The medial temporal lobe contains a set of structures that are essential to the acquisition and organization of new memories as well as the reception of highly processed sensory information (Balakrishnan, Bousquet & Honavar, 1999; Squire, Stark & Clark, 2004). The medial temporal lobe consists of the hippocampal region (described below), amygdala, and adjacent perirhinal, entorhinal, and postrhinal (parahippocampal in primates) cortices (Brown & Aggleton, 2001; Lee, Buckley et al., 2005; Eichenbaum, 2000; Squire et al., 2004; Witter, Wouterlood, Naber, & Van Haeften, 2000). It is simplest to consider the hippocampal formation as a series of adjacent cortical fields extending from the entorhinal cortex to the subiculum. Based on their anatomical connections, these cortical fields have four major corresponding subregions: (1) the entorhinal area, (2) the subicular complex (prosubiculum, subiculum, presubiculum, and parasubiculum), (3) the cornu ammonis region (CA; Ammon’s Horn; which can be divided into four distinct regions of cells: CA1, CA2, CA3 and CA4/hilus), and (4) the dentate gyrus (Amaral & Witter, 1995; Hayman, Fuller, Pfleger, Meyers & Jackson, 1998; Meibach & Siegal, 1977; Swanson, 1977; Swanson & Cohen, 1975, 1976, 1977; Witter, Wouterlood, Naber, & Van Haeften, 2000; Witter, 1993). Understanding the intrinsic circuitry of the hippocampal formation is of critical importance when attempting to understand its functional connectivity to the rest of the MTL as well as its specific role in specialized memory processes.
In the rat, the cytoarchitecture of the hippocampus is quite well known. There are two major efferent pathways that are responsible for hippocampo-cortical communication: (1) the septo-hippocampal circuits through the fimbria-fornix, and (2) the hippocampal circuits that project from CA1 to the subiculum. Additionally, the mamillary body has been shown to receive topographically organized input from the septum and the subicular complex (for detailed review see Swanson & Cowan, 1975, 1976, 1977). The hippocampus is heavily connected to the septum by the fibers of the fimbria-fornix system. However, the organization of the two regions are quite different: the septal region is comprised of clusters of subcortical nuclei that receive no direct neocortical inputs in the rat, whereas the hippocampal formation is comprised of layered laminae that receive cortical inputs through the entorhinal areas (see Witter, 1993). There is a very specific topographic organization of the connections between hippocampus and the septum (Swanson & Cowan, 1977). These efferent fibers from the hippocampus to the septum originate from septotemporal areas of CA3/1 and the adjacent subiculum. As noted by Swanson (1977), these fibers project rostrally in a topographically organized manner such that medially located neurons in the hippocampus project through more lateral parts of the fimbria. Additionally, this arrangement has been shown to be present in the suptum, where fibers from septal CA3/1 and the subiculum innervate the dorsal region of the lateral septal nucleus (lSn; Swanson, 1977). The lSn receives a large topographically organized input from Ammon’s horn and the subiculum, the lSn then projects to the adjacent medial septal-diagonal band complex (Swanson & Cowan, 1976). As noted by Swanson (1977), this is critical as the medial septal-diagonal band projects back to the HPC via the fornix. As summarized by Swanson (1977), in the rat, the subiculum and CA1/3 fields project topographically and bilaterally to the septal region. The septal region then projects back to the entire hippocampal formation. This septo-hippocampal connectivity could provide support to numerous studies that have found rodents with lesions to the fimbria- fornix experience deficits equivalent to rats with full hippocampal lesions (see Whishaw, Cassel & Jarrard, 1995).
The second major hippocampo-cortical circuit projects through the entorhinal cortex (EC). The rodent EC, which is located at the caudal end of the temporal lobe, receives input from a number of cortical regions and all sensory modalities and can be thought of as the facilitator for reciprocal interactions between the hippocampus and neocortex (Paxinos, 2004; Witter, 1993). As noted by Swanson (1977), the cortical inputs do not directly innervate the HPC; rather the EC receives information from primary visual, auditory, and somatosensory cortices. Much like the hippocampal formation, the cellular matrix in the EC is distributed in laminae that spread dorsolaterally (Rakic & Sidman, 1970). Within this distribution of laminae there is a differentiation between superficial layers (I, II, and III) and deep layers ([IV], V, and VI). In the rat, the primary cortical inputs to the superficial layers of the EC originate from the olfactory domain of the telencephalon, perirhinal cortex, parahippocampal cortices, and the subiculum. As elaborated by Witter (1993), superficial layers II and III of the EC give rise to the major components of the perforant path projections into the hippocampal formation. Specifically, bidirectional projections from the pyramidal and stellate cells of layer II of the EC project to the subiculum and separate projections terminate in the dentate gyrus with concurrent innervations in the CA3/2 regions of the hippocampus. Additionally, pyramidal cells from layer III of the EC send projections along the same pathway (the perforant path) that pass through CA3 and terminally innervate both the CA1 region and the subiculum (Swanson, 1977; Witter, 1993). The granule cells of the dentate gyrus, receiving no cortical inputs, are the primary targets of the efferent projections from the EC (via the perforant pathway). There is also some evidence that the EC projects back to many of the cortical association areas from which it receives input and potentially mediates consolidation in those areas (Rolls, 1996). Within the hippocampus, the granule cells of the dentate gyrus project to the pyramidal cells of the CA3 region via mossy fiber connections. CA3 pyramidal cells, in turn, innervate CA1 neurons via the Schaffer collaterals. CA1 sends primary efferent connections to layer IV of the EC, with feed forward output through the alveus to the subiculum (Churchland & Sejnowski, 1992; Swanson, 1977). This circuit from CA1 to the subiculum forms the primary output of the hippocampal system. Both the DG and CA3 regions are somewhat unique, in that they each contain internal recurrent collateral connections that serve to interconnect neurons within each respective region. These recurrent connections are comprised of interneurons that provide reciprocal feedback loops that are internally contained and specific to the principle cells within each distinct network (Amaral & Witter, 1995; Gilbert & Brushfield, 2009; Kesner, 2007; Kesner, Lee & Gilbert, 2004). Specifically, the hilar region of the DG (i.e., hilus/CA4 region) contains a layer of excitatory interneurons that interconnect the granule cells and a layer of inhibitory interneurons, providing continuous recurrent inhibition (see Myers & Scharfman, 2009). The CA3 region contains extensive interconnections among the principle cells through a system of recurrent collateral fibers (Amaral & Witter, 1995). Additionally, the CA1 region of the HPC also contains pyramidal cells and interneurons; however, unlike DG and CA3 cells, CA1 cells do not contain recurrent connections (see Churchland & Sejnowski, 1992; Balakrishnan et al., 1999; Witter & Wouterlood, 2002).