Cholinergic modulation of auditory and prefrontal cortical interactions
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Much of the previous work investigating the influence of cholinergic tone on cortical circuits has emphasized global states of arousal and local circuit dynamics; however the cholinergic system is well-suited to coordinate large-scale cortical interactions due to its diffuse cortically projecting arborization and diverse influence on the various cell types within the cortical microcircuit. In this thesis I examined the function of cortical cholinergic tone in supporting long-range cortical interactions, feed-forward sensory signaling, and active processing of behaviorally relevant stimuli. I utilized optogenetic stimulation and silencing of the cholinergic nucleus basalis while recording from the auditory-prefrontal cortical circuit as well as performing local drug infusions in awake mice. I demonstrate that prefrontal cortex actively responds to cortico-cortical sensory input in animals passively presented with acoustic stimuli and that muscarinic receptor binding within auditory cortex is essential for feedforward pathways from auditory cortex to transmit sensory related neural signals. Specifically, muscarinic antagonists applied to the auditory cortex disrupt sensory signaling within auditory cortex as well as bottom up signaling to prefrontal cortex. Furthermore, muscarinic antagonists attenuated the influence of cortical cholinergic release on recording channels closest to drug infusion, confirming the efficacy of muscarinic antagonism, and demonstrating that aspects of cholinergic modulation are locally generated within cortical circuits, while others are globally generated in large networks. In task performing animals, I observed that optogenetic silencing of cholinergic nucleus basalis neurons attenuates the magnitude of prefrontal cortex alpha power following correct behavioral choice and that alpha in prefrontal and auditory cortical local field potentials are actively involved in behavioral learning during extinction, suggesting that cholinergic tone is involved in maintaining and updating the value of stimuli across behavioral trials. In summary, my thesis supports a model where endogenous cholinergic signaling is an essential component of normal auditory processing during low attentive states, contributes to circuit activation through local and large network mechanisms, and supports essential cortical dynamics that contribute to active behavioral processing of stimuli.