Social Memory and the Role of the Hippocampal CA2 Region

Abstract

The CA2 region of the hippocampus is a somewhat obscure area lacking in an understanding of its form and function. Until recently, the CA2 has been thought of as merely an extension of the CA3, with some referring to it as the CA3a region. Recent investigations into this area have not only delineated the CA2, but also defined it as a region distinct from both CA1 and CA3, with a unique set of cortical inputs and outputs and contributions to cognitive processes. One such process that has been shown to depend on the CA2 is the ability to recognize a novel or familiar conspecific, known as social recognition memory. Here, we review these findings and discuss the parallels between CA2 dysfunction and social impairments.

Keywords: CA2; hippocampus; social memory; social neuroscience; social recognition.

FIGURE 1

Overview of the rat hippocampus. (A) Drawing of the rat brain showing the three-dimensional organization of the hippocampus and locations of the dorsal and ventral hippocampus. (B) Coronal planes showing approximate locations of the images in (C). (C) Golgi images illustrating the dorsal and ventral aspects of the hippocampus. The dorsal hippocampus is generally thought to mediate cognitive processes such as declarative memory formation and spatial learning and memory functions. Functional mapping studies have suggested that activity in the dorsal hippocampus relates to cortical regions that are involved in higher order information processing. The ventral hippocampus appears to be more involved with functions related to stress, emotion and affect. Neural activity in the ventral hippocampus corresponds to regions involved in emotion and stress (e.g., amygdala and hypothalamus). (A,B) Adapted from Cheung TH, Cardinal RN. Hippocampal lesions facilitate instrumental learning with delayed reinforcement but induce impulsive choice in rats. BMC Neurosci. 2005 May 13;6:36. 10.1186/1471-2202-6-36.; PMCID: PMC1156904. https://openi.nlm.nih.gov/detailedresult?img=PMC1156904_1471-2202-6-36-3&req=4. License information found here https://creativecommons.org/licenses/by/2.0/.

FIGURE 2

Coronal cross section of the dorsal hippocampus showing the primary subdivisions. The granule cells (stained with DAPI) make up the major cell type in the dentate gyrus. These neurons project to the CA3 and CA2 regions via the unmyelinated mossy fibers (shown in red, stained with a zinc transporter antibody). The mossy fibers have large presynaptic terminals that enable synaptic connections to be made with CA3 and CA2 pyramidal cells and the mossy cells of the polymorphic layer (or, hilus). Each mossy fiber gives rise to several thin collaterals that synapse in the CA3 stratum lucidum (SL) and CA2 stratum radiatum (SR). The CA areas are all filled with densely packed pyramidal cells that make up the stratum pyramidale (SP; only labeled in CA1 but layer also present in CA2 and CA3). Green staining shows axonal terminal fields in the stratum lacunosum moleculare (SLM) of the CA1, CA2, and CA3 subfields and the molecular layer (ML) of the dentate gyrus. These terminals mainly arise from the entorhinal cortex.

FIGURE 3

Coronal cross section of the dorsal hippocampus stained with the neuron specific antibody, NeuN. Image more clearly shows the various cell types in each hippocampal subfield. The NeuN protein is localized in the nuclei and perinuclear cytoplasm of most neurons in the central nervous system. The hippocampus proper is defined by the dentate gyrus and Cornu Ammonis (CA). The dentate gyrus contains densely packed granule cells in both an upper and lower blade. The hilus (also referred to as the polymorphic layer) within the granule cell layers contains mossy cells. In this coronal plane, the NeuN stain shows the base of the apical dendrite protruding from the CA3 pyramidal cells (arrow under “CA3”). This pattern of staining is absent from the CA2 pyramidal neurons indicating (1) the CA2 apical dendrites are not in the coronal plane and (2) an anatomical distinction between CA2 and CA3 pyramidal cells. Comparison of the NeuN staining in CA2 and CA1 regions shows the CA1 stratum pyramidale (SP) layer to be more densely packed and narrower than the CA2 region. Purple stain from a cresyl violet counterstain shows the corpus callosum.

FIGURE 4

The major signaling pathways through the hippocampal subfields. The most prominent afferent input to the hippocampus originates from the entorhinal cortex (EC). The axons forming the perforant path (blue) arise from layer 2 of the EC and show synaptic contacts in the granule cell molecular layer of the dentate gyrus (DG) and the stratum lacunosum moleculare (SLM) of the CA3 region. There are also distinct projections from layer 3 of the EC to the SLM of the CA1 and CA2 regions (referred to as the temporoammonic pathway; blue). Granule cells of the DG send their axons (mossy fibers; red) through the hilus to the CA3 stratum lucidum (SL) and the border of the CA2 stratum radiatum (SR) and SLM. The mossy fibers also show terminal fields in the stratum oriens (SO) of the CA3 pyramidal cells. Pyramidal cells of the CA3 region send their axons (the Schaffer Collateral pathway; green) to the CA1 and CA2 SR subfields. Pyramidal cells of the CA2 project back to the CA3 SL region and forward to the CA1 SR subfield (yellow). Pyramidal cells of the CA1 region send their axons to the subiculum (not shown) and back to the deep layers of the EC (purple). SP: stratum pyramidale.

FIGURE 5

Neuroanatomical features that distinguish the CA2 region from the CA3 and CA1. (A) Cresyl violet staining shows subtle differences between the CA2 and CA3 regions. Namely, cresyl violet-stained cells in the CA2 region are smaller in size and more densely packed than the CA3 cells. There is also a slight widening of the cell layer at the border of CA2 and CA3 (upward pointing arrow). The higher density of cells in CA1 is a characteristic that delineates the CA2 from CA1 (downward pointing arrow). (B) The neuron specific stain, NeuN, exemplifies the orientation of neurons in the CA3, CA2, and CA1 regions. Specifically, the base of the apical dendrites from CA3 and CA1 pyramidal cells can be seen in this image indicating a coronal plane orientation (ovals). The base of the apical dendrites protruding from the CA2 neurons is less clear (boxed area) suggesting these dendrites are not in the coronal plane. The NeuN stain also highlights the difference in the width of the cell layers between CA2 and CA1 (visible at dashed line). (C) The CA2 region contains a high density of PEP-19 protein (Purkinje cell protein 4, pcp4; red in image). PEP-19 is a small calmodulin (CaM)-binding protein. This is a clear indication of the CA2 boundaries and distinguishes the CA2 region from the CA1 and CA3 where PEP-19 staining is absent. Also shown in this image is the stratum lucidum (SL; green: synaptophysin staining) where the mossy fibers terminate (highlighted by the high density of synaptophysin staining in green). The most dorsal aspect of the mossy fiber projection (asterisk) is adjacent to the CA2, PEP-19 staining pattern. Blue is DAPI staining showing cell layers.

FIGURE 6

Intra- and extra-hippocampal connectivity patterns of CA2 neurons. Neurons within the CA2 region visualized with the Golgi-Cox method and magnified at (A) 20x and (B) 40x. CA2 neurons receive direct innervation from the lateral entorhinal cortex (LEC) via the temporoammonic pathway (blue). This input terminates in the distal dendritic field making up the stratum lacunosum moleculare (SLM). Intrahippocampal inputs arise from the CA3 (green) and the dentate gyrus (red; mossy fibers) that terminate on the more proximal dendritic field of the stratum radiatum (SR). CA2 neurons receive a substantial, extrahippocampal input (orange) from the amygdala (AMY), median raphe (MR), and paraventricular nucleus (PVN) that terminate on the basal dendritic field of the stratum oriens (SO). In addition, CA2 neurons make reciprocal, bilateral extrahippocampal connections (purple) with the medial entorhinal cortex (MEC), supramamillary nucleus (SMN) and medial/lateral septum/diagonal brand of Broca (MS). There are also feedback projections to CA3 pyramidal cells and feedforward to CA1 pyramidal cells (yellow). SP: stratum pyramidale.