Mechanisms of Cholinergic Neuromodulation of Prefrontal Cortex in Health and Disease: A Combined Whole-Cell Electrophysiology and Multiphoton Calcium Imaging Approach

The neuromodulation of the prefrontal cortex (PFC) by acetylcholine is essential for optimal executive function, where it exerts robust excitatory actions together with complex calcium ion signals via the nicotinic and muscarinic acetylcholine receptors. This thesis examines how cholinergic calcium fluxes regulate the ability of acetylcholine to excite prefrontal circuits and how these interactions are disrupted in rodent models of psychiatric and neurological illness. Using whole-cell electrophysiology together with multiphoton calcium imaging in slices of rodent PFC, I have found that cholinergic calcium mobilization can exert important regulatory control over cholinergic excitability: by enhancing sub-threshold cholinergic excitation and by constraining supra-threshold effects via the modulation of spike output. Importantly, these distinct interactions were disrupted in two separate models of neuropsychiatric disease with documented cognitive dysfunction. First, in pyramidal cells of prefrontal output layer 5, acetylcholine-induced calcium release was found to potentiate excitatory cholinergic currents via the electrogenic process of sodium/calcium exchange. This phenomenon was found to emerge in young adulthood, when executive function typically reaches maturity. What is more, this developmental consolidation of cholinergic signaling was abolished subsequent to the early stress of repeated maternal separation—a model of psychiatric vulnerability—where cholinergic responses retained an adolescent phenotype accompanied by a disruption in the expression of multiple developmentally-regulated genes associated with Gαq and calcium signaling. Second, in a well-characterized model of Alzheimer’s disease, I have found that layer 6 PFC pyramidal cells, which are known to be essential for peak attentional performance, are unable to sustain cholinergic excitation to the same extent as those of non-transgenic littermate controls as a result of the excessive activation of calcium-activated hyperpolarizing conductances. Further, I demonstrate that cholinergic excitation can be improved in the cortex of these mice by pharmacological blockade of SK channels, suggesting a novel target for the treatment of executive dysfunction. In sum, this thesis characterizes two distinct and potentially complementary mechanisms whereby calcium can shape cholinergic excitability in prefrontal circuits essential to executive function and how these interactions are disrupted in models of brain disease with documented cognitive dysfunction.Ph.D.2017-02-12 00:00:0