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Understanding Serotonergic Regulation of Working Memory

Functional integrity of the prefrontal cortex (PFC) is essential for higher ‘executive’ functions such as working memory (WM). Serotonin (5-HT) modulates GABAergic neurotransmission in the PFC through different 5-HT receptor subty... ver más

07/11/2022

The Francis Crick...

213K€

Presupuesto del proyecto: 213K€

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THE FRANCIS CRICK INSTITUTE LIMITED No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

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Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2022-11-07

MSCA-IF-2019: Individual Fellowships

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2 Participantes

The Francis Crick Institute

186.32K€ | Lider

IMPERIAL COLLEGE OF SCIENCE...

26.62K€ | Participante

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Duración del proyecto: 32 meses Fecha Inicio: 2020-02-27
Fecha Fin: 2022-11-07

Líder del proyecto

THE FRANCIS CRICK INSTITUTE LIMITED No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 213K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Functional integrity of the prefrontal cortex (PFC) is essential for higher ‘executive’ functions such as working memory (WM). Serotonin (5-HT) modulates GABAergic neurotransmission in the PFC through different 5-HT receptor subtypes that are selectively expressed in distinct GABAergic cell types. Altered GABAergic neurotransmission in the PFC of patients suffering from schizophrenia and depression is believed to be central to their pathophysiology. Currently available treatments targeting 5-HT signaling have addressed different mental health symptoms but typically not cognitive capabilities. Therefore, characterizing the causal role of distinct GABAergic cell types on circuit activity is a critical step in understanding the circuit mechanism of WM. This proposal focuses on the role of 5-HT in the regulation of inhibition in cortical activity and their consequences in influencing WM maintenance. I will simultaneously image the electrical activities of pyramidal and distinct GABAergic interneurons while well-trained mice execute a delayed two alternative forced choice (2AFC) task to read out WM during the delay period. Imaging will be performed in both wide-field and two-photon imaging mode to record cortical activity at the mesoscopic (cortex-wide) and local (PFC) levels, respectively. I will combine optical imaging with optogenetic stimulation/silencing to manipulate GABAergic interneurons in the PFC and serotonin release in the dorsal raphe (DR) during the execution of the 2AFC task. Additionally, I will use a mouse model of schizophrenia that is known to exhibit WM deficits to correlate possible alterations in serotonin signaling during cellular-level WM maintenance with WM performance at the behavioral level. This could allow us to understand why many psychiatric treatments are mostly ineffective at improving cognitive abilities and how modulation of the serotonergic system could reverse these effects, ultimately helping to develop new therapeutic treatments.

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