The striatum (caudate-putamen) a brain area involved in the control of movement and cognitive processes receives a massive excitatory input from the cerebral cortex. During the previous funding period, we obtained evidence that cortical lesions in adult rats produce long term changes in striatal gene expression and little compensatory axonal sprouting. The research described in this application is concerned with the hypothesis that greater neuronal plasticity exists in response to cortical lesions in the immature than in the adult striatum. We will use quantitative approaches to examine the extent and morphological characteristics of the innervation of the dorsolateral striatum by afferent from the contralateral cortex labelled by injection of anterograde tracers in rats. This will be done during normal development, and after lesions of the frontoparietal cortex induced by superficial thermocoagulation of pial blood vessels in pups. Reactive synaptogenesis in the denervated dorsolateral striatum will be measured by electron microscopy. In order to identify factors that may be critical for corticostriatal plasticity, we will examine the pattern of expression of growth factors and adhesion molecules known to play a role in neurite outgrowth in vitro and in vivo, but whose role in the striatum during normal postnatal development and after cortical lesions is unknown. Specifically, quantitative immunohistochemistry and in situ hybridization histochemistry will be used to examine the expression of basic fibroblast growth factor (bFGF), neurotrophins (BDNF, NT3), and the highly polysialilated neural cell adhesion molecule (PSA-NCAM). The results will be analyzed in relation to the development of the corticostriatal pathway, and the induction of compensatory axonal sprouting after lesions. Finally, we will determine the effects of cortical lesions induced at different times during postnatal development on the expression of mRNAs encoding glutamic acid decarboxylase (GAD), the enzyme of GABA synthesis, and neuropeptides present in striatal efferent neurons, which have been shown to be altered after cortical lesions made in adults. These experiments will provide new insights into the molecular mechanisms underlying neuronal plasticity in the striatum during postnatal development and in response to early postnatal cortical injury. This will provide the rational for new approaches to treat striatal dysfunction resulting from cortical alterations occurring in the young or in the adult as a result of neurodcgenarative diseases or brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS029230-05
Application #
2267470
Study Section
Neurology A Study Section (NEUA)
Project Start
1991-02-01
Project End
2000-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Carmichael, S Thomas; Chesselet, Marie-Francoise (2002) Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult. J Neurosci 22:6062-70
Uryu, K; Butler, A K; Chesselet, M F (1999) Synaptogenesis and ultrastructural localization of the polysialylated neural cell adhesion molecule in the developing striatum. J Comp Neurol 405:216-32
Butler, A K; Uryu, K; Rougon, G et al. (1999) N-methyl-D-aspartate receptor blockade affects polysialylated neural cell adhesion molecule expression and synaptic density during striatal development. Neuroscience 89:1169-81
Bordelon, Y M; Mackenzie, L; Chesselet, M F (1999) Morphology and compartmental location of cells exhibiting DNA damage after quinolinic acid injections into rat striatum. J Comp Neurol 412:38-50
Butler, A K; Uryu, K; Morehouse, V et al. (1997) Regulation of the polysialylated form of the neural cell adhesion molecule in the developing striatum: effects of cortical lesions. J Comp Neurol 389:289-308
Szele, F G; Chesselet, M F (1996) Cortical lesions induce an increase in cell number and PSA-NCAM expression in the subventricular zone of adult rats. J Comp Neurol 368:439-54
Szele, F G; Alexander, C; Chesselet, M F (1995) Expression of molecules associated with neuronal plasticity in the striatum after aspiration and thermocoagulatory lesions of the cerebral cortex in adult rats. J Neurosci 15:4429-48
Chesselet, M F; Soghomonian, J J; Salin, P (1995) Anatomical localization and regulation of somatostatin gene expression in the basal ganglia and its clinical implications. Ciba Found Symp 190:51-9;discussion 59-64
Delfs, J M; Ellison, G D; Mercugliano, M et al. (1995) Expression of glutamic acid decarboxylase mRNA in striatum and pallidum in an animal model of tardive dyskinesia. Exp Neurol 133:175-88
Szele, F G; Dowling, J J; Gonzales, C et al. (1994) Pattern of expression of highly polysialylated neural cell adhesion molecule in the developing and adult rat striatum. Neuroscience 60:133-44

Showing the most recent 10 out of 18 publications