Medial Prefrontal Acetylcholine Release Is Modulated by Stimulus During Interval Timing (P6-9.004)

Qiang Zhang; Braedon Kirpatrik; Nandakumar Narayanan

doi:10.1212/WNL.0000000000206121

Abstract only Objective: To study the release of acetylcholine within the medial prefrontal cortex during an interval timing task in freely behaving animals. Background: Cholinergic deficit is a major feature in patients with Alzheimer’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Parkinson’s and Alzheimer’s patients can have impairments in interval timing, or the ability to control movements in time. Timing is preserved across mammalian species, and timing tasks require subjects to estimate an interval of several seconds. These tasks require attention to time and working memory for temporal rules. Mice receiving scopolamine, a cholinergic inhibitor, perform poorly during timing tasks. Interval timing involves medial prefrontal cortical areas that receive prominent cholinergic input; our recent work showed that scopolamine impairs interval timing through disrupting stimulus-processing rather than temporal processing in the medial prefrontal cortex. However, it is unclear how medial prefrontal acetylcholine release is modulated during interval timing. Design/Methods: The acetylcholine fluorescent sensor was employed to evaluate acetylcholine release. Wild type mice were trained on a switch timing task and underwent stereotactic surgeries for AAV-iAchSnFR injections and fiber photometry optic canulae implantation (AP +1.8, ML −0.5, DV AAV injection at −1.8, optic canulae at −1.5). After recovery from surgeries, medial prefrontal acetylcholine release was recorded through fiber photometry, while mice were performing the switch timing task. Results: Medial prefrontal acetylcholine release, as recorded through iAchSnFR fiber photometry, was strongly modulated at the beginning of the switch timing task, responding to the stimulus indicating the start of each trial. Conclusions: During a switch timing task, the release of acetylcholine is strongly modulated by stimulus, suggesting a critical role that the cholinergic circuitry plays during interval timing. These data may have relevance for our understanding of cholinergic function in human diseases such as Parkinson’s disease and Alzheimer’s disease.

Medial Prefrontal Acetylcholine Release Is Modulated by Stimulus During Interval Timing (P6-9.004)

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