Descripción del proyecto
Análisis del papel de la serotonina en la plasticidad sináptica de la corteza prefrontal
La serotonina o 5-hidroxitriptamina (5-HT) es un importante neurotransmisor del encéfalo y la periferia. La corteza prefrontal es fundamental para el control descendente de procesos ejecutivos de orden superior como el aprendizaje, la memoria de trabajo y la flexibilidad cognitiva, y expresa cinco subtipos de receptores de 5-HT. Las pruebas demuestran la existencia de un vínculo entre la modulación serotoninérgica disfuncional y los déficits de memoria de trabajo, aunque se desconocen sus mecanismos celulares. El proyecto PIANISM, financiado con fondos europeos, investiga el papel de la 5-HT en la formación de la memoria de trabajo. El equipo manipula células de cortes encefálicos y mide los efectos sobre la actividad sináptica característica que se cree que subyace a la formación de la memoria en la corteza prefrontal. La información obtenida podría ser importante para determinar dianas terapéuticas para tratar déficits de memoria comunes en algunas enfermedades neurodegenerativas y la esquizofrenia.
Objetivo
The prefrontal cortex (PFC) is essential for higher cognitive tasks such as learning, decision making and, in particular, working memory (WM). To fulfill these tasks, PFC neurons express several serotonin (5HT) receptor subtypes that are modulated by a high density of serotonergic axons projected from the raphe nuclei. Alterations of the neuronal mechanisms within PFC lead to an impaired top-down regulation, causing cognitive dysfunctions in mental disorders such as schizophrenia. A key cellular mechanism related to WM formation and maintenance in the PFC is sustained action potential firing of neurons that outlasts the initial excitatory drive. Persistent firing is likely enabled by synaptic networks and intracellular ionic mechanisms, including voltage sensitive sodium and calcium inward currents or G-Protein-coupled receptor mediated TRPC/ CAN currents. Moreover, experimental data supports a link between dysfunctional serotonergic modulation in the PFC and WM deficits, but yet, the underlying mechanisms are poorly understood. Here, I plan to gain a mechanistic understanding of the serotonergic modulation of WM at the cellular level including the link between 5HT receptor activity and prefrontal cellular circuits dependent WM formation and the role of 5HT in WM-related persistent firing. I will perform patch-clamp electrophysiology and optical voltage imaging (genetically encoded voltage indicators) of prefrontal pyramidal and GABAergic cells (PV-, SST-, VIP-subtypes) in acute slices from naïve and WM deficient mice (chronic ketamine model of schizophrenia), and examine how the activity of these cell types are modulated by optogenetically and pharmacologically controlled 5HT signalling. These experiments aim to understand the serotonergic transmission and intrinsic properties within the PFC involved in WM formation, maintenance and deficiency. Better understanding of these mechanisms will help to develop new and specific therapeutic targets for WM deficiencies.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
NW1 1AT London
Reino Unido