Neuronal excitation as a perturbation of the energetic and osmotic homeostasis: Implications for robust network behaviour
Project C6 focuses
on theoretical aspects of the design and robustness of metabolic
networks. In the previous funding period we investigated the
relationship between metabolic fluxes and gene expression. We developed
a novel concept of flux analysis based on a decomposition of the flux
distribution within a metabolic network into so-called minimal flux
modes which represent minimal flux scenarios needed to accomplish a
single metabolic output. This decomposition allows incorporating
information on changes of enzyme levels (gene expression profiles),
metabolic target functions, thermodynamic constraints on the
directionality of reactions, and availability of external substrates in
the prediction of changes of stationary fluxes.
In the next funding period we want to focus on two other important aspects of network robustness: (i) The problem of kinetic robustness (or homeostasis), i.e. the ability of a metabolic network to keep the concentration of relevant metabolites in a sufficiently narrow interval upon time-dependent variation of utilizing reactions. (ii) The robustness of networks composed of interacting cells showing individual alterations of their functional performance during collective network activity.
Inspired by discussions with partners of the SFB618 and in order to intensify joint research between the two “SFB-columns” neurobiology and organismic systems, we decided to choose as a concrete system the energy metabolism of neuronal cells. Neuronal excitation is an energetically costly process. Generation of action potentials together with the release and reuptake of neurotransmitters have been predicted to stimulate the consumption of ATP by a factor of 10 – 20 compared to the resting state (Attwell & Laughlin 2001). Moreover, excitatory amino acids such as glutamate acting on various receptor subtypes invoke an increase in the concentrations of intracellular Na+, Ca2+, and Cl- that exposes neurons to both an osmotic and a calcium stress during excitation. Our working hypothesis is that during enhanced long-term signalling (e.g., gamma oscillations or series of successive activations sustained over several minutes) complete restoration of the initial ATP-level and trans-membrane ion distribution is not possible (“energetic fatigue”). This should be reflected in temporary changes of frequency distribution of action potentials. Accordingly, this project aims at the establishment of a mathematical electric-metabolic-osmotic (EMO) model of neurons that can be used to simulate temporal changes of the energetic and ionic state of the cell at various signalling modes. Calibration of the model will be based on transient changes of electrophysiological parameters and metabolite concentrations as measured in specific regions of hippocampal slices under different physiological stimulations. In order to assess the possible consequences of neuronal excitation and thus perturbation of cellular homeostasis on the fidelity of signal transfer in the nervous system and to critically test current theories of distributed neuronal coding, we will imbed our single-neuron EMO model into a network of interacting neurons and simulate the network behaviour at various signalling modes. The two central issues addressed by our approach are (i) an assessment of the energetic and osmotic limitations of neuronal coding and (ii) to unravel regulatory mechanisms that warrant robust information processing within neural tissue despite individual variations in the excitability of single neurons.
In the next funding period we want to focus on two other important aspects of network robustness: (i) The problem of kinetic robustness (or homeostasis), i.e. the ability of a metabolic network to keep the concentration of relevant metabolites in a sufficiently narrow interval upon time-dependent variation of utilizing reactions. (ii) The robustness of networks composed of interacting cells showing individual alterations of their functional performance during collective network activity.
Inspired by discussions with partners of the SFB618 and in order to intensify joint research between the two “SFB-columns” neurobiology and organismic systems, we decided to choose as a concrete system the energy metabolism of neuronal cells. Neuronal excitation is an energetically costly process. Generation of action potentials together with the release and reuptake of neurotransmitters have been predicted to stimulate the consumption of ATP by a factor of 10 – 20 compared to the resting state (Attwell & Laughlin 2001). Moreover, excitatory amino acids such as glutamate acting on various receptor subtypes invoke an increase in the concentrations of intracellular Na+, Ca2+, and Cl- that exposes neurons to both an osmotic and a calcium stress during excitation. Our working hypothesis is that during enhanced long-term signalling (e.g., gamma oscillations or series of successive activations sustained over several minutes) complete restoration of the initial ATP-level and trans-membrane ion distribution is not possible (“energetic fatigue”). This should be reflected in temporary changes of frequency distribution of action potentials. Accordingly, this project aims at the establishment of a mathematical electric-metabolic-osmotic (EMO) model of neurons that can be used to simulate temporal changes of the energetic and ionic state of the cell at various signalling modes. Calibration of the model will be based on transient changes of electrophysiological parameters and metabolite concentrations as measured in specific regions of hippocampal slices under different physiological stimulations. In order to assess the possible consequences of neuronal excitation and thus perturbation of cellular homeostasis on the fidelity of signal transfer in the nervous system and to critically test current theories of distributed neuronal coding, we will imbed our single-neuron EMO model into a network of interacting neurons and simulate the network behaviour at various signalling modes. The two central issues addressed by our approach are (i) an assessment of the energetic and osmotic limitations of neuronal coding and (ii) to unravel regulatory mechanisms that warrant robust information processing within neural tissue despite individual variations in the excitability of single neurons.
| description of the 2nd period | german version |