Our research aims at gaining a better functional understanding of disease-related changes of individual neuronal compartments such as single synapses on dendrites during behaviour. Even the smallest changes in the processing of synaptic signals can easily lead to a change in the output signal and thus disturb network function. A balanced interplay of excitatory neurons and inhibitory interneurons, under tight neuromodulatory brain-state dependent control, is required to direct the information flow through our memory systems. We use behavioural, computational, optogenetic, cellular imaging and multiple electrophysiological techniques to understand both the physiological circuits that underlie behaviour and the remodeling of memory-related neuronal networks in neurodegenerative diseases.
- Altered neuronal excitability in mouse models of Alzheimer’s disease. Dendritic structure critically determines the electrical properties of neurons and thereby defines the fundamental process of input to output conversion. It is known that this dendritic integrity is impaired in patients with Alzheimer’s disease and in relevant mouse models. We use in vivo whole-cell patch-clamp recordings, high-resolution STED imaging and computational modeling of CA1 pyramidal neurons in different rodent models to show that structural degeneration and neuronal hyperexcitability are crucially linked. Our results demonstrate that a structure-dependent amplification of input to output conversion might constitute a novel cellular pathomechanism linked to early network hyperexcitability (Šišková et al, 2014). We now investigate the effects of altered neuronal excitability on spatial memory and explore therapeutic avenues by regulation of inhibitory circuit function.
- Subcortical modulation of memory circuits and specific vulnerability in neurodegenerative diseases. Subcortical regions as the locus coeruleus and the medial septum show specific early vulnerability in Alzheimer’s disease. We have shown that a mechanistic coupling of motor signaling and hippocampal theta-oscillations exists on the subcortical level of the medial septum. We have found that the action potential firing of medial septal neurons actively controls movement speed, entrains movement-correlated theta oscillations and alters the membrane potential of hippocampal-entorhinal neurons (Fuhrmann et al, 2015, Justus et al, 2017). We curently investigate the role of locus coeruleus in the control of entorhinal-hippocampal function.
- Dendritic encoding of movement in space (ERC). We investigate the relationship of neural network activity and behaviour based on an understanding of the transformation of inputs to outputs in single neurons. We have developed an approach that allows both the mapping of synaptic inputs and the prediction of output during behaviour. We apply this functional decoding approach to pyramidal neurons in the hippocampal formation. We generate spatial tuning maps of synaptic inputs using two-photon Ca2+ imaging. These patterns are then incorporated into a data-driven biophysical model capable of converting realistic synaptic inputs into output. The goal is to generate a first model that is capable of predicting the membrane potential of individual neurons exclusively from precise behavioural observation.