Abstract
To better understand encoding and decoding of stimulus information in two specific hippocampal sub-regions, we isolated and co-cultured rat primary dentate gyrus (DG) and CA3 neurons within a two-chamber device with axonal connectivity via micro-tunnels. We tested the hypothesis that, in these engineered networks, decoding performance of stimulus site information would be more accurate when stimuli and information flow occur in anatomically correct feed-forward DG to CA3 vs. CA3 back to DG. In particular, we characterized the neural code of these sub-regions by measuring sparseness and uniqueness of the responses evoked by specific paired-pulse stimuli. We used the evoked responses in CA3 to decode the stimulation sites in DG (and vice-versa) by means of learning algorithms for classification (support vector machine, SVM). The device was placed over an 8 × 8 grid of extracellular electrodes (micro-electrode array, MEA) in order to provide a platform for monitoring development, self-organization, and improved access to stimulation and recording at multiple sites. The micro-tunnels were designed with dimensions 3 × 10 × 400 μm allowing axonal growth but not migration of cell bodies and long enough to exclude traversal by dendrites. Paired-pulse stimulation (inter-pulse interval 50 ms) was applied at 22 different sites and repeated 25 times in each chamber for each sub-region to evoke time-locked activity. DG-DG and CA3-CA3 networks were used as controls. Stimulation in DG drove signals through the axons in the tunnels to activate a relatively small set of specific electrodes in CA3 (sparse code). CA3-CA3 and DG-DG controls were less sparse in coding than CA3 in DG-CA3 networks. Using all target electrodes with the three highest spike rates (14%), the evoked responses in CA3 specified each stimulation site in DG with optimum uniqueness of 64%. Finally, by SVM learning, these evoked responses in CA3 correctly decoded the stimulation sites in DG for 43% of the trials, significantly higher than the reverse, i.e., how well-recording in DG could predict the stimulation site in CA3. In conclusion, our co-cultured model for the in vivo DG-CA3 hippocampal network showed sparse and specific responses in CA3, selectively evoked by each stimulation site in DG.
Highlights
Understanding neural coding in the brain has proceeded with difficulty due to limitations on accessibility as well as conceptual precepts
dentate gyrus (DG)-DG and CA3-CA3 networks were used as controls
What is the CA3 neural code for each stimulation site in the DG region? Is the neural code in our CA3 co-cultures “sparse”? How do the target (CA3) neurons decode the sources? In order to answer these questions we studied the information transmission between the DG and CA3 regions by means of a two-chamber device with axonal connectivity via micro-tunnels
Summary
Understanding neural coding in the brain has proceeded with difficulty due to limitations on accessibility as well as conceptual precepts. Identification of the layered structures in the hippocampal formation as the seat of cognitive learning and memory led Marr (1971) to propose constraints on computational models of hippocampal function in memory storage, introducing the efficiency of vast arrays of permuted sparse representations. Access to these arrays of sparse activity has remained limited both in vivo and even in hippocampal slices due extremes of downstream unresponsiveness to single neuron activation and widespread responses to stimulation of bundles of axon fiber tracts. We improve access to activity of single neurons and their axons in small cultured networks of DG connected to CA3 subregions in 2D over an electrode array
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