Availability of genome-scale in situ hybridization data allows systematic analysis of genetic neuroanatomical architecture. Within the hippocampus, electrophysiology and lesion and imaging studies demonstrate functional heterogeneity along the septotemporal axis, although precise underlying circuitry and molecular substrates remain uncharacterized. Application of unbiased statistical component analyses to genome-scale hippocampal gene expression data revealed robust septotemporal molecular heterogeneity, leading to the identification of a large cohort of genes with robust regionalized hippocampal expression. Manual mapping of heterogeneous CA3 pyramidal neuron expression patterns demonstrates an unexpectedly complex molecular parcellation into a relatively coherent set of nine expression domains in the septal/temporal and proximal/distal axes with reciprocal, nonoverlapping boundaries. Unique combinatorial profiles of adhesion molecules within these domains suggest corresponding differential connectivity, which is demonstrated for CA3 projections to the lateral septum using retrograde labeling. This complex, discrete molecular architecture provides a novel paradigm for predicting functional differentiation across the full septotemporal extent of the hippocampus.
Bibliographical noteFunding Information:
This work was sponsored by the Allen Institute for Brain Science. The authors wish to thank the Allen Institute founders, P.G. Allen and J. Patton, for their vision, encouragement, and support. The authors also wish to acknowledge Theresa Zwingman and Maureen Howell for assistance with mining efforts to identify regional hippocampal expression patterns; Simon Smith for assistance with histological preparations; Jolene Kidney, Maureen Howell, Andrew Boe, and Tracy Lemon for assistance with tract tracing and sectioning; John Hohmann and John Morris for assistance with the developmental analysis of hippocampal gene expression; Amanda Ebbert, Lon Luong, Kimberly Smith, Melissa Reding, and Cathy Copeland for supporting production and scanning of fluorescent ISH images; Chinh Dang for supporting database needs; and Paul Wohnoutka for supporting data production.
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