Dataset Information

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat.

ABSTRACT: This study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1-receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects.

SUBMITTER: Lortet S

PROVIDER: S-EPMC3617149 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat.

Lortet Sylviane S Lacombe Emilie E Boulanger Nicolas N Rihet Pascal P Nguyen Catherine C Kerkerian-Le Goff Lydia L Salin Pascal P

PloS one 20130404 4

This study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskin ...[more]

PMID: 23593219

Similar Datasets

Project description:This study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of ParkinsonM-bM-^@M-^Ys disease and its interaction with levoDOPA (L-DOPA), focusing on the striatum. The objectives were 1) to identify the molecular signature of STN-HFS action at striatal level, associated with its efficient antiparkinsonian action, and 2) to investigate the molecular substrates of the interaction between the two treatments in order to evidence possible genes involved in dyskinesia. Striatal gene expression profile was assessed in rats with nigral DOPAmine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 genes with functional or biochemical annotation, including genes sharing the GO terms regulation of growth, regulation of apoptosis, extracellular region. Ttr, Igf2, Sostdc1 and Nr4A3 (Nor-1), are among the 5 genes showing the highest specific upregulation. Down-regulated genes include Prkcd, Sirt5 and Bbc3. These results show that genes involved in neuroprotection and/or neurogenesis are key components of STN-HFS action in the striatum. STN-HFS and LDOPA treatment share very few common gene regulation features suggesting that the molecular substrates underlying their striatal action are mostly different. In addition to genes already reported to be associated with LIDs (Pdyn, Trh, Grm4/mGlu4, Cnr1/CB1), the comparison between DOPA and DOPA/STN-HFS identifies immunity-related genes: C1s, Rt1-Da and Irf7a, as potential players in L-DOPA side effects. Total RNA was extracted from striatal tissue from four groups of 3 animals bearing 6-hydroxyDOPAmine (6-OHDA)-induced lesion of the nigrostriatal DA pathway: lesion alone without any subsequent treatment (L), L-DOPA treatment for 19 days (D), STN-HFS for 5 days (S) and combination of L-DOPA and STN-HFS (DS).

Project description:Methamphetamine-induced circling is used to quantify the behavioral effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in hemiparkinsonian rats. We observed a frequency-dependent transient effect of DBS on circling, and quantified this effect to determine its neuronal basis. High frequency STN DBS (75-260Hz) resulted in transient circling contralateral to the lesion at the onset of stimulation, which was not sustained after the first several seconds of stimulation. Following the transient behavioral change, DBS resulted in a frequency-dependent steady-state reduction in pathological ipsilateral circling, but no change in overall movement. Recordings from single neurons in globus pallidus externa (GPe) and substantia nigra pars reticulata (SNr) revealed that high frequency, but not low frequency, STN DBS elicited transient changes in both firing rate and neuronal oscillatory power at the stimulation frequency in a subpopulation of GPe and SNr neurons. These transient changes were not sustained, and most neurons exhibited a different response during the steady-state phase of DBS. During the steady-state, DBS produced elevated neuronal oscillatory power at the stimulus frequency in a majority of GPe and SNr neurons, and the increase was more pronounced during high frequency DBS than during low frequency DBS. Changes in oscillatory power during both transient and steady-state DBS were highly correlated with changes in firing rates. These results suggest that distinct neural mechanisms were responsible for transient and sustained behavioral responses to STN DBS. The transient contralateral turning behavior following the onset of high frequency DBS was paralleled by transient changes in firing rate and oscillatory power in the GPe and SNr, while steady-state suppression of ipsilateral turning was paralleled by sustained increased synchronization of basal ganglia neurons to the stimulus pulses. Our analysis of distinct frequency-dependent transient and steady-state responses to DBS lays the foundation for future mechanistic studies of the immediate and persistent effects of DBS.

Dataset Information

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat.

Publications

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets