Biology subjects

Girgenti, M. J.

Publications and source records attributed to Girgenti, M. J..

5 recordsLinked to original sources

bioRxiv2025

Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression

There is growing interest to investigate classic psychedelics and ketamine as therapeutics for mental illnesses. Previous studies have demonstrated that one dose of psilocybin or ketamine leads to persisting neural and behavioral changes. The durability of these effects suggests that there are likely alterations in gene expression at the transcriptional level. In this study, we performed single-nucleus RNA sequencing of the dorsal medial frontal cortex of male and female mice. Samples were collected at 1, 2, 4, 24, or 72 hours after psilocybin or ketamine administration and from control animals. At baseline, major subtypes of excitatory and GABAergic neurons selectively express particular serotonin receptor transcripts. The psilocybin-evoked differentially expressed genes in excitatory neurons are involved in synaptic plasticity, distinct from genes enriched in GABAergic neurons, which contribute to mitochondrial function and cellular metabolism, and non-neuronal glial cells. The effect of psilocybin on gene expression is time-dependent, including an early phase at 1 hour followed by a late phase at 72 hours of transcriptional response after administration, and differs from the changes following ketamine administration, which peaks at 2 - 4 hours. Collectively, the results provide a resource for understanding the cell type-specific and time-dependent changes in gene expression induced by psilocybin and ketamine in the mouse medial frontal cortex, which may underpin the drugs long-term effects on neural circuits and behavior.

neuroscience↗

bioRxiv2024

Decoding the transcriptomic signatures of psychological trauma in human cortex and amygdala

Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex. Overall, amygdala regions were more vulnerable to childhood traumas, whereas cortical regions were more vulnerable to adulthood trauma (regardless of childhood experience). Using cell-type-specific expression imputation, we identified a strong transcriptional response of medial amygdala excitatory neurons to childhood trauma, which coincided with dysregulation observed in a human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons exposed to hydrocortisone. We resolved multiscale coexpression networks for each brain region and identified modules enriched in trauma signatures and whose connectivity was altered with trauma. Trauma-associated coexpression modules provide insight into coordinated functional dysregulation with different traumas and point to potential gene targets for further dissection. Together, these data provide a characterization of the long-lasting human encoding of traumatic experiences in corticolimbic regions of human brain.

neuroscience↗

bioRxiv2023

Common genetic variation impacts molecular stress response in the brain

To explain why individuals exposed to identical stressors experience divergent clinical outcomes, we determine how molecular encoding of stress modifies genetic risk for brain disorders. Analysis of post-mortem brain (n=304) revealed 8557 stress-interactive expression quantitative trait loci (eQTLs) that dysregulate expression of 915 eGenes in response to stress, and lie in stress-related transcription factor binding sites. Response to stress is robust across experimental paradigms: up to 50% of stress-interactive eGenes validate in glucocorticoid treated hiPSC-derived neurons (n=39 donors). Stress-interactive eGenes show brain region- and cell type-specificity, and, in post-mortem brain, implicate glial and endothelial mechanisms. Stress dysregulates long-term expression of disorder risk genes in a genotype-dependent manner; stress-interactive transcriptomic imputation uncovered 139 novel genes conferring brain disorder risk only in the context of traumatic stress. Molecular stress-encoding explains individualized responses to traumatic stress; incorporating trauma into genomic studies of brain disorders is likely to improve diagnosis, prognosis, and drug discovery. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/573459v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1e07fa9org.highwire.dtl.DTLVardef@1dd530forg.highwire.dtl.DTLVardef@17822a5org.highwire.dtl.DTLVardef@2a889f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2020

Transcriptomic Organization of Human Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in extreme stress groups, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. Here differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. We also identified marked sexual dimorphism in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and depression despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans.

genomics↗

bioRxiv2019

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to re-experiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 - 0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

genetics↗