Innovating Works

DormantAD

Financiado
The Silent Phase of Alzheimer’s Disease: From Brain States to Homeostatic Failur...
Neuronal circuits must balance stability and plasticity. How this balance is compromised in brain disorders remains one of the most fundamental questions in neuroscience. Pioneering studies in the field established that homeostati... Neuronal circuits must balance stability and plasticity. How this balance is compromised in brain disorders remains one of the most fundamental questions in neuroscience. Pioneering studies in the field established that homeostatic mechanisms stabilize the function of a system at a set-point level of activity. Recently, we have identified bona fide mitochondrial regulator of activity set points and provided support to our standing hypothesis that homeostatic failures destabilize network activity in Alzheimer's disease (AD). However, we have just scratched the surface of the mechanisms stabilizing activity set points in vivo. I propose a conceptual and experimental framework to identify the cellular-molecular and circuit-wide in vivo mechanisms underlying stability of hippocampal circuits across distinct brain states and stability-plasticity balance. Using a wide range of optical, electrophysiological, computational and molecular tools, we will explore homeostatic regulation of activity in hippocampal circuitry, a crucial substrate for memory formation, and its relation to AD. First, we will establish governing principles of homeostatic regulation in physiological context of sleep and learning. Next, we will explore the underlying molecular drivers of homeostatic regulation. Finally, we will test the causal relationship between dyshomeostasis of activity in hippocampal circuits, sleep disturbances and cognitive decline in AD models. To target these questions, we will utilize the basic concepts of control theory and an integrative approach which spans brain-state, neural circuit, synaptic and molecular levels. We believe that this understanding is an essential step to uncover the principle basis underlying the transition from a presymptomatic disease stage to clinically evident cognitive AD impairments. The proposed research will elucidate fundamental principles of neuronal function and reveal conceptually novel insights into how to maintain AD in a dormant state. ver más
30/09/2028
TAU
3M€
Duración del proyecto: 59 meses Fecha Inicio: 2023-10-01
Fecha Fin: 2028-09-30

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-10-01
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG: ERC ADVANCED GRANTS
Cerrada hace 2 años
Presupuesto El presupuesto total del proyecto asciende a 3M€
Líder del proyecto
TEL AVIV UNIVERSITY No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5