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Research Semester

English title Research Semester
Applicant Lüscher Christian
Number 184703
Funding scheme Research semester
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.07.2019 - 31.12.2019
Approved amount 72'479.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Pharmacology, Pharmacy

Keywords (3)

Addiction; Basal Ganglia; Neuroscience

Lay Summary (German)

Lead
Ein Forschungssemester in New York
Lay summary
Während sechs Monaten werde ich an der Columbia Universität mit Rui Costa und René Hen interagieren. Das Ziel ist gemeinsame Projekte zu entwickeln, insbesondere im Gebiet der Gewohnheitsbildung und Zwangshaftigkeit, beides Kardianlsymptome der Drogensucht. Wir werden neueste Technologien der Beobachtung neuronaler Aktivität in transgenen Mäusen zu Einsatz bringen. Das Ziel ist die Wechelwirkung von ventralem und dorsalem Striatum in diesem Kontext zu verstehen, insbesondere bei Opiatsucht.  
Direct link to Lay Summary Last update: 17.10.2019

Responsible applicant and co-applicants

Abstract

Spiraling connectivity between ventral and dorsal striatum in the progression to addiction. Christian Lüscher, UnigeResearch semester at Columbia University, New York (Host Rui M Costa). July to December 2019I propose a research semester to initiate a discussion on the contribution of ventral and dorsal striatum in addiction and locomotion. Traditionally the ventral striatum is considered as the locus of addictive drug action, while the dorsal striatum would control motor action (Arber and Costa, 2018). This segregation is in part justified with the dopamine afferents, which for the ventral striatum is the ventral tegmental area (VTA), while the latter received axons from the substantia nigra, pars compacts (SNc). Much literature now implicates the dorsal striatum in habit formation (Gremel and Costa, 2013) and even compulsion, both behavioural traits of addiction. Conversely, neural activity in the nucleus accumbens (NAc) may correlate with initiation of movement. During the semester, Rui Costa and I will examine the circuits underlying the progression to addiction, (ie. the transition from recreational to compulsive consumption), which begins already with the first exposure to an addictive drug. Once drug use becomes chronic, consumption may become compulsive, resulting in loss of control (Everitt and Robbins, 2016). This progression may involve a form of habit formation, which in some theories is necessary for compulsion. Alternatively, an extreme form of goal-directed actions (Vandaele and Janak, 2017) may best describe the might motivation of an addict to obtain the drug. Regardless of the precise underlying mechanim, clinical studies have estimated that around 20% of people who recreationally use cocaine will eventually become addicts (Egervari et al., 2017; Vsevolozhskaya and Anthony, 2017), which puts additional constraints on the underling neural mechanism. One element is the anatomy of the midbrain to striatum connectivity (Haber et al, 2000). Dopamine (DA) neurons from the medial VTA project to the medial NAc shell from where spiny projection neurons send off axons to the midbrain. Their primary targets are GABA interneurons, which synapse onto DA neurons in the lateral VTA. These cells project to the core and the lateral shell of the nucleus accumbens. The repetition of this disinhibitory motive leads to the recruitment of more and more lateral DA neurons eventually reaching the substantial nigra pars compacta (SNc) in the process, giving off ascending projections to more and more lateral parts of the DST. This anatomical design has been referred to as spiralling connectivity.A second element are the genetic and environmental factors could make a person vulnerable to this progression to addiction while others remain unscathed. An appealing though is that the transition to addiction may represent a form of “stochastic individuality” (Honegger and de Bivort, 2018), which is defined by behavioral variance among conspecifics leading to a life-long endophenotype in identical genotypes and exposure to a nominally identical environment. In the case of addiction, positive feedback mechanisms (e.g. DA, 5HT modulation, separation stress) may amplify the stochastic individuality such that a behavioral bistability would emerge (addicted vs recreational use).During my stay at Columbia I plan to attend lab-meetings, give seminars and animate journal clubs on these topics. I will remain in close contact with my lab in Geneva, which however will be looked after by Dr. Vincent Pascoli (suppléance), a very senior member of my team (currently maître assistant) who will also replace me for the teaching and administrative tasks. The requested budget will be used exclusively towards his salary. I am very excited by the idea of this exchange, which will certainly spark novel collaborative projects between Columbia and the University of Geneva. We will explore the possibility to formalize our collaboration such that students and postdocs can freely travel between the two institutions for lab visits to and We plan to publish the outcome of our discussion in the form of one or several review articles. Arber, S., Costa, R.M., 2018. Connecting neuronal circuits for movement. Science 360, 1403-1404. doi:10.1126/science.aat5994Egervari, G., Ciccocioppo, R., Jentsch, J.D., Hurd, Y.L., 2017. Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms. Neuroscience and Biobehavioral Reviews. doi:10.1016/j.neubiorev.2017.05.019Everitt, B.J., Robbins, T.W., 2016. Drug addiction: updating actions to habits to compulsions ten years on. Annu. Rev. Psychol. 67, 23-50. doi:10.1146/annurev-psych-122414-033457Gremel, C.M., Costa, R.M., 2013. Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nat Commun 4, 2264. doi:10.1038/ncomms3264Honegger, K., de Bivort, B., 2018. Stochasticity, individuality and behavior. Curr. Biol. 28, R8-R12. doi:10.1016/j.cub.2017.11.058Vandaele, Y., Janak, P.H., 2017. Defining the place of habit in substance use disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry. doi:10.1016/j.pnpbp.2017.06.029Vsevolozhskaya, O.A., Anthony, J.C., 2017. Estimated probability of becoming a case of drug dependence in relation to duration of drug-taking experience: a functional analysis approach. Int J Methods Psychiatr Res 26, e1513. doi:10.1002/mpr.1513
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