Addictiontopsychostimulantssuchascocainerepresentsamajorpublichealthissueexactingtremendous financialandsocialcosts.Despitethis,psychostimulantusedisorderremainsarecalcitrantconditionwithno currentlyFDA-approvedmedicationsforitstreatment.Inmanyfieldsofpsychiatricresearch,thelinkbetween thebrainandtheimmunesystemhasbeenheavilystudiedasawaytodeterminepathophysiologyandtofind newmethodsoftreatment.Whileitisknownthatcocainecanalterthefunctionofboththeinnateandadaptive immunesystems,thelinkbetweentheseimmunechangesandmaladaptivedrugtakingandseekingbehaviors remainsminimallyexplored.Inaseriesofinitialexperiments,weexaminedhowexperimenterorself- administeredcocainealteredtheserumprofileof32cytokines.Ofthese,wefoundthatgranulocyte-colony stimulatingfactor(G-CSF)wasincreasedbycocaine,andtheserumlevelsshowedlinearcorrelationwith behavioralresponsetococaine.Behaviorally,injectionsofG-CSFalterthedose-responsecurveforcocaine placepreference,andfacilitateextinctionandreducereinstatementofcocaineseeking.Takentogether,these preliminarystudiesdemonstratethatG-CSFisapotentmodulatorofcocaine-inducedbehavioralplasticity,and maybeapotentialtherapeutictargetforprolongingabstinenceincocaineusedisorder.Underthementorship ofDrs.EricNestlerandYasminHurdIwillseektofurtherclarifytheroleofG-CSFinaddictionwhilegaining additionaltrainingtoallowmetotransitiontoindependence.
In Aim1 ofthisproposalIwillinterrogatethe effectsofG-CSFinthenucleusaccumbens(NAc)inacell-typespecificmannerbyusingviralvectorstoknock downtheG-CSFreceptorinpopulationsofD1andD2positivemediumspinyneuronspriortococaineself- administration,extinctionandreinstatement.Theseexperimentswillprovideinsightintothemicrocircuitry underlyingthebehavioraleffectofG-CSF,andwillprovidemecrucialtraininginself-administrationand targetedmanipulationofgeneexpression.
In Aim2, IwillseektoidentifyG-CSFresponsivegenesinNActhat accountforitsbehavioraleffect.IwillperformmRNAsequencingoftheNAcfromanimalsself-administering cocaine,followedbydifferentialexpressionandpathwayanalysis.Thebehavioraleffectofhighlyregulated genesandpathwayswillbeinterrogatedbyviralgenemanipulationpriortococaineself-administration, extinctionandreinstatement.Theseexperimentswillprovidemewithcrucialmentoringincreation,analysis andutilizationoflargesequencingdatasets,whilealsoprovidingdetailedinformationastohowG-CSFaffects cocaine-relatedbehavioralplasticity.Insummary,theresearchproposedinthisawardwillelucidatetheneural andmolecularmechanismsofatranslationally-relevanttreatmenttarget,whileprovidingmewithsufficient mentorshiptotransitionintoanindependentinvestigator.

Public Health Relevance

Addictivedisordersareagroupofrecalcitrantrelapsing-remittingconditionsthatseverelydamagethelivesof affectedpatientsandtheirfamilies,andexertatremendousburdenonsocietyatlarge.Asignificantportionof thismorbidityisduetoabuseofcocaineandotherpsychostimulants,buttherearecurrentlynoFDA-approved pharmacotherapiesforpsychostimulantusedisorders.Theinterfacebetweenthebrainandtheimmune systemisafieldofconsiderableresearchfortreatmentofpsychiatricconditions,andinthisproposalweseek toclarifytheeffectsofthecytokinegranulocyte-colonystimulatingfactor(G-CSF)onneuronalandbehavioral plasticityinresponsetococaine?withagoalofidentifyingnovelneuroimmunetreatmenttargetstotreat cocaineusedisorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DA044308-04
Application #
9934168
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lin, Yu
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Kutlu, Munir Gunes; Brady, Lillian J; Peck, Emily G et al. (2018) Granulocyte Colony Stimulating Factor Enhances Reward Learning through Potentiation of Mesolimbic Dopamine System Function. J Neurosci 38:8845-8859