The striatum contributes to our ability to learn sensorimotor tasks. It is also heavily involved in the wanting, seeking and self-administration of addictive drugs. Additionally, striatal dysfunction has been linked to a variety of neurological disorders. A major component to all these long-term alterations in brain function is modifications in striatal gene expression and protein synthesis. The diversity of transcription factors that direct these changes in neuronal plasticity are just now being appreciated. Outside of the nervous system, NFATc transcription factors are critical mediators of immune responses, vascular and cardiac development, and muscle growth. Recently, these transcription factors were discovered within brain, and it is the central hypothesis of this proposal that NFAT-dependent transcription is a critical mediator of striatal plasticity.
Specific Aim 1 will characterize the expression of the 4, calcium/calcineurin-sensitive NFATc isoforms within the different neuronal subpopulations of the striatum.
Specific Aim 2 will elucidate the intracellular signaling pathways triggered by dopamine receptor stimulation (D1- and D2-class) that lead to alterations in NFAT-dependent transcription.
Specific Aim 3 will determine whether acute and/or chronic cocaine exposure leads to heightened NFAT-dependent transcription, and also whether inhibition of NFAT results in a diminution of cocaine-induced behavioral sensitization. In sum, utilizing modern cellular and molecular techniques, this study will reveal which NFATc proteins are expressed in the striatum, the stimuli that activate of NFAT-dependent transcription, and whether heightened NFAT activity can be linked to neuronal changes observed following exposure to addictive drugs. Ultimately, this project will lead to a better understanding of the role NFAT-dependent transcription plays in shaping long-term changes in brain function.
| Groth, Rachel D; Weick, Jason P; Bradley, Katherine C et al. (2008) D1 dopamine receptor activation of NFAT-mediated striatal gene expression. Eur J Neurosci 27:31-42 |
| Groth, Rachel D; Coicou, Lia G; Mermelstein, Paul G et al. (2007) Neurotrophin activation of NFAT-dependent transcription contributes to the regulation of pro-nociceptive genes. J Neurochem 102:1162-74 |
| Seybold, V S; Coicou, L G; Groth, R D et al. (2006) Substance P initiates NFAT-dependent gene expression in spinal neurons. J Neurochem 97:397-407 |
| Bradley, Katherine C; Groth, Rachel D; Mermelstein, Paul G (2005) Immunolocalization of NFATc4 in the adult mouse brain. J Neurosci Res 82:762-70 |
