SERWOM · Understanding Serotonergic Regulation of Working Memory

Understanding Serotonergic Regulation of Working Memory

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, this project was aimed at elucidating 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. As a first step, we planned to develop a custom multisensory behavioural task that addresses cross-modal SA to test if and how 5-HT modulates the integration of inputs from different sensory modalities depending on behavioural context. We then wanted to investigate how the dynamic activation of distinct 5-HTRs influences SC networks. 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 wanted to reveal the causal role of 5-HT on the modulation of excitatory and inhibitory neurons. Next, we planned to 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 was envisaged to 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. In conclusion, during the course of this project, we showed that mice can learn to utilise auditory, visual, multisensory and contextual information to localise a target of interest in our behavioural task and that their performance depends on stimulus modality, saliency, congruency of sensory information, context and SC functionality. We could show that the SC receives strong serotonergic innervation and that multiple 5-HTRs are distinctively expressed within the SC. We found out, that external modulation of specific 5-HTRs in the SC significantly and distinctively impacts task performance and thus, we confirmed that serotonergic modulation of the SC is relevant for spatial attention.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз