The Silent Phase of Alzheimer’s Disease: From Brain States to Homeostatic Failures

Introduction

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 regulators 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.

Proposed Framework

I propose a conceptual and experimental framework to identify the cellular-molecular and circuit-wide in vivo mechanisms underlying the stability of hippocampal circuits across distinct brain states and the stability-plasticity balance.

Methodology

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.

1. Establish Governing Principles: First, we will establish governing principles of homeostatic regulation in the physiological context of sleep and learning.
2. Explore Molecular Drivers: Next, we will explore the underlying molecular drivers of homeostatic regulation.
3. Test Causal Relationships: Finally, we will test the causal relationship between dyshomeostasis of activity in hippocampal circuits, sleep disturbances, and cognitive decline in AD models.

Integrative Approach

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.

Significance

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.