Periodic Reporting for period 2 - ANewSpike (A new type of spike: Homoclinic spike generation in cells and networks)
Okres sprawozdawczy: 2022-07-01 do 2023-12-31
Neurons exchange information on the basis of electrical pulses, so-called action potentials. Action potentials, however, are not all equal. Despite shared biophysical principles and even similar pulse shape, neurons with different spike generators can encode vastly different aspects of a stimulus and result in radically different behaviour of the embedding network. Theoretical research has shown that spike generation in regularly firing cells with all-or-none action-potentials can be classified into a few dynamical types with qualitatively distinct computational properties. Among these, so-called homoclinic spikes - unlike the other commonly considered types - have been largely ignored. Yet, homoclinic spike generators are special because only they allow a neuron to react with high sensitivity to inputs during the refractory period, i.e. the period directly after the generation of a pulse.
This property has interesting consequences for the behaviour of the whole neuronal network. Specifically, the action-potential type can impact whether the acitivity of neurons in the network is synchronous or not. Understanding the mechanism by which homoclinic action potentials can set such network states is a primary goal of the project. To this end, we will (i) identify physiological parameters that induce homoclinic spikes in neurons, (ii) develop methods to identify homoclinic spikes in experimental recordings, (iii) determine which networks are sensitive to synchronizing effects of homoclinic spikes and (iv) explore their role in pathologies such as epileptiform activity or spreading depolarization.
The approach is based on mathematical modelling, allowing us to dissect the underlying mechanisms in a very complex system. It is complemented by experimental studies in collaboration with partner labs that enable us to test the theoretical predictions. Our multi-scale study aims to add a novel dimension to our understanding of neural dynamics at the cellular and network level by revealing how homoclinic spiking can shape brain dynamics in both health and pathology.
This property has interesting consequences for the behaviour of the whole neuronal network. Specifically, the action-potential type can impact whether the acitivity of neurons in the network is synchronous or not. Understanding the mechanism by which homoclinic action potentials can set such network states is a primary goal of the project. To this end, we will (i) identify physiological parameters that induce homoclinic spikes in neurons, (ii) develop methods to identify homoclinic spikes in experimental recordings, (iii) determine which networks are sensitive to synchronizing effects of homoclinic spikes and (iv) explore their role in pathologies such as epileptiform activity or spreading depolarization.
The approach is based on mathematical modelling, allowing us to dissect the underlying mechanisms in a very complex system. It is complemented by experimental studies in collaboration with partner labs that enable us to test the theoretical predictions. Our multi-scale study aims to add a novel dimension to our understanding of neural dynamics at the cellular and network level by revealing how homoclinic spiking can shape brain dynamics in both health and pathology.
During the last two years we have made substantial progress in shedding light on these action potentials’ generation and function. Specifically: 1) We have revealed that concentration increases in extracellular potassium ions push neurons into this dynamical regime. This was shown in mathematical models and confirmed in in-vitro experiments in collaboration with the lab of Allen Gulledge (Vanderbilt University, US), see publication Contreras et al., PLoS Computational Biology (2021). 2) We have demonstrated that moderate elevations above physiological temperature can also induce homoclinic spiking. Moreover, we have shown that this type of spike tends to synchronize inhibitory networks and to induce splayed-out, desynchronized states in excitatory networks. Again, the basis forms the mathematical model, an initial experimental confirmation of the switch to homoclinic spikes in hippocampal cells was obtained in collaboration with the lab of Dietmar Schmitz (Charite Berlin, Germany). The results were published in Hesse et al., Nature Communications (2022). 3) As we had found out before the start of the ERC project, also changes in membrane capacitance can induce homoclinic spikes. Membrane capacitance, however, cannot be easily modulated. Hence, we developed a hybrid experimental-in-silico method to artificially modulate membrane capacitance in in-vitro experimental settings. This technique, called 'capacitance clamp’ was applied in collaboration with the lab of Imre Vida (Charite Berlin, Germany) and the results have been published in Pfeiffer et al., eLife (2022). 4) We have mathematically derived the firing statistics of neurons with homoclinic spikes, see Schleimer et al., Phys Rev E (2021). These provide an additional dimension to distinguish homoclinic spikers from other dynamical types. 5) Based on mathematical analysis, we derived a novel desynchronizing effect of neurons with homoclinic spikes when coupled electrically via gap junctions.
We could reveal that cells with, presumably, the most prevalent type of action potential (mathematically based on a so-called saddle-node-on-invariant-circle bifurcation) switch to the generation of homoclinic spikes when their temperature increases or when potassium ions accumulate in the extracellular space. Interestingly, both conditions have previously been associated with epileptiform activity. Moreover, we have demonstrated that increases in temperature tend to synchronize inhibitory networks and, on the other hand, elicit splayed-out network patterns in excitatory networks. We have developed a novel method to modify the membrane capacitance of neurons experimentally, via a hybrid in-silico/in-vitro approach. Such methodology is interesting, because also changes in membrane capacitance can induce homoclinic spiking. Finally, we have uncovered a surprising function of electrical coupling between neurons. Besides chemical coupling, neurons can be coupled directly via so-called gap junctions. This fast interaction route between neurons has so far been thought to fulfill a synchronizing function for the network, aligning the neurons’ firing in time. We showed that electrical coupling of neurons with homoclinic spikes results in splayed-out network states, where individual neurons specifically tend to fire at times when the other neurons do not. This finding assigns a completely novel functional role to electrical coupling and stresses the relevance of both electrical coupling as well as homoclinic action potentials. The theoretical prediction was experimentally confirmed in the fruitfly Drosophila melanogaster in collaboration with the lab of Carsten Duch at the University of Mainz, see Hürkey et al., Nature (2023).
In the next years we aim to further decipher the impact of homoclinic spikes on mixed excitatory-inhibitory networks and to further analyze the role of these intriguing action potentials in pathology.
In the next years we aim to further decipher the impact of homoclinic spikes on mixed excitatory-inhibitory networks and to further analyze the role of these intriguing action potentials in pathology.