Stratum radiatum of CA2 is an additional target of the perforant path in humans and monkeys

Abstract

The perforant path connects two key components of the medial temporal memory system, the entorhinal cortex and hippocampus. Entorhinal layer II projects densely to the outer portion of the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare of CA2 and CA3 of the hippocampus. The present study for the first time reports that the stratum radiatum of CA2 but not of CA3 in the human brains receives “extra”, unique and dense projections from the layer II using an antibody against an abnormally phosphorylated tau (AT8), which stains both degenerating neurons and their processes including axon terminals in aging and early Alzheimer’s disease. This finding is also confirmed in CA2 of monkey hippocampus by means of anterograde tracer injections in the entorhinal cortex. Thus the present results indicate that CA2 in human and nonhuman primates receives stronger activation from the PP than CA3 does. Our finding also suggests that the SR of CA2 is a major converging zone of the projections from the perforant path and Schaffer collaterals. Thus, CA2 may play a unique role in hippocampal memory networks.

Rediscovering area CA2: unique properties and functions

“…In rodents, the primary afferents contacting CA2 pyramidal neurons arise from three primary sources: dentate gyrus (DG) granule cells (shown in blue) that target the stratum lucidum (SL), CA3 neurons that target the stratum radiatum (SR), and medial and lateral entorhinal cortex layer II (EC LII) neurons (shown in dark grey) that target the stratum lacunosum-moleculare (SLM) 9,10,53 . This part of the perforant path was found to dip far into the area normally considered to be SR in monkeys and humans 143 . The main projection target of CA2 pyramidal neurons is ‘deep’ calbindin 1- immunonegative CA1 neurons with dendrites in stratum oriens (SO) 9,29 ; CA2 neurons target the CA1 SR to a lesser extent 29 .…”

Cytoarchitectonically‐driven MRI atlas of nonhuman primate hippocampus: Preservation of subfield volumes in aging

“…Another potential area to which our method could be applied is to human subfield demarcation. There are strong similarities between the monkey and human hippocampus and most aspects of hippocampal neuroanatomy, including relative cell density, cytoarchitecture, chemoarchitecture, and neural connectivity, appear to be conserved (Amaral & Lavenex, ; Amaral et al, ; Ding, ; Ding et al, ; Lim et al, ). Therefore, developing a framework that may improve the accuracy of human subfield labeling based on data drawn from nonhuman primates would be an important advance.…”

“…Traditionally, the complications associated with studying humans have been partially alleviated by turning to nonhuman primate animal models. The anatomy of the rhesus macaque brain is better understood compared with humans (Amaral & Lavenex, ), and although studies comparing human and macaque anatomy are far from comprehensive, the existing data suggest overwhelming similarity in relative cell density, cytoarchitecture, chemoarchitecture, and neural connectivity of the two species (Amaral & Lavenex, ; Amaral, Scharfman, & Lavenex, ; Ding, ; Ding, Haber, & Van Hoesen, ; Lim, Blume, Madsen, & Saper, ). Additionally, healthy subjects both young and old can easily be compared, shedding light on whether anatomical changes occur in healthy aging.…”

Detailed segmentation of human hippocampal and subicular subfields using a combined approach

“…To summarize, human CA2 is characterized by the lack of a mossy fiber layer [1,2,14,15,20,21] , existence of strong CB [20,22] and PCP4 (Fig. 4C) staining, and additional entorhinal innervation in its stratum radiatum [20,23] . The border of CA2 with CA1 can also be identified with HTR2A-ISH, in which much stronger HTR2A expression was observed in CA1 than in CA2 ( Fig.…”