Psychostimulant-induced dendritic spine plasticity in brain reward circuits might be a cellular mechanism of learning and enduring memory associated with addictive behaviors. We hypothesize that two types of dendritic spine formation (silent spines and mature spines) may occur during chronic exposure, withdrawal and re-exposure to psychostimulants. Cell type- and region-specific studies of dendritic spines and of the role of Cdk5 and WAVE1 in the molecular mechanisms underlying the two steps of spine formation are designed with novel and innovative approaches to achieve the following aims.
In Aim I, cell type- and region-specific analysis of 1) dendritic spine morphology of medium-sized spiny neurons (MSNs) and of 2) the levels of glutamate receptor expression in dendritic spines will characterize the structure and function of dendritic spines. We will use Bac-transgenic mice expressing a cell type-specific fluorescent marker protein to identify specific MSNs. We will generate three-dimensional images of dendritic spines from two types of MSNs in subregions of striatum (core and shell of nucleus accumbens and dorsal striatum) during chronic exposure, withdrawal and re-exposure to cocaine. Various morphological parameters of dendritic spines will be analyzed with automatic software.
In Aim II and III, we will use D1- or D2-MSNs-specific Cdk5 or WAVE1 knockout mice. We will also restore the expression of Cdk5 or WAVE1 only in the specific types of MSNs in specific regions of striatum (nucleus accumbens or dorsal striatum) by injection of conditional AAV-floxed-STOP signal-floxed-Cdk5 or WAVE1 (wild-type or phosphorylation site mutants). With these knockout and add-back Cdk5 or WAVE1 mice, we will study the roles of Cdk5, WAVE1 and phosphorylation of WAVE1 in (a) spine morphology, (b) glutamate receptor trafficking, (c) electrophysiology and (d) behavior.
In Aim III. C, we will characterize WAVE1 phosphorylation at tyrosine sites by TrkB, a receptor of mature BDNF, in the actions of psychostimulants. In addition, we will carry out collaborative studies with Project 2 in the analysis of dendritic spines in genetically modified animal models (e.g. CK1 overexpressing mice). We will also collaborate with Project 3 in studies of the role of PP2A in WAVE1 regulation and of the role of Rap1GAP in dendritic spine morphogenesis.

Public Health Relevance

The proposed studies will lead to elucidation of molecular and cellular mechanisms underlying pathological alteration of communication between nerve cells in brain rewarding circuitry and will guide new strategies of drug development for the prevention and treatment of addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA010044-19
Application #
8624676
Study Section
Special Emphasis Panel (ZRG1-MDCN-G)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2014
Total Cost
$358,062
Indirect Cost
$146,191
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Milosevic, Ana; Liebmann, Thomas; Knudsen, Margarete et al. (2016) Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain. J Comp Neurol :
Virk, Michael S; Sagi, Yotam; Medrihan, Lucian et al. (2016) Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum. Proc Natl Acad Sci U S A 113:734-9
Rapanelli, Maximiliano; Frick, Luciana R; Horn, Kyla D et al. (2016) The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. J Biol Chem 291:21042-21052
Liu, Ruijie; Correll, Robert N; Davis, Jennifer et al. (2015) Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations. J Mol Cell Cardiol 87:204-13
Uematsu, Ken; Heiman, Myriam; Zelenina, Marina et al. (2015) Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function. J Neurochem 132:677-86
Engmann, Olivia; Giralt, Albert; Gervasi, Nicolas et al. (2015) DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nat Commun 6:10099
Lee, K-W; Westin, L; Kim, J et al. (2015) Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol Psychiatry 20:1546-56
Yamagata, Yoko; Nairn, Angus C (2015) Contrasting features of ERK1/2 activity and synapsin I phosphorylation at the ERK1/2-dependent site in the rat brain in status epilepticus induced by kainic acid in vivo. Brain Res 1625:314-23
Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100
Colangelo, Christopher M; Ivosev, Gordana; Chung, Lisa et al. (2015) Development of a highly automated and multiplexed targeted proteome pipeline and assay for 112 rat brain synaptic proteins. Proteomics 15:1202-14

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