Abstract
The mouse cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT+ neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT+ neurons in mice are specialized VIP+ interneurons that release GABA strongly onto other inhibitory interneurons and acetylcholine sparsely onto layer 1 interneurons and other VIP+/ChAT+ interneurons. This differential transmission of ACh and GABA based on the postsynaptic target neuron is reflected in VIP+/ChAT+ interneuron pre-synaptic terminals, as quantitative molecular analysis shows that only a subset of these are specialized to release acetylcholine. In addition, we identify a separate, sparse population of non-VIP ChAT+ neurons in the medial prefrontal cortex with a distinct developmental origin that robustly release acetylcholine in layer 1. These results demonstrate both cortex-region heterogeneity in cortical ChAT+ interneurons and target-specific co-release of acetylcholine and GABA.
Highlights
Acetylcholine (ACh) is a neurotransmitter and neuromodulator that is released throughout the mammalian cortex at times of alertness and arousal[1] in order to promote learning and memory[2], modulate sensory perception[3], gate plasticity[4,5], and enhance the detection of salient sensory cues and reinforcement[6,7,8,9]
Both of these genes are expressed in the majority of cortical choline acetyltransferase (ChAT)+ neurons
We found that vasoactive intestinal peptide (VIP)+/ChAT+ neurons largely release gamma-aminobutyric acid (GABA) onto each other (Figure 3I,K), but that a subset received nicotinic ACh receptors (nAChRs)-input which could be blocked by nAChR
Summary
Acetylcholine (ACh) is a neurotransmitter and neuromodulator that is released throughout the mammalian cortex at times of alertness and arousal[1] in order to promote learning and memory[2], modulate sensory perception[3], gate plasticity[4,5], and enhance the detection of salient sensory cues and reinforcement[6,7,8,9]. Putative cholinergic neurons in the cortex were first identified by immunolabeling for choline acetyltransferase (ChAT), the biosynthetic enzyme that produces ACh12,13, and their presence has since been corroborated by both immunohistochemical and transcriptional analyses[14,15,16,17,18,19,20,21,22,23] Both initial immunochemical labeling and recent single-cell transcriptomic classification[24,25,26] demonstrate that cortical ChAT+ neurons express vasoactive intestinal peptide (VIP), indicating that they are a subclass of VIP+ interneurons
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