Alcoholism,alsoknownasalcoholusedisorder,isachronicdebilitatingdisordercharacterizedbyexcessive ingestionofalcoholandimpairmentinsocialandoccupationalfunctioning.Whilemostinvestigationsofbrain mechanisms mediating this disorder have studied the hypothalamus or mesolimbic regions, recent evidence focusesattentiononarelativelyunderstudiedarea,theparaventricularnucleusofthethalamus(PVT),which provides an important relay point between the homeostasisregulating hypothalamus and emotionregulating limbic nuclei. Utilizing the intermittent access model that leads to voluntary consumption of ethanol at pharmacologicallyrelevant levels, I plan to test the overall hypothesis that ethanol drinking stimulates the hypothalamicneuropeptideorexin(OX)toactinthePVT,primarilyattheorexin2ratherthanorexin1receptor (andratherthanmelaninconcentratinghormoneatitsreceptor)andspecificallyintheanteriorratherthanposterior subregion, and that this action, in turn, increases local levels of the opioid enkephalin (ENK) to promote further ethanolintake.Withthissequenceofeventspossiblybeingcriticallyimportantinpromotingdisorderedalcoholuse, I propose, in Aim 1, to investigate the neurochemical events that occur following ethanol drinking, from OX transcriptioninthehypothalamustoENKreleaseintheanteriorPVT.
In Aim2, Iwillexaminethebehavioralresults oftheseneurochemicalchanges,testingtheeffectsofOXandENKinjectioninthePVTonethanoldrinkingand emotional behaviors and the possibility that these behaviors are naturally increased by elevated endogenous peptidelevels.
In Aim3, IwillthenlookatmolecularmechanismsofthisOXtoENKconnectionandexaminethe possibility that this is necessary for promoting ethanol drinking. Collectively, by using techniques as varied as primaryneuronalculture,insituhybridization,andbehavioralassessmenttests,thesestudiesshouldprovide significantnewinformationonarelativelyunderstudiednucleus,thePVT,anditspotentiallymajorinvolvement in ethanol intake. In addition to the publications that should come out of this work, which will allow me to integrate molecular, cellular, and behavioral findings, the funding of this grant proposal will give me the necessary training in both research and career development to attain independence as a scientist. I will additionally take part in advanced coursework and attend seminars and workshops at The Rockefeller University and through the TriInstitutional Collaboration Network, while participating in national society meetings. I will receive expert mentorship from my sponsor, Dr. Sarah Leibowitz, as well as my advisory committee which, together with the abundant resources at The Rockefeller University, will allow me to learn new experimental methods and gain new perspectives on my research questions. Thus, in the process of conductinginnovativenewresearch,Iwillgaintheskillsnecessarytosuccessfullytransitionintoapositionas anindependentresearchscientistandtomakeasignificantcontributiontothefieldofalcoholresearch.
The goal of the current grant application is to examine an understudied region of the brain, the thalamic paraventricularnucleus,foritspotentiallymajorroleintheoverconsumptionofethanol.Theoverallhypothesisis that ethanol intake stimulates the hypothalamic neuropeptide orexin specifically to act at the orexin 2 receptor withintheanteriorregionofthethalamicparaventricularnucleus,astructureassociatedwithmotivatedarousal, and that this effect, through activation of the opioid enkephalin, promotes further ethanol intake and ultimately addiction.Theresultsofthesestudieswillprovideanewdirectionforresearchonalcoholism,pointingtoaspecific brainareaandneurochemicalcircuitthatmaycontributetoexcessiveethanoldrinking.
