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Functional organization of the hippocampal longitudinal axis

Subjects

Key Points

  • The currently accepted model of a dorsal–ventral (posterior–anterior) dichotomy of hippocampal function requires revision.

  • There is evidence for two types of long-axis organization: gradients and discrete transitions.

  • Anatomical studies in rodents and primates show that hippocampal extrinsic connectivity is organized as smooth topographical gradients. The relative size of spatial representation by place cells in the rat hippocampus gradually increases from dorsal to ventral.

  • By contrast, rodent gene expression studies demonstrate multiple long-axis functional domains with sharply demarcated borders: at least nine in CA3 and three in CA1 and the dentate gyrus.

  • Hippocampal intrinsic anatomical connectivity, as well as electrophysiological measures of coherence, show abrupt division from the ventral (anterior) one-third to dorsal (posterior) two-thirds of the hippocampus.

  • Hippocampal involvement in unconditioned fear responses is limited to the ventral one-third.

  • When these levels of organization are superimposed, a new model of hippocampal long-axis organization emerges: gradients with discrete domains, the latter dividing the hippocampus into (at least) three portions along the long axis.

  • This model supersedes a simple dissociation of the dorsal from the ventral hippocampus and provides a potential framework for accommodating the multiple functions ascribed to the hippocampus in rodents and primates.

Abstract

The precise functional role of the hippocampus remains a topic of much debate. The dominant view is that the dorsal (or posterior) hippocampus is implicated in memory and spatial navigation and the ventral (or anterior) hippocampus mediates anxiety-related behaviours. However, this 'dichotomy view' may need revision. Gene expression studies demonstrate multiple functional domains along the hippocampal long axis, which often exhibit sharply demarcated borders. By contrast, anatomical studies and electrophysiological recordings in rodents suggest that the long axis is organized along a gradient. Together, these observations suggest a model in which functional long-axis gradients are superimposed on discrete functional domains. This model provides a potential framework to explain and test the multiple functions ascribed to the hippocampus.

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Figure 1: Cross-species comparison of hippocampal anatomy.
Figure 2: Extrinsic connectivity gradients.
Figure 3: Discrete transitions in the molecular, anatomical and functional organization of the hippocampal long axis.
Figure 4: Schematic of superimposed patterns of long-axis organization.
Figure 5: Gradients for space in the medial temporal lobe in rodents and monkeys.
Figure 6: Forming non-sequential, higher-order connections in the human hippocampus.

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Acknowledgements

The authors thank L. Giocomo for helpful discussion. B.A.S. is supported by the Spanish Ministry of Science and Innovation (SAF2011-27766) and Marie Curie Career Integration Grant (FP7-PEOPLE-2011-CIG 304248), E.IM. and M.P.W. are supported by the Kavli Foundation and Centre of Excellence grant from the Norwegian Research Council, and E.S.L. by the Allen Institute for Brain Science.

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Supplementary information

Supplementary information S1 (box)

Long-axis neurotransmitter projection patterns in the rat (PDF 216 kb)

Supplementary information S2 (table)

Receptor distributions along the hippocampal long axis of, and example functional dichotomies associated with, different neurotransmitter systems (PDF 304 kb)

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Glossary

Hippocampus

In animal studies, the term describes dentate gyrus (DG) and CA subfields. In human functional MRI studies, the term typically includes the DG, CA subfields and subiculum (except in high-resolution functional MRI).

Episodic memory

Long-term memory for events or episodes that is accessible to conscious recollection.

Semantic memory

Long-term memory for facts that is accessible to conscious recollection.

Place cells

Pyramidal cells that fire in specific locations with spatially restricted firing patterns that are maintained on memory retention trials.

Callosal mammals

Mammals with a corpus callosum. In acallosal mammals, such as the opossum, the dorsal portion of the hippocampus extends into the frontal lobe.

Susceptibility artefact

The different magnetic susceptibility of air and tissue cause inhomogeneities in the magnetic resonance scanner's static magnetic field at the air–tissue boundaries. These inhomogeneities result in geometrical distortion and reduced sensitivity of functional images, particularly in the orbitofrontal cortex and anterior medial temporal lobe.

Hippocampal MRI unfolding

The application of cortical unfolding techniques to high-resolution magnetic resonance images of the hippocampus. Structural images are segmented and the grey matter surface is extracted and stretched until it is a two-dimensional, flat surface.

Transitive inference

If A is paired with B, and B paired with C, the transitive inference is A with C.

Theta rhythm

A prominent 4–10 Hz oscillation in the hippocampal local field potential. It is studied mostly in rodents but is also present in humans.

Phase precession

The phenomenon that when a rat first enters the field of firing of a place cell, spiking occurs at late phases but shifts to earlier theta phases as the rat moves through the place field.

Adult neurogenesis

The production of new neurons within the brain of an adult animal. Adult neurogenesis is primarily confined to the subventricular zone and the subgranular zone of the dentate gyrus.

Ischaemia

A restriction in blood supply, which leads to lack of oxygen delivery.

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Strange, B., Witter, M., Lein, E. et al. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci 15, 655–669 (2014). https://doi.org/10.1038/nrn3785

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