Summary: For the first time, researchers have identified a specific neural “bridge” connecting the two halves of the hippocampus that is essential for spatial memory. The study maps a direct projection from neurons in the right CA1 region to the left subiculum, revealing a previously unrecognized interhemispheric pathway that supports navigation and location memory.
This right-to-left hippocampal connection is critical for building and using internal maps of space. The researchers also found that this circuit is weakened in a mouse model of the 22q11.2 deletion—a major genetic risk factor for schizophrenia—providing a plausible neural mechanism for the spatial disorientation and memory problems often observed in neuropsychiatric conditions.
Key Facts
- New pathway identified: Neurons in the right dorsal CA1 (dCA1) project directly to the left dorsal subiculum (dSUB).
- Essential for spatial memory: Optogenetic silencing of this projection disrupts mice’s ability to remember object locations and perform spatial navigation tasks, while leaving anxiety measures and basic object recognition unaffected.
- Link to schizophrenia risk: In the Df16(A) mouse model of the 22q11.2 deletion, researchers observed reduced interhemispheric CA1-to-subiculum connectivity alongside impaired spatial cognition.
- Sex differences: Both sexes carried the genetic alteration, but male mice exhibited more pronounced spatial deficits in some behavioral tests.
- Clinical relevance: The authors suggest this pathway could be examined in humans with tractography and cognitive testing to help detect circuit alterations associated with schizophrenia and related disorders.
Source: UMH
A multidisciplinary team at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and Miguel Hernández University of Elche (UMH), has discovered and characterized an interhemispheric hippocampal circuit required for spatial cognition.
Published in Cell Reports, the study uses anatomical tracing, optogenetics, and behavioral tests to show that right dCA1 neurons send axonal projections not only to contralateral dCA1 but also directly to the left dSUB. Functionally, this projection supports spatial memory and working memory processes that underlie navigation and remembering locations.
“We have long known that the hippocampus is central to memory, but how the two hippocampal hemispheres coordinate was unclear,” says Félix Leroy, lead investigator and director of the Cognition and Social Interactions Laboratory at the Institute for Neurosciences. “This work pinpoints a specific pathway and demonstrates its causal role in spatial cognition.”
A neural bridge that coordinates memory across hemispheres
The brain’s hemispheres perform partially specialized tasks yet must continually share information. While some hippocampal commissural pathways were previously known, commissural outputs from CA1 had not been fully described. Using neuronal tracing methods, the team mapped a precise projection from right dCA1 pyramidal neurons to left dSUB, establishing a structural basis for interhemispheric integration of spatial information.
To test function, researchers used optogenetics to transiently inhibit the right-to-left dCA1→dSUB projection during spatial tasks. Mice with the pathway blocked showed clear impairments in remembering object locations and in spatial working memory tasks, but showed intact performance on anxiety assays and simple object recognition tests. These results indicate the projection serves a specialized role in spatial memory rather than general cognition or sensory processing.
Noelia Sofía de León Reyes, first author of the paper, explains: “This connection acts like a bridge that integrates real-time spatial information with stored representations, enabling accurate navigation and location memory.”
The researchers then examined the circuit in a genetic model linked to schizophrenia risk: mice with the Df16(A) microdeletion, analogous to the human 22q11.2 deletion. These mice displayed both a reduction in the interhemispheric CA1→subiculum projection and measurable deficits in spatial cognition. Although the deletion affected both sexes, males often showed stronger behavioral impairments in specific tests.
“Our findings suggest that disruption of interhemispheric communication within the hippocampus may contribute to the cognitive and navigational problems seen in certain psychiatric conditions,” says de León Reyes.
Beyond the immediate mechanistic insight, the authors note potential translational value: diffusion tractography and other advanced neuroimaging methods could be used to evaluate analogous pathways in humans, supporting earlier detection of circuit-level changes associated with schizophrenia or to guide targeted interventions.
The study combined anatomical mapping, viral circuit tools, optogenetic manipulation, and behavioral assays in mice and was performed in collaboration with laboratories led by Marta Nieto (CNB-CSIC) and Joseph A. Gogos (Columbia University), who developed the Df16(A) mouse model. Cristina García Frigola contributed expertise in viral manipulation of neural circuits.
Funding: The research received support from the European Research Council (ERC) under Horizon 2020, the Spanish State Research Agency through the Severo Ochoa Program, the Generalitat Valenciana, the “la Caixa” Foundation, the Severo Ochoa Foundation, and the U.S. National Institute of Mental Health (NIMH). This project is part of the MotivatedBehaviors initiative (H2020-ERC-STG/0784, no. 949652), which investigates brain circuits that regulate motivated and social behaviors.
Key Questions Answered:
A: Spatial navigation requires combining a current internal map with memories of past locations. The right-to-left CA1→subiculum pathway enables the two hippocampal hemispheres to synchronize and integrate distinct types of spatial information, producing a coherent three-dimensional representation used for navigation.
A: Schizophrenia and related disorders often involve impaired connectivity across brain regions. This study identifies a concrete example—a specific hippocampal interhemispheric pathway that is reduced in a mouse model of the 22q11.2 deletion—linking circuit disruption to spatial memory deficits that mirror symptoms seen in some patients.
A: Direct clinical interventions are still speculative. Identifying the precise neural coordinates is a critical first step. Future approaches might include targeted neurostimulation or specialized cognitive therapies aimed at strengthening hippocampal connectivity, but further research in humans is required.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context was provided by staff writers to clarify implications and methods.
About this neuroscience research news
Author: Angeles Gallar
Source: UMH
Contact: Angeles Gallar – UMH
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Interhemispheric CA1 projections to the subiculum support spatial cognition and are affected in a mouse model of the 22q11.2 deletion syndrome” by Noelia S. de León Reyes, Maria Helena Bortolozzo-Gleich, Helden Natalia Velez Gonzalez, Yuki Nomura, Cristina García Frigola, Marta Nieto, Joseph A. Gogos, and Félix Leroy. Cell Reports
DOI: 10.1016/j.celrep.2026.117114
Abstract
Interhemispheric CA1 projections to the subiculum support spatial cognition and are affected in a mouse model of the 22q11.2 deletion syndrome
Accurate mapping of hippocampal connectivity is vital to understanding learning and memory, yet interhemispheric links within hippocampal formations are not well defined. In rodents, established commissural pathways include dentate gyrus hilar mossy cells and CA2/CA3 outputs, but CA1 commissural outputs have been largely unexplored.
This study demonstrates that dorsal CA1 pyramidal neurons in the right hemisphere project to the contralateral dorsal subiculum as well as to contralateral dCA1. Functional tests reveal that the right-to-left dCA1→dSUB pathway supports spatial memory and spatial working memory—functions that are impaired in the Df16(A)+/− mouse model of 22q11.2 deletion syndrome, a condition associated with higher schizophrenia risk. Importantly, these interhemispheric projections are reduced in Df16(A)+/− mice, suggesting that dysregulation of this circuit may underlie cognitive deficits related to the 22q11.2 deletion.