Since the early time of Descartes at the turn of the 17th century, scientists and philosophers have been searching for the physical correlate of thoughts and memories. During the past 60 years, mounting evidence indicates that experience-dependent changes in synaptic transmission and neuronal wiring, phenomena collectively termed synaptic plasticity, underlie the cellular basis of neural computation, learning and memory. Individual synapses – the elementary units of information transfer – encode and store new information in response to the environmental changes through structural and functional reorganization. However, the key mechanisms that normally maintain plasticity of synapses during adulthood or initiate synapse dysfunction and loss in neurodegenerative disorders remain unknown.
Our research focuses on two key questions:
- How do individual neurons and neural networks achieve an ongoing balance between stability and plasticity under a constantly changing environment?
- What are the mechanisms driving synaptic and network dysfunctions in Alzheimer’s disease?
- Interplay between population firing stability and single neuron dynamics in hippocampal networks.
- Balance between firing stability and synaptic plasticity in hippocampal circuits.
- Do circuits with different functions display similar or distinct homeostatic principles?
- What are the building blocks of the core homeostatic machinery that controls stability of central circuits?
- Does failure in firing homeostasis cause aberrant activity in cortico-hippocampal circuits in Alzheimer’s disease?
- Does stability – plasticity imbalance drive early-phase Alzheimer’s disease?
- What are the main factors that determine circuit-specific vulnerability in Alzheimer’s disease?
- Calcium imaging from large-scale neuronal populations in behaving mice using Inscopix miniature microscope;
- Electrophysiology: intracellular patch-clamp recordings in brain slices and cultures, MEA (multiple-electrode-array) recordings in neuronal cultures, in vivo extracellular recordings;
- Targeted manipulations of neuronal activity using chemogenetic and optogenetic tools;
- High-resolution, quantitative imaging of synaptic vesicle recycling and calcium dynamics at the level of single synapses;
- Two-photon microscopy combined with fluorescence lifetime imaging microscopy (2pFLIM);
- In vivo gene delivery using lentivirus and adenoassociated virus vectors;
- FRET: real-time imaging of inter-molecular interactions at nano-scale in live neurons;
- Molecular tools: target-specific expressing genetically-encoded fluorophore-fused proteins of interest, site-directed mutagenesis, protein knockdown.