Cholinergic M1 Receptor Modulation of Sensory Processing: An Integrative Analysis of Cellular, Behavioural, Circuit Dynamics and Computational Modelling

Abstract

To survive, animals must interpret sensory information differently based on the context; for instance, the sound of rustling leaves might be irrelevant in a burrow but could signal danger from a nearby predator in an open field. Neuromodulators like acetylcholine (ACh) enable animals to adjust sensory processing according to environmental demands. The cholinergic system influences information processing across various cortical areas, thereby affecting the animal's behavioral state and level of attention. However, the specific mechanisms by which ACh receptors modulate cortical neuron activity and influence circuit dynamics and behavior are not well understood.

Neuromodulation through ACh involves various muscarinic and nicotinic receptor subtypes, making it challenging to predict the precise effects without knowing the target cell types and specific receptor subtypes involved. This thesis focuses on cholinergic M1 receptors, the most densely expressed cholinergic receptor subtype in the mammalian brain. The aim is to investigate the role of M1 receptors in modulating sensory processing at the single-cell, network, and behavioral levels, and to use computational modeling to provide a comprehensive understanding of these mechanisms.

The whisker system of the mouse is functionally efficient and anatomically well characterised. I therefore employed the whisker system to investigate the neuronal, network and behavioral modulations produced by choliinergic M1 receptors. I first show that M1 receptors in the mouse somatosensory cortex (S1) play a crucial role in enhancing information processing and detection behavior. I then explore the circuit-level mechanisms of M1 modulation in detail, demonstrating that M1 activation facilitates sensory processing in pyramidal neurons and Somatostatin-expressing interneurons while suppressing the response of Parvalbumin-expressing interneurons.

This reveals a cell-type and layer-specific profile of M1 receptor modulation. Finally, I simulate the effects of M1 modulation in a biophysically detailed model of the mouse S1 to validate the experimental findings and identify specific morpho-electrical cell types in different cortical layers that facilitate M1 modulation. In summary, this thesis investigates the role of cholinergic M1 receptors in modulating sensory processing within the mouse S1, revealing their influence on different neuron types and cortical layers, and validating these findings through computational modeling. Show more