Behavioral alterations in long-term Toxoplasma gondii infection of C57BL/6 mice are associated with neuroinflammation and disruption of the blood brain barrier

PLoS One. 2021 Oct 5;16(10):e0258199. doi: 10.1371/journal.pone.0258199. eCollection 2021.

Abstract

The Apicomplexa protozoan Toxoplasma gondii is a mandatory intracellular parasite and the causative agent of toxoplasmosis. This illness is of medical importance due to its high prevalence worldwide and may cause neurological alterations in immunocompromised persons. In chronically infected immunocompetent individuals, this parasite forms tissue cysts mainly in the brain. In addition, T. gondii infection has been related to mental illnesses such as schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder, as well as mood, personality, and other behavioral changes. In the present study, we evaluated the kinetics of behavioral alterations in a model of chronic infection, assessing anxiety, depression and exploratory behavior, and their relationship with neuroinflammation and parasite cysts in brain tissue areas, blood-brain-barrier (BBB) integrity, and cytokine status in the brain and serum. Adult female C57BL/6 mice were infected by gavage with 5 cysts of the ME-49 type II T. gondii strain, and analyzed as independent groups at 30, 60 and 90 days postinfection (dpi). Anxiety, depressive-like behavior, and hyperactivity were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic T. gondii infection, in a direct association with the presence of parasite cysts and neuroinflammation, independently of the brain tissue areas, and linked to BBB disruption. These behavioral alterations paralleled the upregulation of expression of tumor necrosis factor (TNF) and CC-chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES) in the brain tissue. In addition, increased levels of interferon-gamma (IFNγ), TNF and CCL2/MCP-1 were detected in the peripheral blood, at 30 and 60 dpi. Our data suggest that the persistence of parasite cysts induces sustained neuroinflammation, and BBB disruption, thus allowing leakage of cytokines of circulating plasma into the brain tissue. Therefore, all these factors may contribute to behavioral changes (anxiety, depressive-like behavior, and hyperactivity) in chronic T. gondii infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / complications
  • Anxiety / physiopathology
  • Behavior, Animal*
  • Blood-Brain Barrier / parasitology*
  • Blood-Brain Barrier / pathology*
  • Brain Edema / complications
  • Brain Edema / physiopathology
  • Chronic Disease
  • Cytokines / metabolism
  • Depression / complications
  • Depression / physiopathology
  • Female
  • Inflammation / parasitology*
  • Inflammation / physiopathology
  • Locomotion
  • Mice
  • Mice, Inbred C57BL
  • Muscle Strength
  • Parasites / physiology
  • Time Factors
  • Toxoplasma / physiology*
  • Toxoplasmosis, Cerebral / parasitology*
  • Toxoplasmosis, Cerebral / physiopathology
  • Up-Regulation

Substances

  • Cytokines

Grants and funding

This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/FAPERJ (E-26/210.190/2018) and the Brazilian Research Council/CNPq (BPP-304474/2015-0, BPP 306037/2019-0, INCTV, National Institute for Science and Technology for Vaccines), Grant PAEF2-IOC/Fiocruz. PMRS Martins, HC Santiago, RT Gazzinelli, JR Mineo, NM Silva, and J Lannes-Vieira are research fellows of the Brazilian Research Council/CNPq. JLV is recognized with the grant Scientist of the State of Rio de Janeiro/FAPERJ (E-26/202.572/2019). This study was financed in part by the “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior do Brasil” (CAPES) - Finance Code 001. We are indebted to Joyce Caroline Sá de Lima for the excellent technical assistance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.