, defined by specific cell types and phase relationships, that are dynamically recruited for specific functions.

neuroscience↗