Nonlinear systems analysis of network properties of the in vivo perforant path-dentate gyrus

NONLINEAR SYSTEMS ANALYSIS OF NETWORK PROPERTIES OF THE IN VIVQ PERFORANT PATH-DENTATE GYRUS. T,W. Berber. R.L, Port. J.R. Balzer. and R.J. Sclabassi. Departments of Behavioral Neuroscience, Psychiatry, and Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15260. Nonlinear systems analytic procedures have been utilized to achieve an experimental characterization of network dynamics of the rabbit hippocampal formation, expressed as input/output properties using a functional power series expansion. The hippocampal formation consists of the entorhinal cortex, dentate gyrus, CA3 and CAI pyramidal cell regions of the hippocampus, and the subicular cortex. All five cortical groups are interconnected through a variety of feedforward and feedback pathways. To measure the functional interaction among the components of this complex network, random impulse train stimulation was used as an input stimulus to activate one of the pathways connecting any two regions. In the experiments to be reported, random impulse train stimulation (4064 impulses having a Poisson distribution of inter-impulse intervals, mean of 500 ms) was applied to the perforant path, which contains efferents of the entorhinal cortex projecting to the dentate gyrus. The activity of dentate granule cells, which provide output from the dentate to the CA3 region of the hippocampus, was measured as the amplitude of evoked population spikes. Cross-correlation techniques were used to determine the relation between inter-impulse intervals of the input stimulus and population spike amplitude, expressed as the first, second, and third order kernels of a functional power series expansion. This approach achieves a quantitative characterization of the input/output properties of the dentate gyrus, as the dentate interacts with the network of cortical fields comprising the remaining hippocampal formation. First order kernels, which reflect the average population spike amplitude to all impulses in the random stimulus train, exhibited peak magnitudes averaging 2.2 mV. The majority of activity was contained in the first 10 ms of first order kernels, which is consistent with the monosynaptic nature of perforant path input to granule neurons. Second order kernels, which reflect the modulation of granule cell output as a function of the interval since a previous impulse, revealed significant nonlinearities. Inter-impulse intervals in the range of 10-50 ms resulted in suppression of population spike amplitude that could reach 80-90% of the first order kernel peak; intervals of 90-100 ms produced facilitation equivalent to 75-100% of the first order kernel peak, with lower magnitude facilitation extending to intervals of 400 ms, and in some preparations 1000 ms. Third order kernels reflect the modulation of granule cell output not predicted by the first and second order kernels, as a function of the intervals since two previous impulses. Third order nonlinearities consisted of suppression of spike amplitude (as great as 70-80% of the first order kernel peak) when both of the preceding intervals were less than 200 ms, and smaller magnitude facilitation (10-15%) when intervals of 275-350 ms were followed by intervals of 175-300 ms, and also when intervals of 450-550 ms were followed by intervals of 35-150 ms. These results characterize input/output properties of dentate granule cells, as those properties are determined by their intrinsic membrane characteristics, interneurons local to the dentate gyrus, and feedback to the dentate from other cortical fields of the hippocampal formation. The contribution of each of the remaining cortical fields can be determined by using lesions or transsections of connectivity between the dentate and other components of the network, and by applying the same experimental and computational procedures to characterize input/output properties of the dentate in such open-loop conditions. Likewise, pharmacological blockade can be used to determine the contribution of known interneuron populations. Here we report the effects of unilateral hippocampectomy performed to eliminate the contribution of commissural projections, and picrotoxin blockade of the effect of GABAergic interneurons of the dentate. Second order kernel analysis after unilateral hippocampectomy resulted in a slight increase in the suppression of granule cell population spike amplitude induced by inter-impulse intervals of 10-50 ms, and a robust increase in facilitation induced by intervals of 100-300 ms. Third order nonlinearities generally were suppressed by the loss of commissural input. Second order kernel analysis of the effects of picrotoxin showed a reduction of the suppression of population spike amplitude in response to intervals of 10-50 ms, which is consistent with an hypothesized blockade of recurrently activated GABAergic basket cells of the dentate. These results demonstrate that functional network properties of the hippocampal formation resulting from the complex interaction of its intrinsic neurons can be quantitatively characterized as input/output functions using a nonlinear systems analytic approach. Furthermore, application of this methodology to reduced preparations allows a biologically meaningful interpretation of the obtained input/output characterizations. Through extension of the same experimental and theoretical approach to other cortical fields, network properties of the entire hippocampal formation will be revealed. Supported by The Whitaker Foundation, the Office of Naval Research, and NIMH.

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