Abstract
Cholinergic modulation of brain activity is fundamental for awareness and conscious sensorimotor behaviours, but deciphering the timing and significance of acetylcholine actions for these behaviours is challenging. The widespread nature of cholinergic projections to the cortex means that new insights require access to specific neuronal populations, and on a time-scale that matches behaviourally relevant cholinergic actions. Here, we use fast, voltage imaging of L2/3 cortical pyramidal neurons exclusively expressing the genetically-encoded voltage indicator Butterfly 1.2, in awake, head-fixed mice, receiving sensory stimulation, whilst manipulating the cholinergic system. Altering muscarinic acetylcholine function re-shaped sensory-evoked fast depolarisation and subsequent slow hyperpolarisation of L2/3 pyramidal neurons. A consequence of this re-shaping was disrupted adaptation of the sensory-evoked responses, suggesting a critical role for acetylcholine during sensory discrimination behaviour. Our findings provide new insights into how the cortex processes sensory information and how loss of acetylcholine, for example in Alzheimer’s Disease, disrupts sensory behaviours.
Highlights
Cholinergic modulation of brain activity is fundamental for awareness and conscious sensorimotor behaviours, but deciphering the timing and significance of acetylcholine actions for these behaviours is challenging
We focus on the somatosensory cortex, in particular layer 2/3 (L2/3) pyramidal neuron activity, since L2/3 amplifies layer 5 (L5) pyramidal neuron somatosensory output[34] and provides a long-range broadcasting network connecting different cortical r egions[35,36,37,38]
Somatosensory L2/3 cortical pyramidal neuron activity is powerfully influenced by A Ch19,24,25,33 and basal forebrain (BF) projections to this cortical layer are d ense[8]
Summary
Cholinergic modulation of brain activity is fundamental for awareness and conscious sensorimotor behaviours, but deciphering the timing and significance of acetylcholine actions for these behaviours is challenging. Cholinergic neurons of the basal forebrain (BF) form organised and widespread projections to release ACh across the whole c ortex[8] These extensive cholinergic projections are critical for many behaviours such as body awareness, attention, sleep and arousal and for motor skill development, learning, memory and cognition, in both health and d isease[9,10,11,12,13,14,15,16,17,18]. Perhaps part of the challenge has been our inability to access widespread but specific cortical circuit activity on a time scale that matches ACh actions, and during behaviourally relevant responses in the awake animal To address those experimental issues, we established fast voltage imaging of L2/3 cortical-wide activity in awake, head-fixed mice, asking how ACh influences real-time cortical activity evoked by simple sensory stimulation. Our results extend recent, elegant work in vitro, showing how cholinergic inhibition and Scientific Reports | (2021) 11:17525
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