Understanding Serotonergic Regulation of Inhibition in Cortical Activity (U-SRICA)

Our proposal focuses on investigating serotonin (5-HT)'s causal role in regulating inhibition in cortical activity and its consequences in working memory maintenance. Interestingly, 5-HT modulates inhibition in the prefrontal cortex (PFC) through different receptors which are selectively expressed in distinct GABAergic cell types. Also, altered GABAergic neurotransmission in the PFC of patients suffering from schizophrenia and depression is central to their pathophysiology. However, currently available treatments targeting 5-HT signalling have addressed different mental health symptoms but typically not cognitive capabilities. Therefore, characterising the causal role of each 5-HT receptor-specific GABAergic cell type on circuit activity is a critical step in understanding the circuit mechanism of working memory. We can then ultimately develop new effective treatments. This study will use cell type-specific optical voltage imaging methods, both wide-field, and two-photon imaging, to record cortical activity at the mesoscopic and local levels. First, we will simultaneously monitor pyramidal and 5-HT receptor-specific GABAergic cell types while well-trained mice execute a delayed Go or No-Go auditory task and, additionally, use pharmacological 5-HT modulation to monitor and delineate serotonin-related changes in cortical dynamics and behaviour. Then, we will combine optical imaging with optogenetic silencing to dissect the function of distinct 5-HT receptor-specific GABAergic cell types during the execution of the above-mentioned delayed task. Finally, we will use computational modelling to provide quantitative descriptions of brain networks to understand the underlying circuit dynamics of working memory. Models can help predict mental disorders and monitor disease progression.