Boris Gutkin

Cholinergic modulation of hierarchal inhibitory circuitry in the prefrtonal cortex controls resting state activity.

Local circuitry in the superficial layers includes a hierarchal sub-circuit of interneurons with inhibitory and disinhibitory, subtractive and divisive, influence on the principle cells. These neurons play a significant role in structuring on-going activity and are subject to specific modulation by acetylcholine through nicotinic acetylcholine receptors (nAChRs). We show how the various types of nAChRs, located on specific interneurons, impact the properties of ultra-slow transitions between high and low activity states (H-states and L-states, respectively), recorded in mice during quiet wakefulness. Recent data indicate that a genetic mutation of the α5 nAChR receptors located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, appears to be responsible for hypofrontality observed in schizophrenia. Chronic nicotine application mice restores neural activity to control levels.

We will present a reduced circuit model of the hierarchically organized neural populations. Using this model we show that the change of activity patterns recorded in the genetically modified mice can be explained by a change of activity state stability, differentially modulated by cholinergic inputs to parvalbumin (PV), somatostatin (SOM) or VIP inhibitory populations. We demonstrate that desensitization and upregulation of β2 nAChRs located on SOM interneurons by chronic nicotine application could account for activity normalization recorded in α5 SNP mice. We will use the model to predict effects of nicotine withdrawal on the on going activity. Time permitting we will show how the local circuitry can also explain hyper-activity observed in the early stages of Alzheimer’s disease and how this circuitry interacts with brain oscillations.