1/7/2024 0 Comments Processing pmouse![]() ![]() 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. The majority of L2/3 pyramidal neurons fire sparsely as a consequence of precisely balanced recurrent excitation and feed-forward and feedback inhibition 39, 40, 41 and ACh modifies this balance to influence L2/3 pyramidal neuron activity 20, 21.ĭespite this knowledge, how ACh modifies L2/3 cortical pyramidal neuron activity during awake sensory processing remains unanswered. Somatosensory L2/3 cortical pyramidal neuron activity is powerfully influenced by ACh 19, 24, 25, 33 and BF projections to this cortical layer are particularly dense 8. Here, 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 regions 35, 36, 37, 38. A renaissance of EEG, and whole-cell electrophysiology, with optogenetic stimulation also show how basal forebrain cholinergic activity in vivo promotes attention, wakefulness and visual perception by influencing cortical neuron gain control, signal-to-noise and synchrony 26, 27, 28, 29, 30, 31, 32, 33. Specific optical stimulation and electrophysiology in vitro have significantly advanced our understanding of how nicotinic and muscarinic cholinergic actions alter single pyramidal neuron, inhibitory interneuron and cortical network activity 19, 20, 21, 22, 23, 24, 25. These multiple roles of ACh, for such a variety of behaviours, occurring across various cortical areas, make it particularly challenging to understand how this critical neuromodulator acts. These extensive cholinergic projections are critical for many behaviours such as body awareness, attention, sleep and arousal and also for motor skill development, learning, memory and cognition, in both health and disease 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. Cholinergic neurons of the basal forebrain (BF) form organised and widespread projections to release ACh across the whole cortex 8. 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.Īcetylcholine (ACh) is a widespread neurotransmitter and neuromodulator long known to act throughout the central nervous system across a variety of circuitries and timescales 1, 2, 3, 4, 5, 6, 7. A consequence of this re-shaping was disrupted adaptation of the sensory-evoked responses, suggesting a critical role for acetylcholine during sensory discrimination behaviour. Altering muscarinic acetylcholine function re-shaped sensory-evoked fast depolarisation and subsequent slow hyperpolarisation of L2/3 pyramidal neurons. 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. 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. 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.
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