| 1. |
- Ruud, J., et al.
(författare)
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The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons
- 2019
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 27:11, s. 3182-3189.e9
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Tidskriftsartikel (refereegranskat)abstract
- Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty.
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| 2. |
- Lemberger, T., et al.
(författare)
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CREB has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis
- 2008
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 22:8, s. 2872-2879
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Tidskriftsartikel (refereegranskat)abstract
- Induction of specific gene expression patterns in response to activity confers functional plasticity to neurons. A principal role in the regulation of these processes has been ascribed to the cAMP responsive element binding protein (CREB). Using genomewide expression profiling in mice lacking CREB in the forebrain, accompanied by deletion of the cAMP responsive element modulator gene (CREM), we here show that the role of these proteins in activity-induced gene expression is surprisingly selective and highly context dependent. Thus, only a very restricted subset of activity-induced genes (i.e., Gadd45b or Nr4a2) requires these proteins for their induction in the hippocampus after kainic acid administration, while they are required for most of the cocaine-induced expression changes in the striatum. Interestingly, in the absence of CREB, CREM is able to rescue activity-regulated transcription, which strengthens the notion of overlapping functions of the two proteins. In addition, we show that cholesterol metabolism is dysregulated in the brains of mutant mice, as reflected coordinated expression changes in genes involved in cholesterol synthesis and neuronal accumulation of cholesterol. These findings provide novel insights into the role of CREB and CREM in stimulus-dependent transcription and neuronal homeostasis. © FASEB.
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| 3. |
- Rodriguez Parkitna, J, et al.
(författare)
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Loss of the serum response factor in the dopaminesystem leads to hyperactivity
- 2010
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Ingår i: The FASEB Journal. - : Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 24, s. 2427-2435
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Tidskriftsartikel (refereegranskat)abstract
- The serum response factor (SRF) is a key regulator of neural development and cellular plasticity, which enables it to act as a regulator of long-term adaptations in neurons. Here we performed a comprehensive analysis of SRF function in the murine dopamine system. We found that loss of SRF in dopaminoceptive, but not dopaminergic, neurons is responsible for the development of a hyperactivity syndrome, characterized by reduced body weight into adulthood, enhanced motor activity, and deficits in habituation processes. Most important, the hyperactivity also develops when the ablation of SRF is induced in adult animals. On the molecular level, the loss of SRF in dopaminoceptive cells is associated with altered expression of neuronal plasticity-related genes, in particular transcripts involved in calcium ion binding, formation of the cytoskeleton, and transcripts encoding neuropeptide precursors. Furthermore, abrogation of SRF causes specific deficits in activity-dependent transcription, especially a complete lack of psychostimulant-induced expression of the Egr genes. We inferred that alterations in SRFdependent gene expression underlie the observed hyperactive behavior. Thus, SRF depletion in dopaminoceptive neurons might trigger molecular mechanisms responsible for development of psychopathological conditions involving hyperactivity.
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