The Role of Serotonin in the Modulation of Multisensory Spatial Attention

Attention improves perceptual abilities by modulating sensory processing. The superior colliculus is a brain region involved in directing attention on a reflexive manner by guiding orienting behaviours towards or away from salient stimuli. Serotonin is a chemical naturally produced by the brain that can modulate how sensory information is perceived by our sensory organs according to behavioural context, via suppressing sensory information irrelevant to the ongoing behaviour. We have recently developed a behavioural task that requires mice to report the location of a salient auditory or visual stimulus. While the performance of the mice depends primarily on the saliency of the stimulus, their behaviour is also modulated by contextual information. Mice perform the task in blocks where only one modality is rewarded, such that they need to switch attention between auditory and visual information to obtain a reward. This task allows us to assess the role of the SC in spatial reflexive attention and how this process is modulated by serotonin in a context dependent manner, when only one of the sensory modalities is relevant for the task. In this project we aim to study how serotonin modulates attention through the activation of different receptors. The malfunction of different serotonin receptor types has been implicated in the pathogenesis of several neurological disorders, highlighting the importance of studying how serotonin receptors mediate attentional processes in the healthy brain. Our project will work on multiple scales, such that serotonin action is characterised at the level of single nerve cells, across multiple brain areas and in individual organisms. Our approach to target individual receptors in specific brain regions will enable us to minimise animal numbers while generating a complete and detailed model of serotonin function. This project will allow us to uncover new targets for drugs to treat various types of neurological disorders that affect millions of people in the UK and worldwide.

Attention improves perceptual abilities by modulating sensory processing. Abnormalities in sensory processing and attention are profound problems in several neurological disorders. Serotonin receptors (5-HTRs) have been shown to modulate and maintain sensory processing and attention, and dysregulation of the 5-HT system has been implicated in the pathogenesis of these disorders sharing characteristic symptoms, such as aberrant multisensory processing and spatial attention (SA). Using the mouse as a model system, we will elucidate 5-HT effects on the superior colliculus (SC), a brain area implicated in integrating endogenous with externally driven attention and recipient of dense 5-HT input. Using a custom multisensory behavioural task that addresses cross-modal SA, we will test if 5-HT modulates the integration of inputs from different sensory modalities depending on behavioural context. We will then study if the dynamic activation of 5-HTRs influences SC networks through changes in excitation/inhibition balance. Using a novel genetically encoded 5-HT fluorescent sensor, large-scale neuronal recordings and next-generation optogenetic perturbations during our cross-modal behavioural task, we will reveal the causal role of 5-HT on the modulation of excitatory and inhibitory cells. We will then generate a three-dimensional map of 5-HTR subtypes at cellular resolution using a multiplexed in-situ hybridisation method and reveal the physiological role of the detected 5-HTRs by combining patch-clamp recordings in brain slices, receptor type-specific optogenetic and pharmacological perturbations. Our multiscale approach will allow us to generate a detailed mechanistic model of 5-HT physiological effects on cross-modal SA and elucidate how its dysregulation can be the substrate for the pathogenesis of psychiatric and neurological disorders. Such a mechanistic account, at cellular- and circuit-level, is required to guide the development of next-generation pharmacotherapies.