Robledo Montaña, JavierDavid Martín-HernándezJavier Cuenca-OrtegaMaría MartínezVirto Ruiz, LeireAmbrosio Elejalde, NagoreMontero Solís, EduardoMarín Cuenda, María JoséHerrera González, DavidSanz Alonso, MarianoLeza Cerro, Juan CarlosFiguero Ruiz, ElenaGarcía Bueno, Borja2026-04-132026-04-132025-12-01Robledo-Montaña J, Martín-Hernández D, Cuenca-Ortega J, Martínez M, Virto L, Ambrosio N, Montero E, Marín MJ, Herrera D, Sanz M, Leza JC, Figuero E, García-Bueno B. Alterations in Neuroinflammation, Microglia and Neuroplasticity in the Rat Hippocampus in a Combined Model of Periodontitis and Depression. CNS Neurosci Ther. 2025 Dec;31(12):e70669. doi: 10.1111/cns.706691755-593010.1111/cns.70669https://hdl.handle.net/20.500.14352/134671Aims: The exact causes of major depressive disorder (MDD) are still debated, but its connection with inflammatory diseases and stress is well established. Emerging evidence suggests a potential link between periodontitis (gum disease) and MDD. Methods: Periodontitis (P) was induced in rats through oral rinses with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. Four experimental groups were established: periodontitis with CMS (P + CMS+), periodontitis without CMS (P + CMS-), CMS without periodontitis (P-CMS+), and control (P-CMS-). Inflammatory and synaptic plasticity-related mediators were quantified in hippocampal samples. The number, morphology, and inflammatory phenotype of microglia were also evaluated by ultrastructural and fractal analyses. Results: P + CMS+ animals compared with controls showed: (1) increased protein expression of TLR-4, phospho(p)-nuclear factor kappa B (p-NFκB)/NFκB ratio, and inducible nitric oxide synthase (iNOS); (2) decreased microglial number, shorter branch length, reduced complexity, and increased expression of iNOS; (3) decreased protein levels of BDNF and synaptophysin, and lower ratios of p-protein kinase B (p-Akt)/Akt and p-mammalian target of rapamycin (p-mTOR)/mTOR. Conclusion: Alterations in neuroinflammation and neuroplasticity in the hippocampus may contribute to the comorbidity between periodontitis and MDD, warranting further investigation.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article1755-5949https://doi.org/10.1111/cns.70669Digital Object Identifier (DOI)41326981https://onlinelibrary.wiley.com/doi/10.1111/cns.70669https://pubmed.ncbi.nlm.nih.gov/41326981/open access616.314.17-008.1:616.89-008.454DepressionHippocampusMicrogliaNeuroinflammationPeriodontitisSynaptic plasticityCiencias BiomédicasNeurociencias (Medicina)Neurociencias (Farmacia)Odontología (Odontología)Psicología (Psicología)PeriodonciaEstrés y relajación32 Ciencias Médicas3201 Ciencias Clínicas3201.04 Patología Clínica3205.07 Neurología3207.11 Neuropatología6310.03 Enfermedad3213.13 Ortodoncia-Estomatología