2022
AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids
Endle H, Horta G, Stutz B, Muthuraman M, Tegeder I, Schreiber Y, Snodgrass IF, Gurke R, Liu ZW, Sestan-Pesa M, Radyushkin K, Streu N, Fan W, Baumgart J, Li Y, Kloss F, Groppa S, Opel N, Dannlowski U, Grabe HJ, Zipp F, Rácz B, Horvath TL, Nitsch R, Vogt J. AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids. Nature Metabolism 2022, 4: 683-692. PMID: 35760867, PMCID: PMC9940119, DOI: 10.1038/s42255-022-00589-7.Peer-Reviewed Original ResearchConceptsFasting-induced hyperphagiaCortical excitabilityAgRP neuronsLysophosphatidic acidPeripheral metabolismHigher body mass indexFasting-induced elevationHypothalamic AgRP neuronsEffects of LPABody mass indexHigher cortical excitabilityBrain lipid levelsCentral nervous systemPrevalence of typeGlutamatergic transmissionHypothalamic agoutiMass indexOvernight fastingPeptide neuronsCortical synapsesLipid levelsFood intakeCerebrospinal fluidNervous systemPhospholipid levels
2021
Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior
Yasumoto Y, Stoiljkovic M, Kim JD, Sestan-Pesa M, Gao XB, Diano S, Horvath TL. Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior. Molecular Psychiatry 2021, 26: 2740-2752. PMID: 33879866, PMCID: PMC8056795, DOI: 10.1038/s41380-021-01105-1.Peer-Reviewed Original ResearchConceptsAnxiety-like behaviorReactive oxygen speciesMicroglia-synapse contactsSpine synapse numberHippocampal circuit functionNeuronal circuit dysfunctionMicroglial productionVentral hippocampusCircuit dysfunctionSpine synapsesSynapse numberAdult brainTransient riseMitochondrial ROS generationMicrogliaBrain functionConditional ablationPhagocytic inclusionsSynaptic elementsProtein 2ROS generationSignificant reductionCircuit functionConsequent accumulationOxygen species
2016
Mitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus
Varela L, Schwartz ML, Horvath TL. Mitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus. Neurobiology Of Disease 2016, 90: 68-74. PMID: 26777666, DOI: 10.1016/j.nbd.2016.01.004.Peer-Reviewed Original ResearchConceptsHippocampal neuronsMitochondria-endoplasmic reticulum interactionUCP2-KO miceEarly postnatal exposureLoss of synapsesOxygen tensionHigher brain regionsAdaptive mitochondrial responsesProtein 2 expressionHypothalamic circuitsPostnatal exposureKO miceSynaptic remodelingSystemic metabolismSynaptic inputsBrain cellsMetabolic controlNeuronal mitochondriaBrain regionsAdaptive responseNeuronsHippocampusMitochondrial dynamicsMetabolic challengesCortex
2015
Synaptic lipids in cortical function and psychiatric disorders
Stutz B, Horvath TL. Synaptic lipids in cortical function and psychiatric disorders. EMBO Molecular Medicine 2015, 8: 3-5. PMID: 26671988, PMCID: PMC4718156, DOI: 10.15252/emmm.201505749.Peer-Reviewed Original ResearchConceptsPsychiatric disordersClinical therapeutic strategiesPathophysiologic mechanismsCortical circuitryCortical functionExcitatory neuronsTherapeutic strategiesAnimal modelsReliable biomarkersPsychiatric diseasesPsychiatric consequencesEMBO Molecular MedicinePsychiatric conditionsMillions of peopleHuman subjectsCircuit functionDisordersLipidsMolecular medicinePatientsPathophysiologyEtiologyDiseaseMiceNeurons
2014
Role of Synaptic Plasticity and EphA5-EphrinA5 Interaction Within the Ventromedial Hypothalamus in Response to Recurrent Hypoglycemia
Szepietowska B, Horvath TL, Sherwin RS. Role of Synaptic Plasticity and EphA5-EphrinA5 Interaction Within the Ventromedial Hypothalamus in Response to Recurrent Hypoglycemia. Diabetes 2014, 63: 1140-1147. PMID: 24222347, PMCID: PMC3931406, DOI: 10.2337/db13-1259.Peer-Reviewed Original ResearchConceptsRecurrent hypoglycemiaVentromedial hypothalamusEphA5 receptorNondiabetic ratsCounterregulatory responsesSynaptic plasticityAntecedent recurrent hypoglycemiaCounterregulatory hormone releaseDefective glucose counterregulationExpression of ephrinA5Counterregulatory hormone responsesIntensive insulin treatmentInsulin-induced hypoglycemiaHyperinsulinemic-hypoglycemic clamp studyGlucose infusion rateHypoglycemic clamp studiesGlucose counterregulationSynaptic coverageHypoglycemic stimulusGlucagon secretionGlucagon releaseAcute hypoglycemiaInsulin treatmentHormone releaseInfusion rate
2013
Repeated in vivo exposure of cocaine induces long‐lasting synaptic plasticity in hypocretin/orexin‐producing neurons in the lateral hypothalamus in mice
Rao Y, Mineur YS, Gan G, Wang AH, Liu Z, Wu X, Suyama S, de Lecea L, Horvath TL, Picciotto MR, Gao X. Repeated in vivo exposure of cocaine induces long‐lasting synaptic plasticity in hypocretin/orexin‐producing neurons in the lateral hypothalamus in mice. The Journal Of Physiology 2013, 591: 1951-1966. PMID: 23318871, PMCID: PMC3624862, DOI: 10.1113/jphysiol.2012.246983.Peer-Reviewed Original ResearchConceptsCAMP response element-binding proteinHypocretin neuronsLong-term potentiationSynaptic potentiationLateral hypothalamusCocaine administrationExperience-dependent synaptic potentiationExperience-dependent potentiationHypocretin-producing neuronsVivo cocaine administrationCocaine-treated animalsOrexin-producing neuronsAMPA-type glutamate receptorsVentral tegmental areaHigh-frequency stimulationCocaine-treated micePlace preference protocolResponse element-binding proteinDrugs of abuseCocaine withdrawalTegmental areaGlutamatergic synapsesGlutamate receptorsHypocretin systemElement-binding protein
2012
Ucp2 Induced by Natural Birth Regulates Neuronal Differentiation of the Hippocampus and Related Adult Behavior
Simon-Areces J, Dietrich MO, Hermes G, Garcia-Segura LM, Arevalo MA, Horvath TL. Ucp2 Induced by Natural Birth Regulates Neuronal Differentiation of the Hippocampus and Related Adult Behavior. PLOS ONE 2012, 7: e42911. PMID: 22905184, PMCID: PMC3414493, DOI: 10.1371/journal.pone.0042911.Peer-Reviewed Original ResearchConceptsUCP2 expressionCellular stressHippocampal neuronsChemical inhibitionMitochondrial bioenergeticsNeuronal differentiationGenetic ablationNatural birthProtein 2Adult behaviorCell proliferationCritical roleAdult brainNeuronal numberExpressionBioenergeticsNeuronsBirthDifferentiationRegulationProliferationSynaptogenesisVitroNeuroprotectionHippocampus
2011
CPG15 regulates synapse stability in the developing and adult brain
Fujino T, Leslie JH, Eavri R, Chen JL, Lin WC, Flanders GH, Borok E, Horvath TL, Nedivi E. CPG15 regulates synapse stability in the developing and adult brain. Genes & Development 2011, 25: 2674-2685. PMID: 22190461, PMCID: PMC3248687, DOI: 10.1101/gad.176172.111.Peer-Reviewed Original ResearchConceptsSynaptic maturationDendritic spinesFunctional synaptic contactsNeural circuit developmentSynaptic contactsSpine maintenanceDiolistic labelingDendritic arborsMature brainCircuit refinementSynapse stabilityAdult brainKnockout miceSynapse stabilizationCPG15Active synapsesSpine numberActivity-dependent synapseDevelopmental maturationSpineNeuronal branchesCircuit developmentGradual attritionBrainSynapsesEffects of chronic weight perturbation on energy homeostasis and brain structure in mice
Ravussin Y, Gutman R, Diano S, Shanabrough M, Borok E, Sarman B, Lehmann A, LeDuc CA, Rosenbaum M, Horvath TL, Leibel RL. Effects of chronic weight perturbation on energy homeostasis and brain structure in mice. AJP Regulatory Integrative And Comparative Physiology 2011, 300: r1352-r1362. PMID: 21411766, PMCID: PMC3119157, DOI: 10.1152/ajpregu.00429.2010.Peer-Reviewed Original ResearchConceptsDiet-induced obeseEnergy expenditureArcuate nucleus proopiomelanocortin neuronsWeight lossWeight-reduced individualsSustained weight lossReduced body weightObese human subjectsCentral nervous systemHuman subjectsSustained weight gainProopiomelanocortin neuronsBody massUpward resettingMale miceExcitatory synapsesBody fatMouse modelBody weightNervous systemSynaptic changesPersistent decreaseEnergy homeostasisWeight gainBrain structures
2010
Corticosterone Regulates Synaptic Input Organization of POMC and NPY/AgRP Neurons in Adult Mice
Gyengesi E, Liu ZW, D'Agostino G, Gan G, Horvath TL, Gao XB, Diano S. Corticosterone Regulates Synaptic Input Organization of POMC and NPY/AgRP Neurons in Adult Mice. Endocrinology 2010, 151: 5395-5402. PMID: 20843996, PMCID: PMC2954711, DOI: 10.1210/en.2010-0681.Peer-Reviewed Original ResearchConceptsNPY/AgRP neuronsSynaptic input organizationSham-operated controlsAgRP neuronsADX miceCorticosterone replacementNeuropeptide YArcuate nucleusSynaptic arrangementsInput organizationPair-fed control animalsPutative excitatory synapsesPutative inhibitory synapsesHypothalamic arcuate nucleusEffects of adrenalectomySham-operated animalsNumber of synapsesPOMC neuronsProtein (AgRP) neuronsOrexigenic actionMembrane potentialSynaptic analysisInhibitory synapsesExcitatory synapsesFood intakeAgrp Neurons Mediate Sirt1's Action on the Melanocortin System and Energy Balance: Roles for Sirt1 in Neuronal Firing and Synaptic Plasticity
Dietrich MO, Antunes C, Geliang G, Liu ZW, Borok E, Nie Y, Xu AW, Souza DO, Gao Q, Diano S, Gao XB, Horvath TL. Agrp Neurons Mediate Sirt1's Action on the Melanocortin System and Energy Balance: Roles for Sirt1 in Neuronal Firing and Synaptic Plasticity. Journal Of Neuroscience 2010, 30: 11815-11825. PMID: 20810901, PMCID: PMC2965459, DOI: 10.1523/jneurosci.2234-10.2010.Peer-Reviewed Original ResearchConceptsFood intakeMelanocortin systemAgRP neuronal activityAnorexigenic POMC neuronsHypothalamic melanocortin systemAction of SIRT1Negative energy balanceAgRP neuronsPOMC neuronsCre-lox technologyInhibitory toneMC4R antagonistFat massLean massSynaptic inputsNeuronal activityNeuronal firingAdult miceBody weightSIRT1 inhibitorSynaptic plasticityCalorie restrictionMelanocortin receptorsSIRT1 activityBody metabolismSynaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity
Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, Tschöp MH. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 14875-14880. PMID: 20679202, PMCID: PMC2930476, DOI: 10.1073/pnas.1004282107.Peer-Reviewed Original ResearchConceptsHigh-fat dietSynaptic input organizationReactive gliosisPOMC neuronsDIO ratsDR ratsArcuate nucleusMelanocortin systemPOMC cellsNeuropeptide Y cellsInput organizationLoss of synapsesDiet-induced obesityBlood-brain barrierHFD-fed animalsDIO animalsAnorexigenic proopiomelanocortinGlial ensheathmentSynaptic organizationInhibitory inputsLean ratsDR animalsNeuronal circuitsCell bodiesGliosis
2009
Estrogens Regulate Posttranslational Modification of Neural Cell Adhesion Molecule during the Estrogen-Induced Gonadotropin Surge
Tan O, Fadiel A, Chang A, Demir N, Jeffrey R, Horvath T, Garcia-Segura LM, Naftolin F. Estrogens Regulate Posttranslational Modification of Neural Cell Adhesion Molecule during the Estrogen-Induced Gonadotropin Surge. Endocrinology 2009, 150: 2783-2790. PMID: 19282389, DOI: 10.1210/en.2008-0927.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEstradiolEstrogensEstrous CycleFemaleGonadotropinsMiceMice, Inbred C57BLMidline Thalamic NucleiModels, AnimalNeural Cell Adhesion Molecule L1Neural Cell Adhesion MoleculesNeuronal PlasticityProtein IsoformsProtein Processing, Post-TranslationalRNA, MessengerSialic AcidsSialyltransferasesSynapsesConceptsNeural cell adhesion moleculePeriventricular areaIR-PSAPerineural spacePSA-NCAMCell adhesion moleculeAdhesion moleculesPSA-NCAM stainingExtent of stainingSialyltransferase mRNA levelsGonadotropin surgeNCAM stainingPreovulatory gonadotropinSynaptic plasticityProestrous afternoonEstrogenWestern blotProestrusIndividual neuronsRT-PCRMetestrusMRNA levelsHypothalamus tissueStainingSialyltransferase mRNA
2008
Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation
Dietrich MO, Andrews ZB, Horvath TL. Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation. Journal Of Neuroscience 2008, 28: 10766-10771. PMID: 18923051, PMCID: PMC3865437, DOI: 10.1523/jneurosci.2744-08.2008.Peer-Reviewed Original ResearchConceptsSynaptic plasticityVoluntary exerciseEssential organellesUCP2 functionProtein-2 mRNA expressionDendritic spine synapsesBioenergetic adaptationMitochondrial metabolismMitochondrial oxygen consumptionMitochondrial numberEnergetic needsMitochondrial adaptationsMitochondrial mechanismsExercise inducesDentate gyrusStratum radiatumSpine synapsesCA1 regionGlial morphologyHippocampal formationNeuronal activityGranule cellsAction potentialsNeuronal morphologyMRNA expressionUCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals
Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschöp MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 2008, 454: 846-851. PMID: 18668043, PMCID: PMC4101536, DOI: 10.1038/nature07181.Peer-Reviewed Original ResearchMeSH KeywordsAgouti-Related ProteinAnimalsCarnitine O-PalmitoyltransferaseFatty AcidsFeeding BehaviorGene Expression RegulationGhrelinHypothalamusIon ChannelsMembrane Potential, MitochondrialMiceMitochondriaMitochondrial ProteinsNeuronsNeuropeptide YPhosphorylationReactive Oxygen SpeciesSynapsesUncoupling Protein 2ConceptsNPY/AgRP neuronsAgRP neuronsNeuronal activityCo-express neuropeptide YGut-derived hormone ghrelinAgRP neuronal activityArcuate nucleus neuronsFatty acid oxidation pathwayHypothalamic mitochondrial respirationG protein-coupled receptorsGhrelin actionNeuropeptide YNucleus neuronsHormone ghrelinFood intakeGhrelinFree radicalsSynaptic plasticityNeuronal functionIntracellular mechanismsNeuronsMitochondrial mechanismsProtein 2Mitochondrial proliferationRobust changes
2007
Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons
Rao Y, Liu ZW, Borok E, Rabenstein RL, Shanabrough M, Lu M, Picciotto MR, Horvath TL, Gao XB. Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. Journal Of Clinical Investigation 2007, 117: 4022-4033. PMID: 18060037, PMCID: PMC2104495, DOI: 10.1172/jci32829.Peer-Reviewed Original ResearchConceptsHypocretin/orexin neuronsLong-term potentiationOrexin neuronsGlutamatergic synapsesSynaptic plasticitySleep lossExperience-dependent synaptic plasticityDopamine D1 receptorsChronic sleep lossSleep-wake regulationModafinil treatmentLateral hypothalamusD1 receptorsSimilar potentiationBrain slicesNeuronal activityNeuronal circuitryDopamine systemNervous systemSynaptic strengthNeuronsPathological conditionsGentle handlingMiceWakefulnessEstrogen-Induced Hypothalamic Synaptic Plasticity and Pituitary Sensitization in the Control of the Estrogen-Induced Gonadotrophin Surge
Naftolin F, Garcia-Segura LM, Horvath TL, Zsarnovszky A, Demir N, Fadiel A, Leranth C, Vondracek-Klepper S, Lewis C, Chang A, Parducz A. Estrogen-Induced Hypothalamic Synaptic Plasticity and Pituitary Sensitization in the Control of the Estrogen-Induced Gonadotrophin Surge. Reproductive Sciences 2007, 14: 101-116. PMID: 17636222, DOI: 10.1177/1933719107301059.Peer-Reviewed Original ResearchConceptsGnRH secretionPituitary gonadotrophsGonadotrophin surgeSynaptic plasticityInsulinlike growth factor 1Triggering of ovulationOvarian estrogen secretionGrowth factor-1Neural cell adhesion moleculePituitary sensitizationGnRH cellsGnRH neuronsEstrogen secretionHypothalamic neuronsGonadal functionCell adhesion moleculeSex steroidsSpecific immunoneutralizationOvarian cycleGonadotrophsAdhesion moleculesEstrogenMaximal sensitizationSecretionFactor 1
2006
Ghrelin controls hippocampal spine synapse density and memory performance
Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neuroscience 2006, 9: 381-388. PMID: 16491079, DOI: 10.1038/nn1656.Peer-Reviewed Original ResearchConceptsHippocampal spine synapse densitySpine synapse densitySpine synapse formationGrowth hormone releaseNovel therapeutic strategiesLong-term potentiationHigher brain functionsEnhanced spatial learningGut hormonesGhrelin administrationHypothalamic actionSynapse densitySpine synapsesCA1 regionHormone releaseNeuropeptide ghrelinGhrelin bindingHippocampal formationTherapeutic strategiesMelanocortin systemGhrelinBrain areasMetabolic controlSynaptic changesSynaptic plasticitySynaptic plasticity mediating leptin's effect on metabolism
Horvath TL. Synaptic plasticity mediating leptin's effect on metabolism. Progress In Brain Research 2006, 153: 47-55. PMID: 16876567, DOI: 10.1016/s0079-6123(06)53002-x.Peer-Reviewed Original ResearchConceptsPrimate hypothalamusSynaptic plasticityEnergy homeostasisShort-term fastingLeptin effectsHypothalamic regulationSynaptic inputsNeuromodulator systemsPeptidergic circuitsHypothalamusNonhuman primatesPathological conditionsBasic wiringMetabolic statePhysiological regulationHomeostasisMetabolic circuitsRodent speciesRatsFastingMicePlasticityResponse
2005
Mitochondrial uncoupling proteins in the cns: in support of function and survival
Andrews ZB, Diano S, Horvath TL. Mitochondrial uncoupling proteins in the cns: in support of function and survival. Nature Reviews Neuroscience 2005, 6: 829-840. PMID: 16224498, DOI: 10.1038/nrn1767.Peer-Reviewed Original ResearchConceptsNeuronal functionNeurological disordersTraumatic brain injuryAmyotrophic lateral sclerosisClinical treatment strategiesMitochondrial calcium influxModels of neurodegenerationMitochondrial uncouplingFree radical productionReactive oxygen species productionNeuronal deteriorationNeuronal deathSubstantia nigraBrain injurySpinal cordVentral tegmentumTreatment strategiesOxygen species productionNeuronal microenvironmentSynaptic transmissionCalcium influxLimbic systemNeurological conditionsLateral sclerosisParkinson's disease