Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II

Tucker, H. L.; Karat, B.; De Ruiter, A. T.; Parker, D. M.; Lim, S. A.; Denning, A. E.; Ittyerah, R.; Levorse, L. M.; Trotman, W.; Bahena, A.; Chung, E.; Prabhakaran, K.; Bedard, M. L.; Ohm, D. T.; Xie, L.; Das, S. R.; Pluta, J. B.; Schuck, T.; Liu, W.; Pickup, S.; Artacho-Perula, E.; Martin, M. M. I. d. O.; Munoz, M.; Romero, F. J.; Gonzalez, J. C. D.; Jimenez, M. A.; Rabal, M. M.; Serrano, A. I.; Gonzalez, N. V.; Sanchez, S. C.; de la Rosa, C.; Lee, E. B.; Detre, J. A.; Tisdall, D.; Irwin, D. J.; Wolk, D. A.; Adler, D. H.; de Flores, R.; Berron, D.; Ding, S.-L.; Wisse, L. E.

doi:10.1101/2025.11.21.689744

Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.11.21.689744

Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II

View original source ↗Export metadata ↓

Abstract

High-resolution in vivo magnetic resonance imaging (MRI) of hippocampal subfields is a rapidly advancing field due to their implication in cognition, disorder, and disease. Hippocampal subfield segmentation on in vivo MRI is generally guided by postmortem reference material, which has been limited by small sample sizes that preclude comprehensive characterization of subfield border locations and their variability. Addressing this, we characterized hippocampal subfield border variability in two ultra-high-resolution postmortem MRI datasets with combined annotated histological sections, including cases with and without dementia. We examined: 1) the order of appearance and disappearance of subfields along the long axis of the hippocampus; 2) the order of appearance and disappearance of subicular subregions; 3) the medial-lateral position of subicular subregional boundaries along the hippocampal body; 4) the location of the CA3 relative to hippocampal head digitations; 5) the subfield borders in the hippocampal body relative to a volume proportion of the dark band; and 6) the association of hippocampal length and subiculum-CA1 border location with diagnosis, demographic factors, and factors related to postmortem imaging. Our findings reaffirmed that there is a consistent order of appearance and disappearance of subfields in the hippocampal head and tail, respectively. The subicular subregions exhibited a first in, last out order of appearance and disappearance, and pre/parasubiculum consistently occupied half of the subicular complex in coronal slices throughout the hippocampal body. Hippocampal head digitations were not a reliable landmark for CA3 appearance, but SRLM proportionality did offer a potentially consistent approach for estimating CA2 and CA3 subfield borders in relation to the hippocampal border. No clear relationship was found between the anatomical features and diagnosis, demographic factors, and factors related to postmortem imaging. These findings have implications for the development and harmonization of hippocampal subfield segmentation protocols and interpretation of high-resolution functional MRI studies of the human hippocampus.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Tucker, H. L., Karat, B., De Ruiter, A. T., Parker, D. M., Lim, S. A., Denning, A. E., Ittyerah, R., Levorse, L. M., Trotman, W., Bahena, A., Chung, E., Prabhakaran, K., Bedard, M. L., Ohm, D. T., Xie, L., Das, S. R., Pluta, J. B., Schuck, T., Liu, W., Pickup, S., Artacho-Perula, E., Martin, M. M. I. d. O., Munoz, M., Romero, F. J., Gonzalez, J. C. D., Jimenez, M. A., Rabal, M. M., Serrano, A. I., Gonzalez, N. V., Sanchez, S. C., de la Rosa, C., Lee, E. B., Detre, J. A., Tisdall, D., Irwin, D. J., Wolk, D. A., Adler, D. H., de Flores, R., Berron, D., Ding, S.-L., Wisse, L. E.. 2025-11-24. Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II. https://doi.org/10.1101/2025.11.21.689744

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Different hippocampal subfield volumes predict source memory performance and general cognitive ability in an adult lifespan sample

Modest positive associations between episodic memory performance and whole hippocampal and hippocampal subfield volumes have been reported in numerous prior studies. A smaller number of studies have reported associations between hippocampal volume and performance on tests of non-mnemonic cognition. The present study examined whether these associations were evident in a lifespan sample of cognitively healthy adults. Of particular interest was whether any identified associations were sensitive to age, and whether associations between subfield volumes and mnemonic and non-mnemonic performance were subfield dependent. We acquired high-resolution T1- and T2-weighted structural images from 163 adults (18-87 years of age). Participants also undertook a comprehensive neuropsychological test battery and an in-scanner test of source memory. Principal components analysis was employed to reduce the neuropsychological test scores to 5 cognitive components. Two components reflected memory performance while the other three reflected different aspects of non-mnemonic cognition. Hippocampal subfields (Cornu Ammonis (CA)1, CA2-3, dentate gyrus (DG) and subiculum) were segmented and measured with the Automated Segmentation of Hippocampus Subfields (ASHS) package. Source memory performance was selectively associated across participants with CA2-3 volume. By contrast, both mnemonic and non-mnemonic component scores derived from the test battery were associated exclusively with the volume of the DG. All associations were age-invariant. The findings indicate that different cognitive domains can be dissociated by virtue of their associations with different hippocampal subfields. Of importance, these associations appear to be life-long and hence are unlikely to reflect individual differences in age-related decline in structural integrity.

neuroscience↗

bioRxiv2026

Cell type specific astrocytic feedback regulates excitation inhibition balance and cortical network dynamics

Astrocytes actively regulate synaptic transmission and neuronal excitability, yet their role in orchestrating macroscopic cortical network regimes and slow-wave oscillations remains an active area of reasearch. This study investigates how bidirectional neuron astrocyte interactions shape emergent population dynamics using a computational network model of excitatory and inhibitory neurons coupled to an astrocyte. The results identify astrocytic feedback topology, rather than astrocytic coupling strength alone, as a key determinant of emergent cortical network dynamics. By systematically dissecting pathway-specific connectivity, it has been shown that the neuronal population driving astrocytic activation and the neuronal population receiving gliotransmission jointly determine whether the network occupies asynchronous irregular (AI), synchronous irregular (SI), synchronous regular(SR), asynchronous regular(AR) or quiescent regimes.Directing gliotransmission selectively onto excitatory neurons consistently promotes population synchrony regardless of the population influencing astrocytic dynamics, whereas selective modulation of inhibitory interneurons induces network quiescence via strong suppression. Under dual-target gliotransmission, network synchrony is dictated by the population driving astrocytic dynamics: excitatory-only drive promotes synchrony, while combined or inhibitory-specific drive preserves asynchronous states. Furthermore, the model reveals that astrocytic signaling kinetics provide an additional temporal control mechanism that regulates the frequency and persistence of self sustained up states.

neuroscience↗

bioRxiv2026

VCP inhibition prevents cone photoreceptor degeneration in the cpfl1 mouse model of achromatopsia

Achromatopsia (ACHM) is a rare autosomal recessive retinal disorder characterized by absent cone photoreceptor function from early life, leading to severe visual impairment. Mutations in genes involved in the cone phototransduction cascade frequently result in elevated cyclic guanosine monophosphate (cGMP) levels and activation of stress pathways, including endoplasmic reticulum (ER) stress and the unfolded protein response. Targeting common downstream mechanisms rather than individual mutations may provide a broadly applicable therapeutic strategy. Here, we investigated whether pharmacological inhibition of valosin-containing protein (VCP), a key regulator of ER and protein homeostasis, can prevent cone degeneration in the spontaneous cone photoreceptor function loss 1 (cpfl1) mouse model of ACHM. Organotypic culture of retinal explants from cpfl1 mice were treated with the selective VCP inhibitor ML240. Cone survival, cell death, opsin expression and localization were assessed by TUNEL assay, immunohistochemistry, and quantitative image analysis. ML240 treatment significantly increased cone density and improved cone opsin expression and trafficking to the outer segments (OSs) in cpfl1 explants compared to controls. Importantly, rhodopsin trafficking in rod photoreceptors was unaffected, indicating that VCP inhibition did not impair normal rod phototransduction. These findings demonstrate that VCP inhibition by ML240 effectively preserves cone photoreceptors and improves cone-specific functional markers in the cpfl1 model. Targeting VCP may represent a mutation-independent therapeutic strategy for preventing cone death in ACHM.

neuroscience↗