Friday, April 11, 2025
4/11/2025
Compartment-specific inhibition and laminar circuit dynamics in the primate prefrontal cortex. - Abnormal GABAergic inhibitory neurotransmission in the prefrontal cortex (PFC) is implicated in the cognitive and emotional disturbances present in schizophrenia and mood disorders. Two key PFC areas that exhibit altered activity in neuropsychiatric disorders are the lateral prefrontal cortex (LPFC) and the medial prefrontal anterior cingulate cortex (ACC), which have distinct temporal patterns of activation and roles in executive function and cognitive control. Neurochemically diverse inhibitory interneurons (INs) mediate inhibition in the cortex and target specific somatodendritic compartments of pyramidal (PYR) cells, differentially modulating cortical activity. While somatic inhibition from parvalbumin INs has a well-characterized role in the pathophysiology of schizophrenia, emerging evidence suggests that decreased dendritic inhibition and altered GABAAR composition in the PFC are also associated with schizophrenia and mood disorders. However, the properties of dendritic inhibition on PYR cells across diverse LPFC and ACC areas and layers, and its contribution to oscillations has not yet been elucidated. Thus, our overall objective with this proposal is to compare the spatial distribution, kinetics, and synaptic physiology of dendritic inhibition on PYR cell dendrites in the ACC and LPFC of rhesus macaques, an ideal model organism for studying the primate PFC. Our central hypothesis is that greater dendritic inhibition and slower inhibitory current kinetics are associated with slower oscillatory dynamics in the ACC relative to the LPFC. This would reveal a cellular and subcellular mechanism by which diverse laminar network activity emerges in the PFC and suggest points of intervention to treat altered PFC activity observed in cognitive and psychiatric disorders. In Aim 1, we will study inhibitory postsynaptic currents in PYR cells in the rhesus macaque ACC and LPFC via ex vivo whole-cell patch clamp recordings, along with dendritic calcium imaging via intracellular filling with calcium indicator dye to study subcellular calcium dynamics associated with compartment-specific inhibition. In these experiments, will study the effect of pharmacologically blocking GABAARs containing the α5 subunit. We will additionally perform immunohistochemistry (IHC) and confocal imaging on these electrophysiologically-characterized PYR cells to compare the subcellular distribution of IN- labeled inhibitory appositions between areas. In Aim 2, we will compare local field potentials (LFPs) and spike- field coupling between putative INs and LFPs across cortical layers via acute in vivo laminar recordings in the ACC and LPFC. We will also use IHC and confocal imaging to compare the laminar distribution of IN appositions onto PYR cells in ACC and LPFC subregions along the medio-lateral axis. We will assess relationships between in vivo functional and tissue-based structural laminar parameters using a biophysical PYR-IN-network model and test how dendritic-targeting INs and synapses affect population rhythm generation. These experiments will shed vitally needed insight on the mechanisms of differential susceptibility of these areas to network disruption, potentially aiding diagnosis and treatment of cognitive-affective disorders.
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