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. Hebbian-like plasticity is crucial for refinement of neural circuits and information storage, however, alone it is unlikely to account for the stable functioning of neural networks. Both, stability and plasticity are hallmarks of brain function that enable adaptations to unpredictable and dynamic environment, experience and learning. Coping with constantly changing environments, neural circuits need to spend a considerable amount of their available energy to maintain homeostasis and to minimize the effects of stochastic events. Destabilization of hippocampal and cortical circuits has been widely documented in neurodegenerative disorders, e.g. Alzheimer’s disease, the most frequent form of late-life dementia. However, the key mechanisms that underlie stability of activity patterns in central mammalian neural circuits are largely unknown. Furthermore, how disruption of these mechanisms affects the progression of Alzheimer’s disease remains an enigma.
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 the hippocampus of behaving mice.
- Functional role of firing rate homeostasis in hippocampal circuits of behaving mice.
- Regulation and mysregulation of activity set points by sleep in hippocamapl circuits.
- Do circuits with different functions display distinct homeostatic principles?
- What are the building blocks of the core homeostatic machinery underlying stability of central circuits?
- Do failures in firing homeostasis drive Alzheimer’s disease pathophysiology?
- What is the role of sleep-wake states in dysregulation of activity set points in Alzheimer’s disease?
- Re-adjustment of dysregulated activity set points as a new approach to treat brain disorders associated with aberrant network activity.
- Calcium imaging from large-scale populations of hippocampal neurons in behaving mice using miniaturized fluorescence 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, calcium dynamics and mitochondrial functions;
- 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.