Virginia Tech® home

Gabriela Gabriela Lizana Carrillo's Dissertation Defense (8/1/2022): Mechanisms Underlying Neural Circuit Remodeling in Toxoplasma Gondii Infection

Insert your title here

Gabriela Carrillo

Dissertation Defense: Mechanisms Underlying Neural Circuit Remodeling in Toxoplasma Gondii Infection

Gabriela Lizana Carrillo

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Fox Lab, Fralin Biomedical Research Institute at VTC
Aug. 6, 2022 at 9:00 a.m.,  Room G101 A&B, 4 Riverside Circle

About this Dissertation

The central nervous system (CNS) is protected by a vascular blood-brain barrier that prevents many types of pathogens from entering the brain. Still, some pathogens have evolved mechanisms to traverse this barrier and establish a long-term infection. The apicomplexan parasite, Toxoplasma gondii, is one such pathogen with the ability to infect the CNS in virtually all warm-blooded animals, including humans. Across the globe, an estimated 30% of the human population is infected with Toxoplasma, an infection for which mounting evidence suggests increases the risk for developing neurological and neuropsychiatric disorders, like seizures and schizophrenia. In her dissertation, Carrillo investigates the telencephalic neural circuit changes induced by long-term Toxoplasma infection in the mouse brain and the neuroimmune signaling role of the complement system in mediating microglial remodeling of neural circuits following parasitic infection.

While there has been keen interest in investigating neural circuit changes in the amygdala – a region of the brain involved in fear response and which Toxoplasma infection alters in many species of infected hosts – the hippocampus and cortex have been less explored. These are brain regions for which Toxoplasma also has tropism, and moreover, are rich with fast-spiking parvalbumin perisomatic synapses, a type of GABAergic synapse whose dysfunction has been implicated in epilepsy and schizophrenia. By employing a range of visualization techniques to assess cell-to-cell connectivity and neuron-glia interactions (including immunohistochemistry, ultrastructural microscopy, and microglia-specific reporter mouse lines), Carrillo, mentored by Dr. Michael Fox, discovered that long-term Toxoplasma infection causes microglia to target and ensheath neuronal somata in these regions and subsequently phagocytose their perisomatic inhibitory synapses. These findings provide a novel model by which Toxoplasma infection within the brain can lead to seizure susceptibility and a wider range of behavioral and cognitive changes unrelated to fear response.

In the Toxoplasma infected brain, microglia, along with monocytes recruited to the brain from the periphery, coordinate a neuroinflammatory response against pathogenic invasion. This is characterized by a widespread activation of these cells and their increased interaction with neurons and their synaptic inputs. Yet, whether T. gondii infection triggers microglia and monocytes (i.e. phagocytes) to target, ensheath, and remove perisomatic inhibitory synapses on neuronal somata indiscriminately, or whether specificity exists in this type of circuit remodeling, remained unclear. Through a comprehensive assessment of phagocyte interactions with cortical neuron subtypes, Carrillo demonstrates that phagocytes selectively target and ensheath excitatory pyramidal cells in long-term infection. Moreover, coupling of in situ hybridization with transgenic reporter lines and immunolabeling revealed that in addition to phagocytes, excitatory neurons also express complement component C3 following infection (while inhibitory interneurons do not). Lastly, by employing targeted deletion of complement components, C1q and C3, Carrillo shows that complement is required for phagocyte ensheathment of excitatory cells and the subsequent removal of perisomatic inhibitory synapses on these cells (albeit not through the classical pathway). Together, these studies highlight a novel role for complement in mediating synapse-type and cell-type specific circuit remodeling in the Toxoplasma infected brain.

More About the Candidate and Project

Education

Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Virginia Tech, B.S., Psychology

Training

Graduate Research Assistant, Fox Lab

 

Mentor

Michael Fox, Ph.D., Professor, Fralin Biomedical Research Institute at VTC, and Director, School of Neuroscience, Virginia Tech

Committee Members

  • Shannon Farris, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
  • Stefanie Robel, Ph.D., Associate Professor, Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham
  • Gregorio Valdez, Ph.D., GLF Translational Associate Professor of Molecular Biology, Cell Biology and Biochemistry, Brown University
  • Kenneth J. Oestreich, Ph.D., Associate Professor, Microbial Infection and Immunity, College of Medicine, the Ohio State University

Honors and Fellowships

  • Virginia Tech Graduate Student of the Year Award 2022
  • Edward A. Bouchet Graduate Honor Society Inductee 2022
  • Young Investigator Award, American Society for Neurochemistry 2021
  • TBMH Student of the Year: Science Award, Translational Biology Medicine and Health doctorate program at Virginia Tech 2021
  • Trainee Professional Development Award, Society for Neuroscience 2020
  • Research Highlight, Fralin Biomedical Research Institute at VTC Advisory Board 2020
  • NIH Blueprint D-SPAN F99/K00 Fellowship 2020-2026
  • Neuroscience Scholars Program Associate, Society for Neuroscience 2020-2022
  • James A. Ferguson Emerging Infectious Diseases RISE Fellowship, 2019 (Partnership between the Centers for Disease Control and Prevention, Kennedy Krieger Institute, and Johns Hopkins)
  • HHMI Gilliam Fellowship Nomination (Virginia Tech nomination, not awarded) 2018
  • Howard Hughes Medical Institute “Scieneering” Fellowship 2013
  • Maria Luisa de Moreno International Foundation Scholarship 2012-2014
  • NC ACTS AmeriCorps Fellowship 2010

Travel and Presentation Awards

  • GLIA Scholarship, European Meeting on Glial Cells in Health and Disease 2021
  • 2nd Place Oral Presentation Award, Central Virginia Chapter of Society for Neuroscience 2021
  • Rising Stars in Neuroscience Professional Development Award, University of Utah 2021
  • Best Oral Presentation Award, Interneuron Dysfunction in Autism Meeting 2020
  • NIH Broadening Experience in Scientific Training Award 2019
  • International Society for Neurochemistry Travel Award 2019
  • Virginia-Nordic Precision Neuroscience Travel Award 2018
  • National Conference of Undergraduate Research Travel Award 2014

Peer-reviewed publications

Somaiya RD, Huebschman NA, Chaunsali L, Sabbagh U, Carrillo GL, Tewari BP, Fox MA. Development of astrocyte morphology and function in mouse visual thalamus. Journal of Comparative Neurology. 2021 Oct 11 doi: 10.1002/cne.25261

Glausen T, Carrillo GL, Jin R, Boyle J, Saeij J, Wohlfert EA, Fox MA, Blader IJ. The Toxoplasma polymorphic effector GRA15 mediates seizure induction by modulating interleukin-1 signaling in the brain. mBio. 2021 Jun 22 doi: 10.1128/mBio.01331-21

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Toxoplasma infection induces microglia-neuron contact and the loss of perisomatic inhibitory synapses. Glia. 2020 Feb doi: 10.1002/glia.23816

Also highlighted in special Glia Issue ‘2021 Investigator Stipend Awardees’: https://onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1098-1136.young-investigator

Carrillo GL, Su J, Monavarfeshani A, Fox MA. F-Spondin is essential for the maintenance of circadian rhythmicity. Frontiers Neural Circuits. 2018 Feb 8; 12:13. doi: 10.3389/fncir.2018.00013

Su J, Chen J, Lippold K, Monavarfeshani A, Carrillo GL, Jenkins R, Fox MA. Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex matricryptins trigger inhibitory synaptogenesis. Journal of Cell Biology. 2016 Mar 14;212(6):721-36. doi: 10.1083/jcb.201509085

Brooks JM, Carrillo GL, Su J, Lindsey D, Fox MA, Blader IJ. Toxoplasma gondii infections alter GABAergic synapses and signaling in the central nervous system. mBio. 2016 Oct 27;6(6):1428-15. doi: 10.1128/mBio.01428-15

Hammer S*, Carrillo GL*, Govindaiah G, Monavarfeshani A, Bircher J, Su J, Guido W, Fox MA. Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus. Neural Development. 2014 Jul 10;9(1):16. doi: 10.1186/1749-8104-9-16 *indicates co-first authors

Preprints or in preparation

Carrillo GL, Gill S, Crawley ML, Wei D, Wohlfort EA, Blader IJ, Fox MA. Complement C3 orchestrates selective microglial phagocytosis of inhibitory perisomatic synapses in Toxoplasma gondii infection. Under peer-review.

Carrillo GL, Wei D, Rau K, Wohlfort EA, Blader IJ, Fox MA. The spinal cord architecture and motor defects in Toxoplasma gondii infection. In preparation.

Invited Oral Presentations

Selective remodeling of inhibitory cortical and thalamic circuits in parasitic infection. Gordon Research Seminar on Thalamocortical Interactions. Lucca, Italy. Invited October 2022.

Mechanisms underlying selective remodeling of inhibitory circuits in parasitic infection. “The Back and Forth Impact Between Inflammation and Neuronal Signaling” Colloquium, American Society for Neurochemistry Annual Meeting. Roanoke, VA. Invited April 2022

Title and date TBD. Department of Molecular and Comparative Pathobiology Seminar Series, Johns Hopkins School of Medicine. Baltimore, Maryland.

Complement C3 orchestrates microglial selective phagocytosis of perisomatic inhibitory synapses in Toxoplasma gondii infection. Department of Neurobiology Seminar Series, University of Utah. Salt Lake City, Utah. September 2021

Complement-dependent neuron-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. Neuroscience Summer Retreat, School of Neuroscience, Virginia Tech. Virtual. May 2021

Neuronal-glial interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection.Rising Stars in Neuroscience Symposium, University of Utah. Virtual/Broadcasted. May 2021

Neuronal-glial interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. 2021 Writing Your Own Blueprint: The NIH Blueprint Diversity Conference. Virtual. April 2021

Neuron-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. Central Virginia Chapter of Society for Neuroscience. Virtual. March 2021 *best oral presentation award recipient

Toxoplasma gondii: How a common parasite changes the brain. Virginia Tech Graduate Research Symposium. Virtual. March 2021

Toxoplasma gondii induces phagocytosis of inhibitory perisomatic synapses. Interneuron Dysfunction in Autism Meeting. Virtual. November 2020 *best oral presentation award recipient

Toxoplasma gondii: How a common parasite changes the brain. Fralin Biomedical Research Institute Advisory Board Research Highlight. Roanoke, VA. September 2020

Toxoplasma gondii induces microglia-neuron contact and the loss of perisomatic inhibitory synapses. Research in Progress Seminar Series, Fralin Biomedical Research Institute. Virtual. December 2020

Toxoplasma gondii induces stripping of perisomatic inhibitory synapses. Neuroscience Seminar Series, School of Neuroscience at Virginia Tech. Blacksburg, VA. September 2019

Increasing detection of IgG antibodies to Hepatitis E Virus (HEV) using an optimized and automated immunoblot method. Global Communications Center at the Centers for Disease Control and Prevention, Atlanta, GA. July 2019

Microglia contribute to inhibitory synapse loss in chronic Toxoplasma gondii infection. Carilion Clinic Research Day. Roanoke Memorial Hospital, Roanoke, VA. April 2019

Microglia contribute to inhibitory axo-somatic synapse loss in chronic Toxoplasma gondii infection. Research in Progress Seminar Series, Fralin Biomedical Research Institute at VTC. Roanoke, VA. October 2018

Microglial involvement in inhibitory axo-somatic synapse loss in chronic Toxoplasma gondii infection. Virginia-Nordic Precision Neuroscience Conference. Oslo, Norway. September 2018

F-spondin is essential for maintaining circadian rhythms. Society for Neuroscience Meeting: Neuroscience of Sleep and Circadian Biology 20th Annual Minisymposium. Washington, D.C. November 2017

Novel roles for Spon1 in establishing circuits and behaviors associated with photo-entrainment. American Society for Neurochemistry Annual Conference (47th). Denver, CO. March 2016

Poster Presentations (selected from 35 total first-author presentations)

Carrillo GL, Gill S, Cawley ML, Wei D, Fox MA. Selective remodeling of inhibitory cortical circuits in parasitic infection. Gordon Research Conference: Thalamocortical Interactions. Lucca, Italy. Invited February 2022.

Carrillo GL, Gill S, Cawley ML, Wei D, Fox MA. Selective remodeling of inhibitory cortical circuits in parasitic infection. Gordon  Research Seminar: Thalamocortical Interactions. Lucca, Italy. Invited February 2022.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Complement-dependent neuron-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. Society for Neuroscience Annual Conference. Virtual. November 2021.

Carrillo GL, Kodani M, Mixson-Hayden T. Detection of IgG antibodies to hepatitis e virus using an automated immunoblot method. American Public Health Association Meeting. Denver, CO. October 2021.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Complement-dependent neuron-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. School of Neuroscience Undergraduate Research Mixer. Virginia Tech, Blacksburg, VA. October 2021.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Complement-dependent neuron-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. School of Neuroscience PhD Program Poster Session. Virginia Tech, Blacksburg, VA. August 2021.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA.Neural-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. XV European Meeting on Glial Cells in Health and Disease. Virtual. July 2021. *GLIA Journal Scholarship Recipient

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Complement-dependent neuron-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. American Society for Neurochemistry Meeting. Virtual. June 2021. *Young Investigator Award Recipient

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Dynamic neural-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. Central Virginia Chapter of the Society for Neuroscience Annual Conference. Virtual March 2021.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Neuronal-glial interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. Virtual Glia Meeting. Virtual March 2021.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Dynamic neural-glia interactions mediate the loss of perisomatic inhibitory synapses in Toxoplasma gondii infection. Society for Neuroscience: Global Connectome. Virtual. January 2021 *Trainee Professional Development Award Recipient

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Toxoplasma infection induces microglia-neuron contact and the loss of perisomatic inhibitory synapses. Central Virginia Chapter of the Society for Neuroscience Annual Conference. Charlottesville, VA March 2020.

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Toxoplasma induces stripping of perisomatic inhibitory synapses. Society for Neurochemistry Annual Conference. Chicago, Illinois. October 2019.

Carrillo GL, Boone Z, Teamer J, Hinkson C, Monavarfeshani A, Fox MA. Microglia involvement in inhibitory axosomatic synaptic loss in chronic Toxoplasma gondii infection. International Society for Neurochemistry Annual Meeting. Montreal, Canada. August 2019 *Travel Award Recipient

Carrillo GL, Ballard VA, Glausen T, Boone Z, Teamer J, Hinkson C, Wohlfert EA, Blader IJ, Fox MA. Microglia contribute to the loss of inhibitory axosomatic synapses in chronic Toxoplasma gondii infection. Central Virginia Chapter of the Society for Neuroscience Annual Conference. Charlottesville, VA. March 2019.

Carrillo GL, Fox MA. Microglial involvement in inhibitory axo-somatic synaptic loss in chronic Toxoplasma gondii infection. Virginia-Nordic Precision Neuroscience Conference. Oslo, Norway. September 2018. *Travel Award Recipient

Carrillo GL, Su J, Fox MA. F-spondin is essential for maintaining circadian rhythms. Society for Neuroscience 47th Annual Conference. Washington, D.C. November 2017.

Carrillo GL, Su J, Fox MA. The extracellular matrix protein F-Spondin is required for the maintenance of circadian rhythms. American Society for Neurochemistry 48th Annual Conference. Little Rock, Arkansas. March 2017.

Carrillo GL, Su J, Fox MA. Novel roles for Spon1 in establishing circuits and behaviors associated with photo-entrainment. Virginia- Nordic Precision Neuroscience Conference. Roanoke, VA. October 2016. *Travel Award Recipient

Carrillo GL, Su J, Fox, MA. Novel roles for Spon1 in establishing circuits and behaviors associated with photo-entrainment. Central Virginia Chapter of the Society for Neuroscience Annual Conference. Charlottesville, VA. March 2016.

Carrillo GL, Su J, Fox MA. Novel roles for Spon1 in establishing circuits and behaviors associated with photo-entrainment. Central Virginia Chapter of the Society for Neuroscience Annual Conference. Richmond, VA. March 2015.

Carrillo GL, Hammer, S., Bircher, J., Guido, W., Fox, M. A. Differences in the organization and distribution of retinal terminals in the distinct thalamic nuclei. Society for Neuroscience 44th Annual Conference. Washington, D.C. November 2014.

Carrillo GL, Hammer S, Bircher J, Guido W, Fox MA. Differences in the organization and distribution of retinal terminals in the distinct thalamic nuclei. National Conference of Undergraduate Research. University of Kentucky, Lexington, KY. April 2014. *Travel Award Recipient

University and Professional Organizations (selected)

  • Instructor, Professional Development Course, VTC Summer Undergraduate Research Fellowship (SURF) 2021
  • Graduate Student Councilor, Central Virginia Chapter of the Society for Neuroscience Conference (CVCSN) 2020-2021
  • Graduate Delegate, Commission on Graduate and Professional Studies and Policies, Virginia Tech (CGPSP) 2020-2021
  • Graduate Delegate, Degree Requirements, Standards, Criteria, and Academic Progress Committee (DRSCAP) 2020-2021
  • Peer-Mentor, Translational, Biology, Medicine and Health Peer-Mentorship Program 2018-2020
  • Founding Chair and Director, The Big Event at Virginia Tech at Roanoke 2017-2020
  • Social Chair, Roanoke Graduate Student Association 2017-2018
  • Research Mentor and Instructor, NeuroSurf Summer Undergraduate Research Fellowship at Virginia Tech 2016-2021
  • Member, Planned Parenthood South Atlantic Title X Information & Education Advisory Committee 2016-2020 

Public Outreach and Service (selected)

  • Volunteer, Carilion Clinic Hospice Care 2013-2022
  • Pen Pal, Letters to a Pre-Scientist Program 2021-2022
  • Mentor, Women in STEM Mentorship Program, Virginia Western Community College 2018-2020
  • Co-Organizer and Volunteer, Kids Tech University at Virginia Tech 2020
  • Mentor, Big Brothers Big Sisters of Southwest Virginia 2018-2020
  • Judge, Roanoke Governor School Project Forum (Science Competition) 2019, 2020
  • Judge, Western Virginia Regional Science Fair 2019
  • Judge, ‘Cell and Molecular Biology’ and ‘Grand Prize’ categories, Virginia State Science and Engineering Fair 2018, 2019
  • Co-organizer and Volunteer, Neuroscience ‘Senses’ Exhibit, West Salem Elementary STEM Night 2017, 2018, 2019
  • Co-organizer and Volunteer, Neuroscience ‘Vision’ Exhibit, STEM Day at the Taubman Museum of Fine Art 2017, 2018
  • Co-organizer and Volunteer, Neuroscience Exhibit, Virginia Science Festival 2015