The degree to which individual neuronal input-output functions are modulated by voltage fluctuations, however, is not well established across different cortical areas.

Additionally, the extent and mechanisms of input-output modulation through fluctuations have been explored largely in simplified models of spike generation, and with limited consideration for the role of nonlinear and voltage-dependent membrane properties.

To address these issues, we studied fluctuation-based modulation of input-output responses in medial entorhinal cortical (MEC) stellate cells of rats, which express strong subthreshold nonlinear membrane properties.

For this to be true, neuronal spike input-output behavior must be sensitive to physiological membrane voltage fluctuations.

Using a combination of single cell recordings and modeling, we investigated the mechanisms through Which voltage fluctuations modulate neuronal input-output responses.

We find that neurons that express an increase in membrane input resistance With depolarization show low levels of noise-mediated modulation of input-output responses due, in part, to voltage trajectories that suppress the likelihood of generating a spike in response to random current input fluctuations.

Because probabilistic threshold crossings associated with fluctuations lower spike threshold, enabling spike response to otherwise subthreshold inputs [5,6] , it has been hypothesized that background activity amplifies neuronal sensitivity, and in doing so permits fluctuations to modify the input-output functions of neurons [7—12].

Linealities are reversible cycles or input-output pathways (boundary to boundary metabolite(s), see 81 Fig.

Rays are irreversible (thermodynamically infeasible) cycles or input-output pathways.

In the optimum, these subnetworks consist of reactions with correlated flux variability and have a fixed net input-output stoichiometry of reactants and products.

In the constructed Ecoli subnetworks, the input-output relationship was the only constraint.

CoPE-FBA subnetworks are defined Within this flux space and have a fixed input-output relationship, Which we can write mathematically as:

Subsequently, N A and I A are the stoichiometric matrix and the flux vector of the subnetwork, and d is the fixed input-output relationship of the subnetwork.