PIANISM · Prefrontal Cortex Circuit Dynamics underlying Working Memory and its Serotonin Modulation

Prefrontal Cortex Circuit Dynamics underlying Working Memory and its Serotonin Modulation

Attention is the cognitive process of selectively focusing on a particular stimulus or task while filtering out distractions. It allows us to selectively process and respond to important or relevant information, while ignoring irrelevant stimuli. Attention is a limited resource, and we can only attend to a certain amount of information at a given time. Research has shown that serotonin (5-HT) receptors play a role in regulating sensory processing and attention. Dysfunction in the 5-HT system has been linked to the development of disorders with symptoms, such as abnormal processing of multiple senses and problems with spatial attention. 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. Our initial plan was to create a behavioural task that examines how different senses work together in spatial attention, focusing on how 5-HT may influence information integration from these senses. This would allow us to test the effects of 5-HT on cross-modal spatial attention. Next, we investigated how the dynamic activation of 5-HT receptors influences SC networks. Using a new genetically encoded fluorescence sensor for 5-HT, large-scale neuronal recordings, and optogenetic techniques during the task, our goal was to determine the causal role of 5-HT in the modulation of excitatory and inhibitory neurons. To link specific 5-HT receptors to the circuit mechanism, we created a 3D map of 5-HT receptor subtypes at a cellular level using a multiplexed in-situ hybridisation method. Next, we aimed to understand the physiological role of these receptors by combining patch-clamp recordings with optogenetic and pharmacological techniques that target specific receptor types. Our method aims to create a comprehensive understanding of how 5-HT affects attention and how disruptions in its regulation may contribute to the development of neuropsychiatric disorders. Such a mechanistic account, at cellular- and circuit levels is required to guide the development of next-generation pharmacotherapies. In summary, we demonstrate that mice can learn to locate a target using various types of sensory information. We found that the mice's ability to perform this task is affected by factors such as the type of information being used, its importance, consistency, and the state of a specific brain region called the superior colliculus. Additionally, we found that the SC receives dense serotonergic input and expresses various 5-HT receptors. Our research revealed that altering specific 5-HT receptors in the SC has a notable and distinct effect on task performance, confirming the importance of serotonergic modulation in the SC for spatial attention.

Data: CORDIS, © European Union