Summary: For the first time, researchers have identified a precise neural bridge between the two halves of the hippocampus that is critical for spatial memory. The study describes a circuit in which neurons in the right CA1 region send direct projections to the left subiculum.
This interhemispheric connection is essential for how animals and humans navigate and remember locations. The team also found that this circuit is significantly weakened in a mouse model of schizophrenia risk, providing a plausible neural mechanism for the spatial disorientation and memory problems observed in some neuropsychiatric disorders.
Key Facts
- The New Pathway: A direct projection links the right hippocampal CA1 region to the left hippocampal subiculum.
- Spatial Necessity: Using optogenetics to control neurons with light, researchers showed that disrupting this bridge prevents mice from remembering locations and navigating effectively, while leaving anxiety levels and basic object recognition intact.
- The Schizophrenia Link: In a mouse model of the 22q11.2 deletion—a major genetic risk factor for schizophrenia—the interhemispheric connection was reduced and spatial memory was impaired.
- Sex Differences: The genetic alteration affected both sexes, but males displayed more pronounced deficits on some spatial tests.
- Clinical Potential: The authors suggest these projections might be detectable in humans with advanced imaging such as tractography and could help identify brain changes linked to schizophrenia risk.
Source: UMH
A multidisciplinary team led by the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and Miguel Hernández University of Elche (UMH), has mapped a previously unknown hippocampal circuit that supports spatial memory.
Published in Cell Reports, the study reveals a novel interhemispheric pathway in which CA1 neurons in the right hemisphere project not only to contralateral CA1 but also to the left subiculum. This right-to-left CA1→subiculum pathway appears to be a functional bridge that integrates information necessary for navigation and remembering locations.
The authors used neuronal tracing methods to map the projection and then applied optogenetics to test its role. By selectively silencing the projection in mice, they observed clear impairments in tasks requiring spatial memory and spatial working memory. Importantly, behaviors unrelated to spatial mapping—such as general anxiety measures and simple object recognition—remained unaffected, indicating a specific role for this pathway in spatial cognition.
“We already knew the hippocampus is central to memory, but how the two hemispheres exchange information was poorly defined. Here we identify a precise pathway and demonstrate its necessity for core cognitive functions,” explains Félix Leroy, lead investigator and director of the Cognition and Social Interactions Laboratory at the Institute for Neurosciences.
A Functional “Bridge” for Spatial Memory
The brain’s hemispheres often process information differently and must coordinate continuously. While some hippocampal commissures were previously described, outputs from CA1 had not been explored in depth. This study fills that gap by showing that dorsal CA1 neurons in the right hemisphere project to the contralateral dorsal subiculum, forming a pathway that supports the construction and use of spatial maps.
Noelia Sofía de León Reyes, first author, summarizes: “This circuit works as a bridge, allowing the right and left hippocampal regions to combine current spatial information with stored memory, which is essential for navigation.” The targeted disruption experiments confirmed that interfering with this projection selectively impairs spatial tasks.
To investigate relevance for psychiatric conditions, the researchers examined a mouse model carrying the Df16(A) mutation, which models the human 22q11.2 deletion syndrome linked to elevated schizophrenia risk. These Df16(A)+/− mice showed both weakened right-to-left CA1→subiculum projections and deficits in spatial cognition. Although the genetic alteration is present in both sexes, male mice tended to show stronger impairments in some behavioral assays.
“Our findings suggest that interhemispheric disconnection in this hippocampal circuit could contribute to the cognitive and navigational deficits associated with neuropsychiatric disorders,” says De León Reyes.
The work integrates anatomical mapping, circuit manipulation, and behavioral testing to build a coherent picture of how a specific interhemispheric pathway supports spatial memory and how its disruption may underlie aspects of neurodevelopmental and psychiatric disease.
The study includes collaboration with Marta Nieto’s laboratory at the Spanish National Center for Biotechnology (CNB-CSIC), and with Joseph A. Gogos from Columbia University, who developed the Df16(A) mouse model. Viral tools and circuit-level manipulations were contributed by IN CSIC-UMH expert Cristina García Frigola.
Funding: This research received support from the European Research Council (ERC) under Horizon 2020, the Spanish State Research Agency – Ministry of Science, Innovation and Universities 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 how the lateral septum regulates motivated behaviors and how these circuits change in disorders affecting social behavior.
Key Questions Answered:
A: The two hemispheres frequently specialize in different aspects of processing. Spatial navigation requires combining a current sensory-based map with stored memories of places. The identified bridge allows the right and left hippocampus to coordinate in real time, integrating incoming spatial cues with prior experience to form a coherent three-dimensional mental map.
A: Schizophrenia and related conditions are often linked to disrupted connectivity across brain regions. This study shows a concrete example: a specific interhemispheric highway that is reduced in a mouse model of the 22q11.2 deletion. When communication between the two sides of the hippocampus falters, spatial memory and navigation can suffer, which may contribute to the cognitive symptoms observed in patients.
A: Restoring or strengthening such pathways in humans remains a long-term goal. Identifying the exact anatomical pathway is a crucial first step—future research could explore targeted neuromodulation, cognitive training, or other interventions to enhance connectivity, guided by advanced imaging and behavioral testing.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional contextual information was added by the editorial team.
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.
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
Mapping hippocampal connectivity is essential for understanding the neural mechanisms of learning and memory, but interhemispheric connections within the hippocampal formation have been poorly defined. In rodents, established commissural pathways include dentate gyrus mossy cell projections and CA2/CA3 collaterals to contralateral regions, while outputs from CA1 remained largely unexplored.
This study demonstrates that dorsal CA1 pyramidal neurons in the right hemisphere project to the contralateral dorsal subiculum in addition to contralateral CA1. Functional tests show that the right-to-left dCA1→dSUB projection supports spatial memory and spatial working memory—functions that are impaired in the Df16(A)+/− mouse model of 22q11.2 deletion syndrome, a genetic condition associated with increased schizophrenia risk. Notably, these interhemispheric projections are disrupted in Df16(A)+/− mice, suggesting that circuit dysregulation may contribute to cognitive deficits associated with the syndrome.