Hippocampal anatomy, Altered

The hippocampus is a major brain region located in the medial temporal lobe in humans and other mammals (West, 1990). Developmentally it is derived from neuronal and glial cells in the neural tube and differentiates in the proencephalon and telencephalon.  The hippocampus is a cortical structure, but only contains 3-layers, distinct from the 6-layered neocortical structures. For this reason, it is known as archicortex or paleocortex meaning old cortex. Within humans, the structure is identified as early as fetal week 13 and matures rapidly until 2 to 3 years of age (Kier et al 1997), with continuing slow growth thereafter until adult ages (Utsunomiya et al., 1999).  In rodents, the hippocampus begins to form in midgestation, with the CA fields forming in advance of the dentate gyrus. Dentate gyrus forms in late gestation with most of its development occurring in the first 2-3 postnatal weeks (Altman and Bayer, 1990a; 1990b).

The structure of the hippocampus has been divided into regions that include CA1 through CA4 and the dentate gyrus. The principal cell bodies of the CA field are pyramidal neurons, those of the dentate gyrus are granule cells. The dentate gyrus forms later in development than the CA fields of the hippocampus. These regions are generally found in all mammalian hippocampi.

The major input pathway to the hippocampus is from the layer 2 neurons of the entorhinal cortex to the dentate gyrus via the perforant path forming the first connection of the trisynaptic loop of the hippocampal circuit. Direct afferents from the dentate gyrus (mossy fibers) then synapse on CA3 pyramidal cells which in turn send their axons (Schaeffer Collaterals) to CA1 neurons to complete the trisynaptic circuit (Figure 1). From the CA fields information then passes through the subiculum entering the fiber pathways of the alveus, fimbria, and fornix and it routed to other areas of the brain (Amaral and Lavenex, 2006). Through the interconnectivity within the hippocampus and its connections to amygdala, septum and cortex, the hippocampus plays a pivotal role in several learning and memory processes, including spatial behaviors. The primary input pathway to the CA regions of the hippocampus is from the septum by way of the fornix and direct input from the amygdala. Reciprocal outputs from the hippocampus back to these regions and beyond also exist.

Trisynaptic Hippocampal Circuitry

Data in support of this key event have been collected using a wide variety of standard biochemical, histological and anatomical methods (e.g., morphometrics, immunohistochemical staining, in situ hybridization and imaging procedures). Many of methods applied to reveal anatomical abnormalities are routine neurohistopathology procedures similar to those recommended in EPA and OECD developmental neurotoxicity guidelines (US EPA, 1998; OCED, 2007). Subtle cytoarchitectural features depend on more specialized birth dating procedures and staining techniques. It is essential to consider the timing of events during development for detection to occur, as well as the timing for detection (Hevner, 2007; Garman et al., 2001; Zgraggen et al., 2012). Similar techniques used in rodent stydies have been applied to postmortem tissue in humans. 

In humans, structural neuroimaging techniques are used to assess hippocampal volume with an analysis technique known as voxel-based morphometry (VBM). Volume of brain regions is measured by drawing regions of interest (ROIs) on images from brain scans obtained from magnetic resonance imaging (MRI) or positron emission tomography (PET) scans and calculating the volume enclosed. (Mechelli et al., 2005). Similar imaging techniques can be applied in rodent models (Powell et al., 2009; Hasegawa et al., 2010; Pirko et al., 2005; Pirko and Johnson, 2008).

The hippocampus is generally similar in structure function across most mammalian species (West, 1990). The vast majority of information on the structure of the hippocampus is from mice, rats and primates including humans.

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