Work during the fiscal year extended our prior research on the function of the basal ganglia in animal models of neurologic disorders. Our work was the first to demonstrate that there is an abnormal coupling of Drd1a dopamine receptors to activation of Extracellular Receptor Kinase (ERK1/2) in an animal model of Parkinson's Disease (Gerfen et al., 2002). During the past year we demonstrated that there are distinct forms of Drd1a-mediated activation of ERK signaling in the dorsal striatum and the nucleus accumbens (Gerfen et al., 2008). Using Drd1a- and DARPP32-deficient transgenic mice we show that in the dopamine intact accumbens, psychostimulants activate ERK1/2 via a Drd1a- and DARPP32-dependent mechanism. This mechanism is activated in the dorsal striatum only following dopamine depletion as occurs in Parkinson's Disease. ? ? Further work on the cellular mechanisms underlying neurologic and pscyhiatric disorders is limited by the fact that neurons throughout the brain utilize common mechanisms for critical functions such as synaptic plasticity, whereas specific neural systems are affected in different disorders. A large part of the Laboratory is now working with the Gene Expression Nervous System Atlas (GENSAT) project ( funded by NINDS and NIMH ) to produce transgenic mice with Cre-recombinase under the regulation of promoters to drive expression in specific neuron populations. Our part of this work is to characterize the expression of Cre in the brains of such transgenic lines and to provide such lines to the Mutant Mouse Regional Resource Center (MMRRC) for distribution to the research community. In the past year we characterized 14 Cre driver lines and are in the process of characterizing 25-50 lines for the current year ( Gong et al., 2007)

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH002497-19
Application #
7735115
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2008
Total Cost
$722,053
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ruiz, Sarah K; Harris, Susan J; Martinez, Pedro et al. (2018) Young adult's attachment style as a partial mediator between maternal functioning and young adult offsprings' functioning. J Affect Disord 232:393-399
Gerfen, Charles R; Economo, Michael N; Chandrashekar, Jayaram (2018) Long distance projections of cortical pyramidal neurons. J Neurosci Res 96:1467-1475
Gerfen, Charles R; Paletzki, Ronald; Heintz, Nathaniel (2013) GENSAT BAC cre-recombinase driver lines to study the functional organization of cerebral cortical and basal ganglia circuits. Neuron 80:1368-83
Gerfen, Charles R; Paletzki, Ronald; Worley, Paul (2008) Differences between dorsal and ventral striatum in Drd1a dopamine receptor coupling of dopamine- and cAMP-regulated phosphoprotein-32 to activation of extracellular signal-regulated kinase. J Neurosci 28:7113-20
Szklarczyk, Arek; Oyler, George; McKay, Ron et al. (2007) Cleavage of neuronal synaptosomal-associated protein of 25 kDa by exogenous matrix metalloproteinase-7. J Neurochem 102:1256-63
Szklarczyk, A; Conant, K; Owens, D F et al. (2007) Matrix metalloproteinase-7 modulates synaptic vesicle recycling and induces atrophy of neuronal synapses. Neuroscience 149:87-98
Manning-Bog, Amy B; Caudle, W Michael; Perez, Xiomara A et al. (2007) Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter. Neurobiol Dis 27:141-50
Kim, D S; Palmiter, R D; Cummins, A et al. (2006) Reversal of supersensitive striatal dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine-deficient mice. Neuroscience 137:1381-8
Brown, Pierre; Gerfen, Charles R (2006) Plasticity within striatal direct pathway neurons after neonatal dopamine depletion is mediated through a novel functional coupling of serotonin 5-HT2 receptors to the ERK 1/2 map kinase pathway. J Comp Neurol 498:415-30
Gerfen, Charles R (2006) Indirect-pathway neurons lose their spines in Parkinson disease. Nat Neurosci 9:157-8

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