Abstract
SummaryCholinergic neurotransmission throughout the neocortex and hippocampus regulates arousal, learning, and attention. However, owing to the poorly characterized timing and location of acetylcholine release, its detailed behavioral functions remain unclear. Using electrochemical biosensors chronically implanted in mice, we made continuous measurements of the spatiotemporal dynamics of acetylcholine release across multiple behavioral states. We found that tonic levels of acetylcholine release were coordinated between the prefrontal cortex and hippocampus and maximal during training on a rewarded working memory task. Tonic release also increased during REM sleep but was contingent on subsequent wakefulness. In contrast, coordinated phasic acetylcholine release occurred only during the memory task and was strongly localized to reward delivery areas without being contingent on trial outcome. These results show that coordinated acetylcholine release between the prefrontal cortex and hippocampus is associated with reward and arousal on distinct timescales, providing dual mechanisms to support learned behavior acquisition during cognitive task performance.
Highlights
Cholinergic neurons in the basal forebrain (BF) and medial septum/diagonal band of Broca (MS-DBB) innervate cortical and subcortical structures, including the prefrontal cortex and hippocampus, respectively (Mesulam et al, 1983)
We find that tonic acetylcholine release is coordinated in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) and predicts the transition of behavior between different arousal states
To measure the spatiotemporal dynamics of acetylcholine release, choline biosensors were co-implanted in the mPFC and dHPC of mice (Figure S1)
Summary
Cholinergic neurons in the basal forebrain (BF) and medial septum/diagonal band of Broca (MS-DBB) innervate cortical and subcortical structures, including the prefrontal cortex and hippocampus, respectively (Mesulam et al, 1983). These projections play an important role in attention and memory processes (Hasselmo and Sarter, 2011), likely by desynchronizing neuronal networks to enhance the signal-to-noise ratio for salient information (Chen et al, 2015; Everitt and Robbins, 1997; Fu et al, 2014; Harris and Thiele, 2011; Hasselmo, 2006; Pinto et al, 2013). The limited temporal resolution of microdialysis prevents detection on a sub-minute timescale that is most relevant to many cognitive processes and, leaves open the question of whether fluctuations in acetylcholine are mediated by an increase in non-synchronized release from multiple presynaptic boutons over a period of minutes (tonic release) or highly synchronized release within a few seconds (phasic release) (Sarter et al, 2009)
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