Scientific Understanding of Consciousness
Hippocampal CA3 network Pattern Completion
Science 09 Sep 2016: Vol. 353, Issue 6304, pp. 1117-1123
Synaptic mechanisms of pattern completion in the hippocampal CA3 network
Segundo Jose Guzman, et.al.
IST Austria (Institute of Science and Technology Austria), Am Campus 1, A-3400 Klosterneuburg, Austria.
Center for Molecular Neurobiology Hamburg, Falkenried 94, D-20251 Hamburg, Germany.
The hippocampal CA3 region plays a key role in learning and memory. Recurrent CA3–CA3 synapses are thought to be the subcellular substrate of pattern completion. However, the synaptic mechanisms of this network computation remain enigmatic. To investigate these mechanisms, we combined functional connectivity analysis with network modeling. Simultaneous recording from up to eight CA3 pyramidal neurons revealed that connectivity was sparse, spatially uniform, and highly enriched in disynaptic motifs (reciprocal, convergence, divergence, and chain motifs). Unitary connections were composed of one or two synaptic contacts, suggesting efficient use of postsynaptic space. Real-size modeling indicated that CA3 networks with sparse connectivity, disynaptic motifs, and single-contact connections robustly generated pattern completion. Thus, macro- and microconnectivity contribute to efficient memory storage and retrieval in hippocampal networks.
The hippocampal CA3 region plays a key role in learning and memory. A hallmark property of the network is its ability to retrieve patterns from partial or noisy cues, a process referred to as autoassociative recall, attractor dynamics, or pattern completion. However, the synaptic mechanisms underlying pattern completion have remained enigmatic. Previous neuronal network models suggested that recurrent CA3–CA3 pyramidal cell synapses play a key role in this process. In the storage phase, a stimulus pattern will activate an ensemble of interconnected neurons and induce synaptic potentiation in the corresponding recurrent synapses. In the recall phase, a partial pattern will initially activate only a fraction of the ensemble, but subsequently recruit the remaining cells via potentiated synapses. Successful pattern completion requires sufficient synaptic efficacy and network connectivity. Whether the biological properties of the CA3 network are consistent with these assumptions remains unclear.
Our results suggested that connectivity in the CA3 cell network was sparse, with a mean connection probability of 0.92%. Both experimental data and simulations using fully reconstructed CA3 neurons labeled in vivo indicated that connectivity was only moderately dependent on slice orientation. However, connectivity may decline with distance. Furthermore, connectivity might be nonrandom, with ensembles of highly connected cells embedded in a sparsely connected population. To test these hypotheses, we first examined whether the connection probability was dependent on intersomatic distance. The average connection probability did not significantly change with distance, for intersomatic distances of up to 400 μm. Furthermore, both EPSP and EPSC peak amplitudes were not significantly dependent on distance.
Previous theories of the hippocampal formation often depicted the CA3 region as a network of highly interconnected cells, in which connectivity is all-to-all, random, or distance dependent. Our experimental results challenge this view in multiple ways.
First, the macroconnectivity in the CA3 cell network is sparse, spatially uniform, and highly enriched in disynaptic connectivity motifs. This is different from the neocortex, where connection probability is higher (~10%), more distance dependent, and less enriched in disynaptic motifs.
Second, the microconnectivity in individual CA3–CA3 connections is characterized by a small number of synaptic contacts and functional release sites per connection. Again, this is different from the neocortex, where unitary synaptic interactions involve a large number of contacts (up to eight in layer 5–layer 5 pyramidal neuron pairs).
Finally, despite the small number of synaptic contacts, the efficacy of unitary connections is high. Therefore, coincident firing of a small number of presynaptic cells is sufficient to initiate action potentials in a postsynaptic cell. Thus, the properties of recurrent CA3–CA3 synapses allow efficient encoding of information by small neuronal ensembles.
Our results give important insights into the synaptic mechanisms of pattern completion. First, they provide a proof of principle that real-size networks with a realistic connection probability of 1% can perform pattern completion. Second, they demonstrate that connectivity motifs increase the efficacy and robustness of recall under conditions of sparse connectivity and sparse activity. Intuitively, incorporation of motifs will increase the variance in the number of inputs and outputs of each cell, which will facilitate the spread of activity in the network and thereby enhance the robustness of recall. Finally, they suggest that the design of CA3–CA3 synapses with few synaptic contacts per connection is favorable, because it enables maximally efficient use of postsynaptic space. Thus, both macro- and microconnectivity facilitate pattern completion in the CA3 cell network. Similar conclusions were independently reached in a theoretical study, which deduced sparse connectivity and high motif abundance from the assumption of maximal storage capacity.
The mechanisms generating the motif structure are currently unknown. Anisotropy of axonal connections may contribute, but it is unlikely to be the only factor. One possibility is that connectivity motifs are formed during development, connecting clonally related groups of sister cells. Alternatively, the motifs may arise from structural plasticity in synchronously active neuronal ensembles. Because mossy fiber synapses may “detonate” postsynaptic CA3 pyramidal neurons, CA3 neurons innervated by the same mossy fiber axon might become preferentially connected through activity-dependent synaptic plasticity. This would provide a structured connection between pattern separation circuits of the dentate gyrus and pattern completion networks of the CA3 region. Similarly, CA3 neurons targeted by the same entorhinal inputs could become connected. Finally, the CA3 connectome may be altered during chronic inactivity or brain diseases. How this would affect pattern completion in the network remains to be determined.
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