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MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology

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Abstract

Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.

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This study does not include material from living or dead patients. However, all the mice data and/or biological material will be made available under request.

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Funding

This work was supported by the National Council of Science and Technology in Mexico (CONACYT) (Grant number: 255317), 708452 CONACYT for L. J. Montalvo-Martínez, 573686 CONACYT for R. Maldonado-Ruiz, and PAICYT 2020 and IBRO-LARC 2020 for Alberto Camacho-Morales.

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Authors and Affiliations

  1. Department of Biochemistry, College of Medicine, Universidad Autónoma de Nuevo León, Calle Dr. Eduardo Aguirre Pequeño s/n, Colonia Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico

    Roger Maldonado-Ruiz, Luis A. Trujillo-Villarreal, Larisa Montalvo-Martínez & Alberto Camacho-Morales

  2. Neurometabolism Unit, Center for Research and Development in Health Sciences, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, México

    Roger Maldonado-Ruiz, Luis A. Trujillo-Villarreal, Larisa Montalvo-Martínez & Alberto Camacho-Morales

  3. Deparment of Physiology, College of Medicine, Universidad Nacional Autónoma de México, Mexico City, México

    Octavio Fabián Mercado-Gómez, Virginia Arriaga-Ávila & Rosalinda Guevara-Guzmán

  4. Department of Pharmacology and Toxicology, College of Medicine, Universidad Autonoma de Nuevo Leon, San Nicolás de los Garza, México

    Lourdes Garza-Ocañas

  5. Tecnológico de Monterrey, School of Medicine and Health Sciences, Monterrey, México

    Rocío Ortiz-López

  6. Universidad Nacional Autónoma de México, Instituto de Neurobiología, Mexico City, México

    Eduardo A. Garza-Villarreal

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  1. Roger Maldonado-Ruiz
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  2. Luis A. Trujillo-Villarreal
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Contributions

RMR, LATV, LMM, OFMG, and VAA performed the experiments. RMR, LATV, LMM, OFMG, VAA, LGO, ROL, EAGV, RGG, and ACM designed and analyzed the experiments. RMR, LATV, LMM, OFMG, VAA, LGO, ROL, EAGV, RGG, and ACM wrote the original manuscript. All authors reviewed, edited, and approved the final manuscript.

Corresponding author

Correspondence to Alberto Camacho-Morales.

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All animal experiments were performed according to the NIH Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23, revised in 1996). We followed the Basel Declaration to implement the ethical principles of Replacement, Reduction, and Refinement of experimental animal models. Our study was approved by the local Animal Care Committee (BI20-00004) at the Universidad Autónoma de Nuevo León, Mexico.

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Maldonado-Ruiz, R., Trujillo-Villarreal, L.A., Montalvo-Martínez, L. et al. MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology. Mol Neurobiol 59, 932–949 (2022). https://doi.org/10.1007/s12035-021-02649-7

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