Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Hippocampal Learning and CA3 Output



Science 29 February 2008:   Vol. 319 no. 5867 pp. 1260-1264

Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning

Toshiaki Nakashiba, Jennie Z. Young, Thomas J. McHugh, Derek L. Buhl and Susumu Tonegawa

The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, RIKEN-MIT Neuroscience Research Center, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.


The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex → dentate gyrus → CA3 → CA1 → entorhinal cortex) and the monosynaptic pathway (entorhinal cortex → CA1 → entorhinal cortex). We developed a generally applicable tetanus toxin–based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion–based memory recall, and for spatial tuning of CA1 cells.

The medial temporal lobes of the brain, including the hippocampus, are crucial for learning and memory of events and space across species. The hippocampus receives input from virtually all associative areas of the neocortex via the entorhinal cortex (EC). In the main excitatory hippocampal network, information flows from the superficial layer (layer II) of the EC to the dentate gyrus (DG) to CA3 to CA1 and finally to the deep layers of EC directly or indirectly through the subiculum. This loop is referred to as the trisynaptic pathway (TSP). The hippocampus also contains a parallel excitatory monosynaptic pathway (MSP) [EC (layer III) → CA1 → EC (layer V)] as well as other excitatory and inhibitory circuits.

The prevailing view of the contribution of these circuits to hippocampal function is that synaptic transmission and plasticity in the feed-forward pathway from EC → DG → CA3, a part of the TSP, are primarily responsible for pattern separation, whereas those in a recurrent network  within CA3 are crucial for the rapid association of diverse sets of information and pattern completion. Furthermore, CA1 may be instrumental in recognizing the novelty of an event or context.

Some of these ideas have been tested by lesioning portions of the hippocampus or EC, although it is difficult to restrict damage to specific subregions and cell types in a quantitative and reproducible manner. These difficulties have in part been addressed by deleting the N-methyl-d-aspartate (NMDA) receptor gene NR1 in specific hippocampal subregions with Cre-loxP recombination technology. These studies found that NMDA receptor–dependent synaptic plasticity in postnatal excitatory neurons of each of several hippocampal subregions is required for specific aspects of hippocampal learning and memory. In order to completely analyze hippocampal function, we developed a method to block neural transmission rather than synaptic plasticity and used it to assess the differential role of CA3 and EC outputs into area CA1 in hippocampus-dependent learning and memory.

Our data show that CA3 output in the TSP is dispensable for both acquisition and recall of incremental spatial learning and memory recall.

Our data also show that CA3 output is crucial for rapid one-trial learning in a novel context.

Application of the DICE-K method to CA3 pyramidal cells demonstrates that the MSP (which bypasses CA3) can support slow incremental learning in familiar environments but that the CA3 output of the TSP is needed for rapid acquisition of memories in novel environments and for pattern completion–based recall.

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