The Flow of Axonal Information Among Hippocampal Subregions: 1. Feed-Forward and Feedback Network Spatial Dynamics Underpinning Emergent Information Processing

Abstract

The tri-synaptic pathway in the mammalian hippocampus enables cognitive learning and memory. Despite decades of reports on anatomy and physiology, the functional architecture of the hippocampal network remains poorly understood in terms of the dynamics of axonal information transfer between subregions. Information inputs largely flow from the entorhinal cortex (EC) to the dentate gyrus (DG), and then are processed further in the CA3 and CA1 before returning to the EC. Here, we reconstructed elements of the rat hippocampus in a novel device over an electrode array that allowed for monitoring the directionality of individual axons between the subregions. The direction of spike propagation was determined by the transmission delay of the axons recorded between two electrodes in microfluidic tunnels. The majority of axons from the EC to the DG operated in the feed-forward direction, with other regions developing unexpectedly large proportions of feedback axons to balance excitation. Spike timing in axons between each region followed single exponential log-log distributions over two orders of magnitude from 0.01 to 1 s, indicating that conventional descriptors of mean firing rates are misleading assumptions. Most of the spiking occurred in bursts that required two exponentials to fit the distribution of inter-burst intervals. This suggested the presence of up-states and down-states in every region, with the least up-states in the DG to CA3 feed-forward axons and the CA3 subregion. The peaks of the log-normal distributions of intra-burst spike rates were similar in axons between regions with modes around 95 Hz distributed over an order of magnitude. Burst durations were also log-normally distributed around a peak of 88 ms over two orders of magnitude. Despite the diversity of these spike distributions, spike rates from individual axons were often linearly correlated to subregions. These linear relationships enabled the generation of structural connectivity graphs, not possible previously without the directional flow of axonal information. The rich axonal spike dynamics between subregions of the hippocampus reveal both constraints and broad emergent dynamics of hippocampal architecture. Knowledge of this network architecture may enable more efficient computational artificial intelligence (AI) networks, neuromorphic hardware, and stimulation and decoding from cognitive implants.

Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus

“…Since axons are more excitable than dendrites or the cell body 22 , 54 , DBS-evoked subthreshold depolarization at the axon is expected to arrive at the soma on a sub-millisecond timescale due to the short chronaxie 15 , 54 , 55 . Furthermore, the observation that spikes did not occur until ~7–8 ms after the onset of individual electrical pulses of 40 Hz DBS further argues against direct antidromic activation of the stimulated neuron, since antidromic spiking typically has a latency shorter than a couple of milliseconds given the axon conduction velocity 56 , 57 . Finally, individual pulses delivered at 140 Hz failed to evoke prominent changes in Vm or spike rate, consistent with the delayed response to DBS.…”

Structure-function dynamics of engineered, modular neuronal networks with controllable afferent-efferent connectivity

“…Since the pioneering work by Taylor et al in 2003, advancements in microfluidic technologies have been widely adopted by the neuroscience community for preclinical research [1]. The ability to segregate and integrate neuronal populations across compartmentalized microfluidic chips has facilitated the construction of robust, physiologically relevant model systems for studying neuronal networks in vitro with unparalleled experimental control [2][3][4][5]. However, these platforms do not inherently aid the establishment of feedforward projection sequences.…”

Hippocampal responses to electrical stimulation of the major input pathways are modulated by dentate spikes

“…Consistent with this we found that most of the DSs were simultaneous in the anterior and posterior dorsal hippocampus. This finding is explained by the fact that the perforant path spreads feed‐forward projections to all parts of the DG (Amaral & Witter, 1989 ; Vakilna et al, 2021 ). Surprisingly, contrary to previous reports (Bragin et al, 1995 ), we found that only a fraction of DSs were bilaterally synchronous.…”