We plan to extend our work on the electrogenesis of magnetoencephalographic (MEG) signals in order to help interpret MEG signals that are commonly measured non-invasively outside the brain of patients and healthy volunteers. Our earlier studies have shown that MEG signals may be directly due to intracellular currents produced by active neurons. However, we still have not addressed the issue of how various types of post-synaptic currents in the dendrites and soma of cortical neurons may contribute to MEG signals. The concept of post-synaptic currents has undergone dramatic transformations in the past twenty years with the discoveries of active conductances in the dendrites that can produce spikes in dendrites. These discoveries call for a re-examination of the role of dendritic and somatic currents in the generation of MEG signals as well as evoked potential. We chose the guinea pig hippocampal slice for our preparation, since its three-layer anatomy is relatively simple, its physiology is well understood and sophistical mathematical models are already available to interpret the data. Our empirical studies in the past year and half has brought our MEG technique to a level where we can reliably measure not only averaged responses, but also single-epoch MEG signals from CA1 and CA3 slices during spontaneous and evoked activities. Thus we can assess effects of various channel blockers on the slice. We will extend this effort by systematically measuring effects of pharmacological agents on the MEG signals and thereby inferring, with the aid of mathematical models, the relative magnitudes and time course of the MEG signals due to the population currents produced by opening of various ligand-gated channels and ion channels.The mathematical model of R. D. Traub incorporates six active conductances (gNa, gCa, gK(DR), gA, gK(C), and gK(AHP)) and two ligand-gated channels (NMDA- and AMPA-channels) within each model pyramidal cell and connects such cells with excitatory synaptic connections and inhibitory interneurons. This model and its more recent versions have been successfully used to account for intracellular potentials in CA3, and a variation of the model can be applied for data from CA1.The proposed experiments will manipulate the active conductances incorporated in the model by using selective channel blockers and measure the effects of the manipulations on the magnetic evoked fields (MEFs) produced by the longitudinal CA3 and CA1 slices. These particular slices turned out to be well suited for selectively measuring the MEFs produced by the pyramidal cells represented in the model. These cells appear to be the sole contributor to the MEF in these preparations because of the simple slice geometry. The data will be compared with model predictions for the pyramidal cells to gain insight into the physiological basis of MEG signals in our preparations. Field potential, extracellular unit recordings and intracellular recordings will be combined, as in our previous studies, with MEG to gain further insight into the cellular currents generating the MEFs in the hippocampus.
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