Hippocampal subfields

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The hippocampus is composed of multiple subfields. Though terminology varies among authors, the terms most frequently used are dentate gyrus and the cornu ammonis (literally "Amun's horns", abbreviated CA). The dentate gyrus contains the fascia dentata and the hilus, while CA is differentiated into fields CA1, CA2, and CA3.

Cut in cross section, the hippocampus is a C-shaped structure that resembles a ram's horns. The name cornu ammonis refers to the Egyptian deity Amun, who has the head of a ram. The horned appearance of the hippocampus is caused by cell density differentials and the existence of varying degrees of neuronal fibers.

In rodents, the hippocampus is positioned so that, roughly, one end is near the top of the head (the dorsal or septal end) and one end near the bottom of the head (the ventral or temporal end). As shown in the figure, the structure itself is curved and subfields or regions are defined along the curve, from CA4 through CA1 (only CA3 and CA1 are labeled). The CA regions are also structured depthwise in clearly defined strata (or layers):

• The alveus is the most superficial layer and contains the axons from pyramidal neurons, passing on toward the fimbria/fornix, one of the major outputs of the hippocampus.

• Stratum oriens (str. oriens) is the next layer below the alveus. The cell bodies of inhibitory basket cells and horizontal trilaminar cells are located in this stratum. The basal dendrites of pyramidal neurons are also found here, where they receive input from other pyramidal cells (recurrent connections, especially in CA3 and CA2), septal fibers and commissural fibers from the contralateral hippocampus. In rodents the two hippocampi are highly connected, but in primates this commissural connection is much sparser.

• Stratum pyramidale (str. pyr.) contains the cell bodies of the pyramidal neurons which are the principal excitatory neurons of the hippocampus. This stratum tends to be one of the more visible strata to the naked eye. In region CA3, this stratum contains synapses from the mossy fibers which course through stratum lucidum. This stratum also contains the cell bodies of many interneurons, including axo-axonic cells, bistratified cells, and radial trilaminar cells.

• Stratum lucidum (str. luc.) is one of the thinnest strata in the hippocampus. Mossy fibers from the dentate gyrus granule cells course through this stratum in CA3, though synapses from these fibers can be found in str. pyr.

• Stratum radiatum (str. rad.), like str. oriens, contains septal and commissural fibers. It also contains Schaffer collateral fibers which are the projection forward from CA3 to CA1. Some interneurons that can be found in more superficial layers can also be found here, including basket cells, bistratified cells, and radial trilaminar cells.

• Stratum lacunosum (str. lac.) is a thin stratum that too contains Schaffer collateral fibers, but it also contains perforant path fibers from the superficial layers of entorhinal cortex. Due to its small size, it is often grouped together with stratum moleculare into a single stratum called stratum lacunosum-moleculare (str. l-m.).

• Stratum moleculare (str. mol.) is the deepest stratum in the hippocampus. Here the perforant path fibers form synapses onto the distal, apical dendrites of pyramidal cells.

• The hippocampal sulcus (sulc.) or fissure is a cell-free region that separates the CA1 field from the dentate gyrus. Because the phase of recorded theta rhythm varies systematically through the strata, the fissure is often used as a fixed reference point for recording EEG as it is easily identifiable.

The dentate gyrus is composed of a similar series of strata:

• The polymorphic layer (poly. lay.) is the most superficial layer of the dentate gyrus and is often considered a separate subfield (see CA4/hilus below). This layer contains many interneurons and the axons of the dentate granule cells pass through this stratum on the way to CA3.

• Stratum granulosum (str. gr.) contains the cell bodies of the dentate granule cells.

• Stratum moleculare, inner third (str. mol. 1/3) is where both commissural fibers from the contralateral dentate gyrus run and form synapses as well as where inputs from the medial septum terminate, both on the proximal dendrites of the granule cells.

• Stratum moleculare, external two thirds (str. mol. 2/3) is the deepest of the strata, sitting just superficial to the hippocampal fissure across from stratum moleculare in the CA fields. The perforant path fibers run through this strata, making excitatory synapses onto the distal apical dendrites of granule cells.

Subfields

• The fascia dentata is the earliest stage of the hippocampal circuit. Its primary input is the perforant path from the superficial layers of entorhinal cortex. Its principal neurons are tiny granule cells which give rise to unmyelinated axons called the mossy fibers which project to the hilus and CA3. The fascia dentata of the rat contains approximately 1,000,000 granule cells. It receives feedback connections from mossy cells in the hilus at distant levels in the septal and temporal directions. The fascia dentata and the hilus together make up the dentate gyrus. As with all regions of the hippocampus, the dentate gyrus also receives GABAergic and cholinergic input from the medial septum and the diagonal band of Broca.

• Region CA4 (often called the hilus or hilar region when considered part of the dentate gyrus, as neurons here do not have pyramidal morphology like those of areas CA1 & CA3 (suggested by Lorente de No & verified by David G. Amaral)) contains mossy cells that primarily receive inputs from granule cells located nearby in the dentate gyrus in the form of mossy fibers. They also receive a small number of connections from pyramidal cells located in CA3. They, in turn, project back into the dentate gyrus at distant septotemporal levels.

• Region CA3 receives input along the mossy fibers from granule cells in the dentate gyrus (DG) and from projection cells in entorhinal cortex along the perforant path. The mossy fiber pathway terminates in stratum lucidum while the perforant path passes through stratum lacunosum and terminates in stratum moleculare. The inputs from the medial septum and diagonal band of Broca terminate in stratum radiatum, along with commisural connections from the contralateral hippocampus. The pyramidal cells in CA3 (of which there are approximately 200,000 in each hemisphere in the rat) send some axons back to the hilus, but the majority project to regions CA2 and CA1 (a pathway called the Schaffer collaterals), in addition to a significant number of connections that terminate within CA3 (called recurrent connections). Both the recurrent connections and the Schaffer collaterals terminate preferentially in the septal or dorsal direction from the originating cells. CA3 also sends a small set of output fibers to the lateral septum.

• Region CA2 is a small region located between CA3 and CA1. Anatomically, in the rat, it is best defined as the strip of cells that receive perforant path input from EC layer II but do not receive mossy fiber connections from DG. Its pyramidal cells are more similar to those in CA3 than those in CA1, so it is grouped as a separate region. Due to its small size, it is often ignored in discussions of the hippocampus, but its high resistance to epileptic damage makes it notable.

• Region CA1 is the first region in the hippocampal circuit that yields a significant output pathway, which goes to entorhinal cortex layer V. It also sends significant output forward to the subiculum. Like CA3, it receives input from superficial entorhinal cortex along the perforant pathway (note that some authors only consider the input to DG and CA3 to be the perforant pathway, referring to the input to CA1 as the temporoammonic pathway). Unlike CA3, however, it contains very few recurrent connections. In the rat, CA1 contains approximately 250,000 pyramidal cells.

• The subiculum is the end point of the hippocampal circuit. Its primary inputs are axons from region CA1 and from layer III of entorhinal cortex. As with CA1, it sends output to layer V of entorhinal cortex (primarily to medial entorhial cortex), but it also projects to many other areas, including the nucleus accumbens, the anterior thalamic nuclei, the medial mammillary nucleus, the lateral septum, and the presubiculum.

References

• Amaral, DG. A Golgi study of cell types in the hilar region of the hippocampus in the rat. J Comp Neurol. 1978 Dec 15;182(4 Pt 2):851-914
• Duvernoy H. The human hippocampus, 3rd ed. Berlin: Springer-Verlag. 2005.
• Lorente De Nó, Rafael. Studies on the structure of the cerebral cortex. Continuation of the study of the ammonic system. J Psychol Neurol. 1934; 46:113–177.
• Shepherd, GM. The Synaptic Organization of the Brain. New York: Oxford University Press. 1998.