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Matthew J Girgenti, PhD

Assistant Professor of Psychiatry

Contact Information

Matthew J Girgenti, PhD

Mailing Address

  • 34 Park Street

    CMHC

    New Haven, CT 06508

    United States

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Research Summary

Research in our lab is directed at determining the molecular pathologies underlying stress disorders such post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and suicidal behavior. We identify therapeutic and biomarker targets relevant to those disorders by utilizing human brain derived data from frozen postmortem tissue. We conduct research focused on the connection between stress and brain functions. My lab employs functional genomics to dissect transcriptomic and cell-type-specific regulatory elements and risk loci underlying the genetics of stress-related mental disorders and engages in translational research using animal models and donor-derived human induced pluripotent stem cells (hiPSCs) to validate causal genes and variants. In addition, my lab employs “big data” approaches to investigate single cell-type molecular dysregulations of complex neuropsychiatric traits to gain a deeper understanding of the individual differences in the expression of symptoms. Together, this work is contributing importantly to the evolving understanding of PTSD and depression and their treatment at the molecular, cellular, and behavioral levels.

Extensive Research Description

While recent large-scale genetic association studies have identified numerous risk loci for PTSD and MDD, the mechanisms through which they contribute to disease remain largely unknown. By applying single cell molecular approaches to the affected tissue (in this case, the human brain), we can uncover novel cellular subpopulations that are associated with these disorders. In parallel, cell type-specific molecular studies allow us to characterize the effect of genetic variation on the complex mechanisms that regulate gene expression in those cells relevant to disease. The goal of our research is to identify causal genes and therapeutic targets relevant to stress-related disorders utilizing human brain derived datasets from frozen postmortem tissue across multiple brain regions and diagnostic groups and couple those with hIPSCs and animal models to understand the neurobiological mechanisms involved.

Current projects include:

  • Cell type-specific genomic atlas of stress disorders- we are currently profiling 2 molecular modalities (transcriptome and epigenome) in 10 human postmortem brain regions across 3 diagnostic cohorts PTSD, MDD, and normal control donors.
  • Functional characterization of PTSD risk variants- here we are expanding upon the rich transcriptomic data generated from our PTSD and MDD postmortem brain tissue by incorporating genome-scale DNA methylation (DNAm) data, alternative splicing, and non-coding RNAs with genetic data to better determine how genetic risk for PTSD and MDD manifests in the human brain.
  • iPSC Functional Validation of PTSD causal genes- we are applying hiPSC-based approaches to manipulate the genotype and/or expression levels of a putative causal risk genes identified in large GWAS and postmortem datasets.
  • Animal models of traumatic and chronic stress- we are validating our molecular findings using a broad array of mouse models and techniques (viral vectors and genetic mutants) in females and males to characterize the behavioral and molecular mechanisms of stress-related disorders.
  • Molecular pathology of suicide- We are identifying cell types, networks, and genes with causal roles in suicide by comparing transcriptomic signatures of PTSD and MDD subjects with or without death by suicide.

Coauthors

Research Interests

Anxiety Disorders; Behavior and Behavior Mechanisms; Genetics; Neurobiology; Neurosciences; Stress Disorders, Post-Traumatic; Stress, Psychological; Suicide; Genomics; Proteomics; Transcriptome

Selected Publications

  • Cortical Transcriptomic Alterations in Association With Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder.Stone LA, Girgenti MJ, Wang J, Ji D, Zhao H, Krystal JH, Duman RS. Cortical Transcriptomic Alterations in Association With Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder. The International Journal Of Neuropsychopharmacology / Official Scientific Journal Of The Collegium Internationale Neuropsychopharmacologicum (CINP) 2021, 24: 118-129. PMID: 32951025, PMCID: PMC8611677, DOI: 10.1093/ijnp/pyaa072.
  • Transcriptomic organization of the human brain in post-traumatic stress disorder.Girgenti MJ, Wang J, Ji D, Cruz DA, Stein MB, Gelernter J, Young KA, Huber BR, Williamson DE, Friedman MJ, Krystal JH, Zhao H, Duman RS. Transcriptomic organization of the human brain in post-traumatic stress disorder. Nature Neuroscience 2021, 24: 24-33. PMID: 33349712, DOI: 10.1038/s41593-020-00748-7.
  • Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program.Stein MB, Levey DF, Cheng Z, Wendt FR, Harrington K, Pathak GA, Cho K, Quaden R, Radhakrishnan K, Girgenti MJ, Ho YA, Posner D, Aslan M, Duman RS, Zhao H, Polimanti R, Concato J, Gelernter J. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program. Nature Genetics 2021, 53: 174-184. PMID: 33510476, PMCID: PMC7972521, DOI: 10.1038/s41588-020-00767-x.
  • Posttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological Sex.Wang J, Zhao H, Girgenti MJ. Posttraumatic Stress Disorder Brain Transcriptomics: Convergent Genomic Signatures Across Biological Sex. Biological Psychiatry 2022, 91: 6-13. PMID: 33840456, DOI: 10.1016/j.biopsych.2021.02.012.
  • Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents.Ghosal S, Duman CH, Liu RJ, Wu M, Terwilliger R, Girgenti MJ, Wohleb E, Fogaca MV, Teichman EM, Hare B, Duman RS. Ketamine rapidly reverses stress-induced impairments in GABAergic transmission in the prefrontal cortex in male rodents. Neurobiology Of Disease 2020, 134: 104669. PMID: 31707118, DOI: 10.1016/j.nbd.2019.104669.
  • GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions.Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS. GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. The Journal Of Clinical Investigation 2020, 130: 1336-1349. PMID: 31743111, PMCID: PMC7269589, DOI: 10.1172/JCI130808.
  • PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies.Bhatt S, Hillmer AT, Girgenti MJ, Rusowicz A, Kapinos M, Nabulsi N, Huang Y, Matuskey D, Angarita GA, Esterlis I, Davis MT, Southwick SM, Friedman MJ, Duman RS, Carson RE, Krystal JH, Pietrzak RH, Cosgrove KP. PTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies. Nature Communications 2020, 11: 2360. PMID: 32398677, PMCID: PMC7217830, DOI: 10.1038/s41467-020-15930-5.
  • Molecular and cellular studies of PTSD: Postmortem transcriptome analysis and novel therapeutic targets.Duman RS, Girgenti MJ. Molecular and cellular studies of PTSD: Postmortem transcriptome analysis and novel therapeutic targets. Journal Of Neuroscience Research 2019, 97: 292-299. PMID: 30136735, DOI: 10.1002/jnr.24306.
  • Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes.Girgenti MJ, Wohleb ES, Mehta S, Ghosal S, Fogaca MV, Duman RS. Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes. Translational Psychiatry 2019, 9: 292. PMID: 31712551, PMCID: PMC6848179, DOI: 10.1038/s41398-019-0642-z.
  • Transcriptome Alterations in Posttraumatic Stress Disorder.Girgenti MJ, Duman RS. Transcriptome Alterations in Posttraumatic Stress Disorder. Biological Psychiatry 2018, 83: 840-848. PMID: 29128043, DOI: 10.1016/j.biopsych.2017.09.023.
  • Analysis of Bulk Tissue Transcriptome Data Reveals Convergence of Cell Types Altered in Schizophrenia and Bipolar Disorder.Girgenti MJ, Duman RS. Analysis of Bulk Tissue Transcriptome Data Reveals Convergence of Cell Types Altered in Schizophrenia and Bipolar Disorder. Biological Psychiatry 2018, 84: 772-774. PMID: 30409264, DOI: 10.1016/j.biopsych.2018.09.014.
  • Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence.Holmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, Matuskey D, Southwick S, Duman RS, Carson RE, Krystal JH, Esterlis I. Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 8390-8395. PMID: 28716937, PMCID: PMC5547601, DOI: 10.1073/pnas.1701749114.
  • Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD.Girgenti MJ, Hare BD, Ghosal S, Duman RS. Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD. Current Psychiatry Reports 2017, 19: 85. PMID: 28944401, PMCID: PMC5907804, DOI: 10.1007/s11920-017-0841-3.
  • Ketamine accelerates fear extinction via mTORC1 signaling.Girgenti MJ, Ghosal S, LoPresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiology Of Disease 2017, 100: 1-8. PMID: 28043916, PMCID: PMC5907920, DOI: 10.1016/j.nbd.2016.12.026.
  • ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2.Girgenti MJ, LoTurco JJ, Maher BJ. ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PloS One 2012, 7: e32404. PMID: 22384243, PMCID: PMC3288100, DOI: 10.1371/journal.pone.0032404.
  • Transcriptomics of the depressed and PTSD brain.Zhang J, Kaye AP, Wang J, Girgenti MJ. Transcriptomics of the depressed and PTSD brain. Neurobiology Of Stress 2021, 15: 100408. PMID: 34703849, PMCID: PMC8524242, DOI: 10.1016/j.ynstr.2021.100408.
  • Stress and Its Impact on the Transcriptome.Girgenti MJ, Pothula S, Newton SS. Stress and Its Impact on the Transcriptome. Biological Psychiatry 2021, 90: 102-108. PMID: 33637305, PMCID: PMC8213869, DOI: 10.1016/j.biopsych.2020.12.011.
  • Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD.Logue MW, Zhou Z, Morrison FG, Wolf EJ, Daskalakis NP, Chatzinakos C, Georgiadis F, Labadorf AT, Girgenti MJ, Young KA, Williamson DE, Zhao X, Grenier JG, Huber BR, Miller MW. Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD. Neurobiology Of Stress 2021, 15: 100398. PMID: 34646915, PMCID: PMC8498459, DOI: 10.1016/j.ynstr.2021.100398.
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