2024
Characterizing the Most Vulnerable Prefrontal Cortical Neurons in Schizophrenia
Arnsten A, Datta D. Characterizing the Most Vulnerable Prefrontal Cortical Neurons in Schizophrenia. American Journal Of Psychiatry 2024, 181: 861-864. PMID: 39350618, DOI: 10.1176/appi.ajp.20240731.Peer-Reviewed Original Research
2022
The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion
Arnsten A, Joyce M, Roberts A. The Aversive Lens: Stress effects on the prefrontal-cingulate cortical pathways that regulate emotion. Neuroscience & Biobehavioral Reviews 2022, 145: 105000. PMID: 36529312, PMCID: PMC9898199, DOI: 10.1016/j.neubiorev.2022.105000.Peer-Reviewed Original ResearchConceptsCortical pathwaysStress exposureDendritic spine lossChronic stress exposureAnti-depressant treatmentDeep brain stimulationPrefrontal cortical areasExcessive dopamineNeuromodulatory treatmentSSRI medicationNorepinephrine releaseSpine lossSubgenual cingulateCortical areasBrain stimulationChronic stressBA25MedicationsDorsolateral PFCTreatmentExposurePsychic painPainKetamineSymptoms
2020
Muscarinic M1 Receptors Modulate Working Memory Performance and Activity via KCNQ Potassium Channels in the Primate Prefrontal Cortex
Galvin VC, Yang ST, Paspalas CD, Yang Y, Jin LE, Datta D, Morozov YM, Lightbourne TC, Lowet AS, Rakic P, Arnsten AFT, Wang M. Muscarinic M1 Receptors Modulate Working Memory Performance and Activity via KCNQ Potassium Channels in the Primate Prefrontal Cortex. Neuron 2020, 106: 649-661.e4. PMID: 32197063, PMCID: PMC7244366, DOI: 10.1016/j.neuron.2020.02.030.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFemaleKCNQ Potassium ChannelsMacaca mulattaMaleMemory, Short-TermNeuronsPrefrontal CortexReceptor, Muscarinic M1ConceptsKCNQ channelsInverted-U dose responseCell firingPrefrontal cortexMuscarinic M1 receptorsKCNQ potassium channelsSingle-unit recordingsPrimate prefrontal cortexDorsolateral prefrontal cortexCholinergic alterationsKCNQ isoformsM1 receptorsPyramidal neuronsCholinergic depletionMuscarinic M1Cognitive disordersAged monkeysPersistent firingRecurrent excitationPotassium channelsAppropriate targetsDose responseM1R stimulationSensory inputCortex
2019
Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex
Datta D, Yang ST, Galvin VC, Solder J, Luo F, Morozov YM, Arellano J, Duque A, Rakic P, Arnsten A, Wang M. Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex. Journal Of Neuroscience 2019, 39: 2722-2734. PMID: 30755491, PMCID: PMC6445993, DOI: 10.1523/jneurosci.2472-18.2019.Peer-Reviewed Original ResearchConceptsΑ1-AR stimulationPosttraumatic stress disorderExcitatory effectsNeuronal firingDorsolateral prefrontal cortexBasal conditionsPrefrontal cortexΑ1-ARΑ1-adrenoceptorsInverted-U dose responseUncontrollable stressStress disorderTreatment of PTSDPrimate dorsolateral prefrontal cortexΑ1-AR expressionMajority of neuronsΑ1-AR agonistsPrefrontal cortical physiologyNoradrenergic releasePresynaptic excitationEndogenous NEPostsynaptic actionsExcitatory actionGlutamate releaseAxon terminals
2017
The aged rhesus macaque manifests Braak stage III/IV Alzheimer's‐like pathology
Paspalas CD, Carlyle BC, Leslie S, Preuss TM, Crimins JL, Huttner AJ, van Dyck C, Rosene DL, Nairn AC, Arnsten AFT. The aged rhesus macaque manifests Braak stage III/IV Alzheimer's‐like pathology. Alzheimer's & Dementia 2017, 14: 680-691. PMID: 29241829, PMCID: PMC6178089, DOI: 10.1016/j.jalz.2017.11.005.Peer-Reviewed Original ResearchConceptsLate-onset Alzheimer's diseaseCortical pathologyEntorhinal cortexAnimal modelsBraak stage III/IVAlzheimer's diseaseStage III/IVRhesus macaquesProgression of tauAlzheimer-like pathologyPrimary visual cortexSequence of tauDorsolateral prefrontal cortexTau pathologyPreventive strategiesAssociation cortexVisual cortexPrefrontal cortexCortexPathologyDiseaseOld animalsProtein kinase A (PKA) phosphorylationGenetic insultsMacaquesmGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks
Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AF, Paspalas CD. mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks. Cerebral Cortex 2017, 28: 974-987. PMID: 28108498, PMCID: PMC5974790, DOI: 10.1093/cercor/bhx005.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsDose-Response Relationship, DrugExcitatory Amino Acid AgentsEye MovementsFemaleImage Processing, Computer-AssistedMacaca mulattaMagnetic Resonance ImagingMaleMemory, Short-TermNeuronsPost-Synaptic DensityPrefrontal CortexRatsReceptors, Metabotropic GlutamateSpatial LearningSubcellular FractionsConceptsPrimate dorsolateral prefrontal cortexMetabotropic glutamate receptorsDorsolateral prefrontal cortexGlutamate receptorsCell firingPrefrontal cortexMGluR2 positive allosteric modulatorsFocus of pathologyNovel therapeutic targetPositive allosteric modulatorsMGluR3 agonistGlutamate transmissionAstrocytic expressionGlial receptorsPostsynaptic componentsSpine synapsesInhibition of cAMPN-acetylaspartylglutamateMGluR3Therapeutic targetCognitive disordersLayer IIIMGluR2Postsynaptic cAMPAlzheimer's disease
2015
Stress weakens prefrontal networks: molecular insults to higher cognition
Arnsten AF. Stress weakens prefrontal networks: molecular insults to higher cognition. Nature Neuroscience 2015, 18: 1376-1385. PMID: 26404712, PMCID: PMC4816215, DOI: 10.1038/nn.4087.Peer-Reviewed Original ResearchDopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders
Arnsten AF, Wang M, Paspalas CD. Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders. Pharmacological Reviews 2015, 67: 681-696. PMID: 26106146, PMCID: PMC4485014, DOI: 10.1124/pr.115.010512.Peer-Reviewed Original ResearchConceptsCell firingPyramidal cell dendritesD2 receptor familyFrontal eye fieldPrimate prefrontal cortexGABA interneuronsCortical dopamineDopamine actionGlutamate releaseEndogenous dopamineDA cellsCell dendritesD1R agonistDendritic spinesCognitive disordersOrbital PFCEye fieldPositive symptomsLikely projectResponse cellsCognitive deficitsPrefrontal cortexStimulation speedFeedback neuronsD1R
2014
A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation
McKee SA, Potenza MN, Kober H, Sofuoglu M, Arnsten A, Picciotto MR, Weinberger AH, Ashare R, Sinha R. A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. Journal Of Psychopharmacology 2014, 29: 300-311. PMID: 25516371, PMCID: PMC4376109, DOI: 10.1177/0269881114562091.Peer-Reviewed Original ResearchConceptsPlacebo-treated subjectsFunctional magnetic resonance imagingCentral noradrenergic pathwaysPrefrontal cognitive dysfunctionSystolic blood pressureClinical outcome dataAd libitum smokingNovel translational approachStress-induced reinstatementMagnetic resonance imagingNicotine-deprived smokersBlood pressureNoradrenergic pathwaysAgonist guanfacineCognitive dysfunctionTreatment periodTobacco cravingQuit attemptsOutcome dataSmokingComplete abstinenceCortisol levelsTranslational investigationsCigarette useGuanfacinecAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex
Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE, Simen AA, Ramos BP, Bordner KA, Craft GE, Davies P, Pletikos M, Šestan N, Arnsten AF, Paspalas CD. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 5036-5041. PMID: 24707050, PMCID: PMC3977284, DOI: 10.1073/pnas.1322360111.Peer-Reviewed Original ResearchConceptsNeurofibrillary tanglesAssociation cortexAlzheimer's diseaseSpine apparatusPhosphorylated tauPattern of neurodegenerationLate-stage diseaseHigh-risk factorsNormal aged miceGenetic rodent modelsPrefrontal association cortexPrimary sensory cortexPrimary visual cortexAge-related increasePyramidal neuronsCorticocortical connectionsAged miceRisk factorsGlutamate synapsesSpine synapsesSelective vulnerabilityRodent modelsDendritic spinesSensory cortexProtein kinase phosphorylation
2013
Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex
Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 12078-12083. PMID: 23818597, PMCID: PMC3718126, DOI: 10.1073/pnas.1307849110.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcholineAconitineAlpha7 Nicotinic Acetylcholine ReceptorAnalysis of VarianceAnimalsBridged Bicyclo Compounds, HeterocyclicCholinergic AgonistsCholinergic AntagonistsCognitionFemaleIontophoresisMacaca mulattaMaleMecamylamineMicroscopy, ImmunoelectronN-MethylaspartatePhenolsPiperidinesPrefrontal CortexQuinuclidinesReceptors, NicotinicSpatial BehaviorSynapsesVisual PerceptionConceptsDorsolateral prefrontal cortexΑ7 nAChRsPrefrontal cortexΑ7 nicotinic acetylcholine receptorGlutamatergic NMDA receptorsCognitive circuitsNicotinic α7 receptorsPrimary visual cortexNMDA receptor actionGenetic insultsNicotinic acetylcholine receptorsDlPFC circuitsPrimate dlPFCACh depletionNMDA actionNMDA receptorsPyramidal cellsΑ7 receptorsNeuronal firingNAChR blockadeAcetylcholine receptorsVisual cortexPersistent firingCognitive functionLow-dose stimulationNMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex
Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF. NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex. Neuron 2013, 77: 736-749. PMID: 23439125, PMCID: PMC3584418, DOI: 10.1016/j.neuron.2012.12.032.Peer-Reviewed Original ResearchConceptsPersistent firingDorsolateral prefrontal cortexAMPA receptorsPrefrontal cortexPrimate dorsolateral prefrontal cortexSystemic ketamine administrationPersistent neuronal firingAMPAR blockadePrimate dlPFCKetamine actionKetamine administrationNMDAR blockadeNMDA receptorsSystemic ketamineNetwork firingNeuronal firingAlzheimer's diseaseReceptor influencesImpair cognitionResponse cellsRecurrent excitationSensory stimulation
2012
Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses
Arnsten AF, Wang MJ, Paspalas CD. Neuromodulation of Thought: Flexibilities and Vulnerabilities in Prefrontal Cortical Network Synapses. Neuron 2012, 76: 223-239. PMID: 23040817, PMCID: PMC3488343, DOI: 10.1016/j.neuron.2012.08.038.Peer-Reviewed Original ResearchGuanfacine for the treatment of cognitive disorders: a century of discoveries at Yale.
Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. The Yale Journal Of Biology And Medicine 2012, 85: 45-58. PMID: 22461743, PMCID: PMC3313539.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCognition DisordersDrug DiscoveryGuanfacineHistory, 20th CenturyHumansMemory, Short-TermPrefrontal CortexUniversitiesConceptsAttention deficit hyperactivity disorderPrefrontal cortexCognitive disordersHigher-order cognitive abilitiesDeficit hyperactivity disorderPFC cognitive functionCognitive abilitiesHyperactivity disorderCognitive functionMemory functionPFC functionAgonist guanfacineBrain regionsGuanfacineRecent researchNeurobiologyYale Medical SchoolCentury of discoveryDisordersTherapeutic targetTourette syndromePostsynaptic spinesEmotionsMemorySyndrome
2010
The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder
Arnsten A. The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Review Of Neurotherapeutics 2010, 10: 1595-1605. PMID: 20925474, PMCID: PMC3143019, DOI: 10.1586/ern.10.133.Peer-Reviewed Original ResearchConceptsAttention-deficit/hyperactivity disorderPrefrontal cortexHyperactivity disorderPFC functionPFC gray matterPFC pyramidal cellsPyramidal cell networksDorsolateral prefrontal cortexPFC connectionsReceptors inhibitsPyramidal cellsAdrenergic agonistsDendritic spinesVentromedial prefrontal cortexGray matterRelated disordersBrain regionsNeuropsychiatric disordersPotassium channelsDisordersPatientsRecent dataPhysiological connectionTreatmentExecutive functioningDynamic Network Connectivity: A new form of neuroplasticity
Arnsten AF, Paspalas CD, Gamo NJ, Yang Y, Wang M. Dynamic Network Connectivity: A new form of neuroplasticity. Trends In Cognitive Sciences 2010, 14: 365-375. PMID: 20554470, PMCID: PMC2914830, DOI: 10.1016/j.tics.2010.05.003.Peer-Reviewed Original Research
2009
Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience 2009, 10: 410-422. PMID: 19455173, PMCID: PMC2907136, DOI: 10.1038/nrn2648.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrain ChemistryHumansNerve NetNeural PathwaysPrefrontal CortexSignal TransductionStress, PsychologicalConceptsPrefrontal functionMemory abilityUncontrollable stressPrefrontal cortex structurePrefrontal pyramidal cellsControl of behaviorCognitive abilitiesEmotional operationsPrefrontal networkImpair performanceMental illnessPrefrontal dysfunctionPrefrontal cortexPrefrontal gray matterPrefrontal neuronsMemory functionStress impairsPersistent firingNeurochemical environmentStress exposureNeurochemical eventsCortex structureHigh levelsEmotionsChronic stress
2007
α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex
Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF. α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex. Cell 2007, 129: 397-410. PMID: 17448997, DOI: 10.1016/j.cell.2007.03.015.Peer-Reviewed Original ResearchConceptsHCN channel blockadePrefrontal cortical neuronsDelay-related firingΑ2A adrenoceptorsChannel blockadeCortical neuronsInhibition of cAMPAlpha2A adrenoceptorsDendritic spinesNetwork firingElectrophysiological studiesPFC neuronsRecurrent excitationFunctional connectivityHCN channelsPrefrontal cortexHCN1 channelsPFC networksCAMP inhibitionStimulationBlockadeInverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nature Neuroscience 2007, 10: 376-384. PMID: 17277774, DOI: 10.1038/nn1846.Peer-Reviewed Original ResearchAction PotentialsAnalysis of VarianceAnimalsBehavior, AnimalCyclic AMPDopamine AgentsDose-Response Relationship, DrugDrug InteractionsIontophoresisMacaca mulattaMaleMaze LearningMemory, Short-TermNeuronsNeuropsychological TestsPrefrontal CortexRatsRats, Sprague-DawleyReceptors, Dopamine D1Sensitivity and SpecificityThionucleotides
2000
The Selective Dopamine D4 Receptor Antagonist, PNU-101387G, Prevents Stress-Induced Cognitive Deficits in Monkeys
Arnsten A, Murphy B, Merchant K. The Selective Dopamine D4 Receptor Antagonist, PNU-101387G, Prevents Stress-Induced Cognitive Deficits in Monkeys. Neuropsychopharmacology 2000, 23: 405-410. PMID: 10989267, DOI: 10.1016/s0893-133x(00)00133-0.Peer-Reviewed Original ResearchConceptsD4 receptor antagonistReceptor mechanismsReceptor antagonistDopamine D1 receptor mechanismsStress-induced cognitive dysfunctionPrefrontal cortexSelective dopamine D4 receptor antagonistSelective D4 receptor antagonistD1 receptor mechanismsDose-related reversalDopamine D4 receptor antagonistCognitive dysfunctionPharmacological stressorHigh dosesLow dosesMemory deficitsCognitive deficitsStress exposureFurther studiesCognitive functioningAntagonistFG7142DosesPreliminary findingsMonkeys