2022
Molecular and cellular evolution of the primate dorsolateral prefrontal cortex
Ma S, Skarica M, Li Q, Xu C, Risgaard RD, Tebbenkamp ATN, Mato-Blanco X, Kovner R, Krsnik Ž, de Martin X, Luria V, Martí-Pérez X, Liang D, Karger A, Schmidt DK, Gomez-Sanchez Z, Qi C, Gobeske KT, Pochareddy S, Debnath A, Hottman CJ, Spurrier J, Teo L, Boghdadi AG, Homman-Ludiye J, Ely JJ, Daadi EW, Mi D, Daadi M, Marín O, Hof PR, Rasin MR, Bourne J, Sherwood CC, Santpere G, Girgenti MJ, Strittmatter SM, Sousa AMM, Sestan N. Molecular and cellular evolution of the primate dorsolateral prefrontal cortex. Science 2022, 377: eabo7257. PMID: 36007006, PMCID: PMC9614553, DOI: 10.1126/science.abo7257.Peer-Reviewed Original ResearchConceptsMolecular differencesSingle-nucleus transcriptomesSubset of speciesNeuropsychiatric risk genesCellular evolutionCellular repertoireEvolutionary specializationDorsolateral prefrontal cortexRate-limiting enzymeDivergent featuresRisk genesAnthropoid primatesPrefrontal cortexPrimate dorsolateral prefrontal cortexCertain interneuronsNeuropeptide somatostatinDopamine productionGranular neuronsTyrosine hydroxylaseCell subtypesExpressionTranscriptomeAdult humansGenesPrimatesPositive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear
Lee B, Pothula S, Wu M, Kang H, Girgenti MJ, Picciotto MR, DiLeone RJ, Taylor JR, Duman RS. Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear. Molecular Psychiatry 2022, 27: 2580-2589. PMID: 35418600, PMCID: PMC9135632, DOI: 10.1038/s41380-022-01498-7.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderFear extinctionInfralimbic medial prefrontal cortexFear conditioning modelEnhanced fear extinctionFear-based behaviorsProlonged stress modelMedial prefrontal cortexSpontaneous recoveryIL-mPFCPTSD modelPTSD treatmentStress disorderPrefrontal cortexSPS modelN-methyl-D-aspartate receptor modulatorsBrain-derived neurotrophic factorN-methyl-D-aspartate receptorsBehavioral effectsIncreased attentionMPFCPreclinical findingsPyramidal neuronsNeurotrophic factorMale mice
2020
Stress and Its Impact on the Transcriptome
Girgenti MJ, Pothula S, Newton SS. Stress and Its Impact on the Transcriptome. Biological Psychiatry 2020, 90: 102-108. PMID: 33637305, PMCID: PMC8213869, DOI: 10.1016/j.biopsych.2020.12.011.Peer-Reviewed Original ResearchConceptsTranscriptomic dysregulationMajor gene expression changesGene expression changesDevelopmental time pointsAnimal modelsGenomic studiesNeuropsychiatric disordersTranscriptomic methodsAnimal kingdomComparable animal modelsGene expressionExpression changesEarly life stressPhenotypic signaturesSex-specific changesTransgenerational impactTranscriptomeSingle cellsEntire brain regionsPowerful approachDiseased brainBrain regionsChronic stressMolecular profileSame disorderGABA 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. Journal Of Clinical Investigation 2020, 130: 1336-1349. PMID: 31743111, PMCID: PMC7269589, DOI: 10.1172/jci130808.Peer-Reviewed Original ResearchConceptsRapid antidepressant actionsAntidepressant actionGABA interneuronsMedial prefrontal cortexCell-specific knockdownPrinciple neuronsPrefrontal cortexDeletion of GluN2BSingle subanesthetic doseBehavioral actionsAction of ketamineNMDA receptor antagonistExcitatory postsynaptic currentsCellular triggersMajor unmet needKetamine's rapid antidepressant actionsGABA subtypeGluN2B-NMDARsSST interneuronsPostsynaptic currentsReceptor antagonistDepressed patientsSubanesthetic doseExtracellular glutamateMood disorders
2019
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.Peer-Reviewed Original ResearchConceptsFluorescence-activated cell sortingInitiation factor 2Distinct transcriptome profilesTranslational machineryTranscriptome profilesEnriched pathwaysTranscriptional pathwaysTranscriptional profilesRNA sequencingDepressive-like behaviorSST interneuronsKey pathwaysChronic stressInterneuron subtypesSex-specific differencesPrefrontal cortexCell sortingSignificant dysregulationFactor 2PathwayStress-induced depressive-like behaviorDecreased expressionReporter miceGrowth factorNon-stressed femalesKetamine 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 2019, 134: 104669. PMID: 31707118, DOI: 10.1016/j.nbd.2019.104669.Peer-Reviewed Original ResearchConceptsChronic unpredictable stressMedial prefrontal cortexInhibitory post-synaptic currentsGABAergic transmissionSingle doseMale rodentsPrefrontal cortexImbalance of inhibitoryMPFC pyramidal neuronsDepressive-like behaviorDepression-like behaviorStress-induced impairmentModel of depressionPost-synaptic currentsPrecise cellular mechanismsGABAergic proteinsAntidepressant ketamineSynaptic deficitsGABAergic synapsesPyramidal neuronsSynaptic markersGABA markersGlutamate neurotransmissionDepressive behaviorGABA neurotransmission
2018
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 2018, 97: 292-299. PMID: 30136735, DOI: 10.1002/jnr.24306.Peer-Reviewed Original ResearchConceptsFear memoryPrefrontal cortexPTSD patientsFear memory processesNeurobiology of PTSDMemory processesInhibitory controlNeurobiological underpinningsPFC subregionsPTSD subjectsPTSDMemory studiesBrain regionsMemorySpecific gene expression alterationsNovel therapeutic targetPostmortem brain tissueEfficacious treatmentNeurobiologySynaptic alterationsSynapse numberEarlier findingsRodent modelsTherapeutic targetGene expression alterations
2017
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.Peer-Reviewed Original ResearchConceptsPathophysiology of PTSDPreclinical modelsReviewPosttraumatic stress disorderPeripheral blood studiesMolecular changesGlucocorticoid receptor signalingPrimary brain regionsPeripheral bloodInflammatory systemBlood studiesGlucocorticoid signalingHuman studiesPTSD patientsMolecular alterationsBrain regionsStress disorderAltered gene expressionPathophysiologyReceptor signalingCellular pathophysiologyNeurobiological determinantsCellular effectsMechanistic evidencePTSDPatients
2016
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 2016, 100: 1-8. PMID: 28043916, PMCID: PMC5907920, DOI: 10.1016/j.nbd.2016.12.026.Peer-Reviewed Original ResearchConceptsPost-traumatic stress disorderMedial prefrontal cortexTreatment of PTSDFear conditioningRetrieval of extinctionExpression of extinctionActivity-dependent effectsTraumatic memoriesStress disorderExtinction exposurePTSD patientsPrefrontal cortexEffects of ketamineGlutamate NMDA receptor antagonistSymptom severityConditioningInfusion of ketamineExtinctionCuesRodent modelsMemoryKetamine administrationReceptor antagonistPresent studyNMDA receptor antagonist
2012
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.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCatechol O-MethyltransferaseCell NucleusCyclic Nucleotide Phosphodiesterases, Type 4Gene Expression ProfilingGene Expression RegulationGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansImmunohistochemistryKruppel-Like Transcription FactorsRatsReceptors, Dopamine D2Recombinant ProteinsSchizophreniaSerine EndopeptidasesStem CellsTranscription, GeneticConceptsC2H2-type zinc finger domainsTranscript levelsPromoter regionGenome-wide statistical significanceZinc finger domainChromatin immunoprecipitation assaysWide association studyAmino acid sequenceRat neural progenitor cellsNeural progenitor cellsTranscriptional networksMolecular functionsTranscriptional controlSingle nucleotide polymorphismsImmunoprecipitation assaysDNA bindingAcid sequenceTranscription levelsAssociation studiesGenesNucleotide polymorphismsProgenitor cellsZNF804ATranscriptionDirect upregulation