A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit.

Overview

Authors: Benjamin G Gunn¹, Chenyi C Yang¹, Julie C Lauterborn¹, Benedict S Pruess¹, Julian Quintanilla¹, Katelyn Ge¹, Christine M Gall^1,2, Gary Lynch^1,3

ORCID iDs: Benjamin G Gunn, Julie C Lauterborn, Christine M Gall

Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697 USA
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697 USA
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697 USA

Institutions: University of California, Irvine (United States)

Journal: Translational psychiatry, volume 16, issue 1, article 350

Dates: received 15 May 2025; accepted 30 April 2026; published online 16 May 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41398-026-04094-3 · PMID 42143033 · PMCID PMC13346759 · OpenAlex W4410884602

Open access: gold, a free copy (OpenAlex)

Preprint: doi:10.21203/rs.3.rs-6207277/v1

Status: code on request (how the code is found and verified)

Categories: mouse (organism), depression (population), systems (subfield)

Keywords: Hippocampus, Molecular neuroscience

MeSH: CA1 Region, Hippocampal*, CA3 Region, Hippocampal*, Depression*, Hippocampus*, Major Depressive Disorder*, Social Isolation*, Animals, Behavior, Animal, Disease Models, Animal, Habenula, Male, Mice, Mice, Inbred C57BL, Perforant Pathway, Phenotype (* major topic)

Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex

Funding: United States Department of Defense | United States Navy | Office of Naval Research (ONR) (N00014-24-1-2014, N00014-21-1-2940); National Science Foundation (NSF) (BCS-1941216); NIDA NIH HHS (P50 DA044118, T32 DA050558); U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) (T32-DA050558-05, DA044118); U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD101642); NICHD NIH HHS (R01 HD101642); NIGMS NIH HHS (T32 GM008620); U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (T32NS045540)

Citations: cited by 1 paper (Europe PMC); 119 references in the paper

Abstract

Major depressive disorder is known to disturb the hippocampus, but how this impacts signal processing performed by the structure remains poorly understood. Here, we report that single housing (7-10 days) promotes a depression-like phenotype in young adult mice that is associated with a robust, yet surprisingly discreet defect in information flow across the primary hippocampal circuit. In addition to sociability disturbances and despair-like behavior, single housing eliminated preference for novelty and impaired episodic memory encoding. Additionally, the lateral habenula, an epithalamic structure critically involved in depression, was hyperactive. Although the CA1 waveform and associated spike output elicited by single-pulse lateral perforant path (LPP) activation of hippocampus was largely unaffected by single housing, pronounced disturbances emerged when the circuit was activated with physiologically relevant frequencies and patterns. The characteristic ‘theta/gamma’ pattern was distorted such that a pronounced facilitation was present in the single-housed group, while the filtering of CA1 output to brief beta (25 Hz) and gamma (50 Hz) frequency LPP stimulation evident in group-housed slices was absent. Within field CA3, the recruitment of inhibitory interneurons suppresses spike output, and subsequent signal propagation to CA1, in response to beta frequency LPP inputs but not those arriving at gamma frequencies. This CA3 beta filter was significantly impaired following single housing. These results suggest that a depression phenotype is associated with a highly selective and partial loss of inhibition within the CA3 and CA1 links of the hippocampal circuit, providing new insights into the relationship between depression and hippocampal function.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data availability

Data and code for electrophysiological analysis are available upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 2 keywords, 15 MeSH terms, 8 funders, 119 references.

Cite

This paper

Gunn, B. G., Yang, C. C., Lauterborn, J. C., Pruess, B. S., Quintanilla, J., Ge, K., Gall, C. M., & Lynch, G. (2026). A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit. Translational psychiatry, 16(1), 350. https://doi.org/10.1038/s41398-026-04094-3

BibTeX

@article{gunn2026depression, author = {Gunn, Benjamin G and Yang, Chenyi C and Lauterborn, Julie C and Pruess, Benedict S and Quintanilla, Julian and Ge, Katelyn and Gall, Christine M and Lynch, Gary}, title = {{A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit}}, journal = {Translational psychiatry}, year = {2026}, month = may, volume = {16}, number = {1}, pages = {350}, publisher = {Nature Publishing Group}, issn = {2158-3188}, doi = {10.1038/s41398-026-04094-3}, url = {https://doi.org/10.1038/s41398-026-04094-3}, pmid = {42143033}, pmcid = {PMC13346759} }

RIS

TY - JOUR AU - Gunn, Benjamin G AU - Yang, Chenyi C AU - Lauterborn, Julie C AU - Pruess, Benedict S AU - Quintanilla, Julian AU - Ge, Katelyn AU - Gall, Christine M AU - Lynch, Gary TI - A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit T2 - Translational psychiatry J2 - Transl Psychiatry PY - 2026 DA - 2026/05/16 VL - 16 IS - 1 SP - 350 SN - 2158-3188 PB - Nature Publishing Group DO - 10.1038/s41398-026-04094-3 UR - https://doi.org/10.1038/s41398-026-04094-3 LA - en ER -

CSL-JSON

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