Nenad Sestan, MD, PhD
Harvey and Kate Cushing Professor of Neuroscience, and Professor of Comparative Medicine, of Genetics and of PsychiatryCards
About
Research
Publications
2025
Early developmental origins of cortical disorders modeled in human neural stem cells
Mato-Blanco X, Kim S, Jourdon A, Ma S, Choi S, Giani A, Paredes M, Tebbenkamp A, Liu F, Duque A, Vaccarino F, Sestan N, Colantuoni C, Rakic P, Santpere G, Micali N. Early developmental origins of cortical disorders modeled in human neural stem cells. Nature Communications 2025, 16: 6347. PMID: 40634286, PMCID: PMC12241556, DOI: 10.1038/s41467-025-61316-w.Peer-Reviewed Original ResearchConceptsSingle-cell transcriptomicsNeural stem cellsNeural stem cell lineage commitmentGene regulatory networksEarly developmental originHuman neural stem cellsRegulatory networksExpression dynamicsRisk genesStem cellsCortical disordersTransition in vitroTelencephalic developmentEarly phaseGene dysfunctionLineage commitmentCell trajectoriesHuman corticogenesisHuman brain dysfunctionGenesNSCs in vitroMultiple diseasesIn vivoBrain dysfunctionCorticogenesisHigher dopamine D1 receptor expression in prefrontal parvalbumin neurons underlies higher distractibility in marmosets versus macaques
Joyce M, Ivanov T, Krienen F, Mitchell J, Ma S, Inoue W, Nandy A, Datta D, Duque A, Arellano J, Gupta R, Gonzalez-Burgos G, Lewis D, Sestan N, McCarroll S, Martinez-Trujillo J, Froudist-Walsh S, Arnsten A. Higher dopamine D1 receptor expression in prefrontal parvalbumin neurons underlies higher distractibility in marmosets versus macaques. Communications Biology 2025, 8: 974. PMID: 40594842, PMCID: PMC12214923, DOI: 10.1038/s42003-025-08297-0.Peer-Reviewed Original ResearchConceptsLevels of dopamine D1 receptorDopamine D1 receptor-expressingPV neuronsD1 receptor expressionDopamine D1 receptorsDorsolateral prefrontal cortexModels of cognitionPrefrontal cortexD1 receptorsDistractor resistanceD1R expressionDopaminergic modulationSalient stimuliVisual fixation taskHigh distractionSustained attentionCognitive tasksCognitive performanceInhibitory parvalbuminFunctional microcircuitryPrimate modelDLPFCParvalbumin neuronsFixation taskD1RSingle-cell transcriptomic and chromatin dynamics of the human brain in PTSD
Hwang A, Skarica M, Xu S, Coudriet J, Lee C, Lin L, Terwilliger R, Sliby A, Wang J, Nguyen T, Li H, Wu M, Dai Y, Duan Z, Srinivasan S, Zhang X, Lin Y, Cruz D, Deans P, Huber B, Levey D, Glausier J, Lewis D, Gelernter J, Holtzheimer P, Friedman M, Gerstein M, Sestan N, Brennand K, Xu K, Zhao H, Krystal J, Young K, Williamson D, Che A, Zhang J, Girgenti M. Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD. Nature 2025, 643: 744-754. PMID: 40533550, PMCID: PMC12267058, DOI: 10.1038/s41586-025-09083-y.Peer-Reviewed Original ResearchPost-traumatic stress disorderPrefrontal cortexDorsolateral prefrontal cortexHuman prefrontal cortexTraumatic stress responseHuman brainDepressive disorderStress disorderTrauma exposureCell type-specific contextRegulatory mechanismsGABAergic transmissionCell-type clusteringCell type-specific mannerMolecular regulatory mechanismsGlucocorticoid signalingGene expression changesChromatin dynamicsCredible variantsDisordersTranscriptional regulationEpigenetic dataCortexPersistent effectsPolygenic disorderSpatial transcriptomics reveals human cortical layer and area specification
Qian X, Coleman K, Jiang S, Kriz A, Marciano J, Luo C, Cai C, Manam M, Caglayan E, Lai A, Exposito-Alonso D, Otani A, Ghosh U, Shao D, Andersen R, Neil J, Johnson R, LeFevre A, Hecht J, Micali N, Sestan N, Rakic P, Miller M, Sun L, Stringer C, Li M, Walsh C. Spatial transcriptomics reveals human cortical layer and area specification. Nature 2025, 644: 153-163. PMID: 40369074, PMCID: PMC12328223, DOI: 10.1038/s41586-025-09010-1.Peer-Reviewed Original ResearchNeuronal subtypesMid-gestationHuman fetal cortexExcitatory neuron subtypesCortical layersLayer 4 neuronsCortical areasHuman cortical developmentGestational weeksFetal cortexSingle-nucleus RNA sequencingCortical developmentCerebral cortexSingle-cell transcriptomic studiesHuman cerebral cortexDevelopmental time pointsLaminar distributionAreal specificationCortical arealizationTime pointsSubtypesCortexVisual cortexSingle-cell resolutionCytoarchitectural developmentDecoding human brain evolution: Insights from genomics
Liu Y, Li M, Segal A, Zhang M, Sestan N. Decoding human brain evolution: Insights from genomics. Current Opinion In Neurobiology 2025, 92: 103033. PMID: 40334295, DOI: 10.1016/j.conb.2025.103033.Peer-Reviewed Original ResearchConceptsHuman brain evolutionNonhuman primatesBrain evolutionHigh-throughput functional screeningSingle-cell resolutionAdvanced cognitive abilitiesGenetic basisCognitive abilitiesFunctional screeningGenetic changesGenetic underpinningsBrain featuresLiving relativesHuman-specific featuresComprehensive atlasGenomic profilingHuman brainFunctional specializationMolecular level54. Molecular Specification of Claustro-Amygdalar and Paleocortical Excitatory Neurons and Connectivity
Kaur N, Kovner R, Andrijevic D, Zhu T, Shibata M, Shibata A, Pattabiraman K, Minuer Y, Picciotto M, Huang H, Sestan N. 54. Molecular Specification of Claustro-Amygdalar and Paleocortical Excitatory Neurons and Connectivity. Biological Psychiatry 2025, 97: s117. DOI: 10.1016/j.biopsych.2025.02.291.Peer-Reviewed Original ResearchMechanisms and strategies for organ recovery
Andrijevic D, Spajic A, Hameed I, Sheth K, Parnia S, Griesemer A, Montgomery R, Sestan N. Mechanisms and strategies for organ recovery. Nature Reviews Bioengineering 2025, 3: 596-611. DOI: 10.1038/s44222-025-00293-7.Peer-Reviewed Original ResearchMechanisms of cellular injuryPerfusion systemHeart-lung machineSecondary cellular damageDecreased ATP productionIntracellular acidosisOrgan transplantationViability of mammalian cellsCirculating perfusateOxygen deliveryBlood supplyCellular injuryBlood flowInjured tissuePerfusionRestore circulationPharmacological compoundsIn vitroCell deathCellular demiseMammalian cellsATP productionResuscitation medicineOrgan recoveryBiological mechanismsSpecification of claustro-amygdalar and palaeocortical neurons and circuits
Kaur N, Kovner R, Gulden F, Pletikos M, Andrijevic D, Zhu T, Silbereis J, Shibata M, Shibata A, Liu Y, Ma S, Salla N, de Martin X, Klarić T, Burke M, Franjic D, Cho H, Yuen M, Chatterjee I, Soric P, Esakkimuthu D, Moser M, Santpere G, Mineur Y, Pattabiraman K, Picciotto M, Huang H, Sestan N. Specification of claustro-amygdalar and palaeocortical neurons and circuits. Nature 2025, 638: 469-478. PMID: 39814878, PMCID: PMC11821539, DOI: 10.1038/s41586-024-08361-5.Peer-Reviewed Original ResearchConceptsBasolateral amygdala complexPrefrontal cortex connectivityPrefrontal cortexNeuropsychiatric disordersExcitatory neuronsSymptoms of neuropsychiatric disordersEarly-life disruptionAmygdala complexPiriform cortexTemporal cortexDevelopmental shiftReciprocal connectionsCortexClaustrumBehavior modificationSensory informationTranscription factor SOX4DisordersTfap2dNeuronsSimilar alterationsCross-species analysisPiriformSOX11Transcription factorsThe human and non-human primate developmental GTEx projects
Bell T, Blanchard T, Hernandez R, Linn R, Taylor D, VonDran M, Ahooyi T, Beitra D, Bernieh A, Delaney M, Faith M, Fattahi E, Footer D, Gilbert M, Guambaña S, Gulino S, Hanson J, Hattrell E, Heinemann C, Kreeb J, Leino D, Mcdevitt L, Palmieri A, Pfeiffer M, Pryhuber G, Rossi C, Rasool I, Roberts R, Salehi A, Savannah E, Stachowicz K, Stokes D, Suplee L, Van Hoose P, Wilkins B, Williams-Taylor S, Zhang S, Ardlie K, Getz G, Lappalainen T, Montgomery S, Aguet F, Anderson L, Bernstein B, Choudhary A, Domenech L, Gaskell E, Johnson M, Liu Q, Marderstein A, Nedzel J, Okonda J, Padhi E, Rosano M, Russell A, Walker B, Sestan N, Gerstein M, Milosavljevic A, Borsari B, Cho H, Clarke D, Deveau A, Galeev T, Gobeske K, Hameed I, Huttner A, Jensen M, Jiang Y, Li J, Liu J, Liu Y, Ma J, Mane S, Meng R, Nadkarni A, Ni P, Park S, Petrosyan V, Pochareddy S, Salamon I, Xia Y, Yates C, Zhang M, Zhao H, Conrad D, Feng G, Brady F, Boucher M, Carbone L, Castro J, del Rosario R, Held M, Hennebold J, Lacey A, Lewis A, Lima A, Mahyari E, Moore S, Okhovat M, Roberts V, de Castro S, Wessel B, Zaniewski H, Zhang Q, Arguello A, Baroch J, Dayal J, Felsenfeld A, Ilekis J, Jose S, Lockhart N, Miller D, Minear M, Parisi M, Price A, Ramos E, Zou S. The human and non-human primate developmental GTEx projects. Nature 2025, 637: 557-564. PMID: 39815096, PMCID: PMC12013525, DOI: 10.1038/s41586-024-08244-9.Peer-Reviewed Original ResearchConceptsChromatin accessibility dataFunctional genomic studiesWhole-genome sequencingEffects of genetic variationSpatial gene expression profilesNon-human primatesGenotype-Tissue ExpressionGene expression profilesGenomic studiesGene regulationGenetic dataGenetic variationGenomic researchDonor diversityCommunity engagementHuman evolutionEarly developmental defectsGene expressionCell statesDevelopmental programmeHuman diseasesExpression profilesAdult tissuesDevelopmental defectsSingle-cellDysregulation of mTOR signalling is a converging mechanism in lissencephaly
Zhang C, Liang D, Ercan-Sencicek A, Bulut A, Cortes J, Cheng I, Henegariu O, Nishimura S, Wang X, Peksen A, Takeo Y, Caglar C, Lam T, Koroglu M, Narayanan A, Lopez-Giraldez F, Miyagishima D, Mishra-Gorur K, Barak T, Yasuno K, Erson-Omay E, Yalcinkaya C, Wang G, Mane S, Kaymakcalan H, Guzel A, Caglayan A, Tuysuz B, Sestan N, Gunel M, Louvi A, Bilguvar K. Dysregulation of mTOR signalling is a converging mechanism in lissencephaly. Nature 2025, 638: 172-181. PMID: 39743596, PMCID: PMC11798849, DOI: 10.1038/s41586-024-08341-9.Peer-Reviewed Original ResearchP53-induced death domain protein 1Miller-Dieker lissencephaly syndromeMolecular mechanismsDysregulation of protein translationDysregulation of mTOR signalingDomain protein 1Activity of mTOR complexesMTOR pathwayRelevant molecular mechanismsProtein translationHuman lissencephalyClinically relevant molecular mechanismsRecessive mutationsRare mutationsMiller-DiekerGene expressionCerebral cortex developmentMTOR complexesSpectrum disorderMolecular defectsMTOR signalingCongenital brain malformationsProtein 1GeneticsAssociated with epilepsy
Academic Achievements & Community Involvement
News & Links
News
- October 23, 2025
2025 Yale-KU Forum: Clinical and Basic Neuroscience
- July 10, 2024
Highlighting Yale’s Neuroscience Research
- July 03, 2024
Bandler Honored with 2024 National Institute of Mental Health Outstanding Resident Award
- October 26, 2023Source: Yale News
Researchers Identify Key Genes in the Development of the Primate Brain
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Mar 20262Monday
Yale Only Morgan Sheng, MD, PhD