Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA–Induced Dyskinesia

Engeln, Michel; Bastide, Matthieu F.; Toulmé, Estelle; Dehay, Benjamin; Bourdenx, Mathieu; Doudnikoff, Évelyne; Li, Qin; Gross, Christian E.; Boué‐Grabot, Éric; Pisani, Antonio; Bézard, Erwan; Fernagut, Pierre‐Olivier

doi:10.1016/j.biopsych.2014.07.007

Cited by 72 publications

(89 citation statements)

References 53 publications

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“…It has been proposed that the dorsomedial and ventromedial subdivisions of the mPFC, including the prelimbic (PL) and IL areas, exert opposing control over drug-seeking behaviors (Peters et al, 2008a(Peters et al, ,b, 2009. The demonstration of functional ensembles suggests a more complex view of behavioral control involving coexistence of many ensembles within one brain region supporting a variety of functions (Cruz et al, 2014a). However, although functional ensembles in a brain region can be identified by the Daun02 approach, it is difficult to distinguish the functional role of a local circuit inactivated by this method from that of the entire brain region.…”

Section: Introductionmentioning

confidence: 99%

“…The stimulus-conditioning phase started immediately after completion of the saccharin-fading procedure. A combination of discriminative (olfactory) and contingent (visual) cues was used for conditioning, according to a well validated protocol published by Ciccocioppo et al, (2002Ciccocioppo et al, ( , 2003 and Meinhardt et al (2013). Two stimuli were used to predict the availability of 10% (v/v) ethanol and were presented during each daily 30 min conditioning session.…”

Section: Behavioral Proceduresmentioning

confidence: 99%

“…Although early studies linked cFos expression to neuronal activity (Sommer et al, 1993(Sommer et al, , 1996, only recently these neurons were directly implicated in internal representation and behavioral expression of distinct memories (Cruz et al, 2013(Cruz et al, , 2014a. Specific silencing of cFosexpressing neurons can be achieved in cFos-lacZ transgenic animals whose ␤-galactosidase (␤-gal) activity converts the inactive prodrug Daun02 into daunorubicin, which disrupts functioning of c-Fos activated neurons Cruz et al, 2013). According to these pharmacogenetic studies, behavioral control is exerted by a distinct subset of neurons, thereby challenging results from classical brain site-specific manipulations of neuronal activity.…”

Section: Introductionmentioning

confidence: 99%

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Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex

Pfarr¹,

Meinhardt²,

Klee³

et al. 2015

Journal of Neuroscience

134

149

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Loss of control over drinking is a key deficit in alcoholism causally associated with malfunction of the medial prefrontal cortex (mPFC), but underlying molecular and cellular mechanisms remain unclear. Cue-induced reinstatement of alcohol seeking activates a subset of mPFC neurons in rats, identified by their common expression of the activity marker cFos and comprised of both principal and interneurons. Here, we used cFos-lacZ and pCAG-lacZ transgenic rats for activity-dependent or nonselective inactivation of neurons, respectively, which by their lacZ encoded ␤-galactosidase activity convert the inactive prodrug Daun02 into the neurotoxin daunorubicin. We report that activity-dependent ablation of a neuronal ensemble in the infralimbic but not the prelimbic subregion induced excessive alcohol seeking. The targeted neuronal ensemble was specific for the cue-induced response because stress-induced reinstatement was not affected in these animals. Importantly, nonselective inactivation of infralimbic neurons, using pCAG-lacZ rats, was without functional consequence on the cue-induced reinstatement task. Thus, inhibitory control over alcohol seeking is exerted by distinct functional ensembles within the infralimbic cortex rather than by a general inhibitory tone of this region on the behavioral output. This indicates a high level of functional compartmentation within the rat mPFC whereat many functional ensembles could coexist and interact within the same subregion.

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Section: Introductionmentioning

confidence: 99%

Section: Behavioral Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex

Pfarr¹,

Meinhardt²,

Klee³

et al. 2015

Journal of Neuroscience

134

149

View full text Add to dashboard Cite

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“…For each animal, optical density was calculated as the mean of the five striatal levels and corrected for nonspecific background, measured in the corpus callosum. After tissue processing for GFP staining, coronal sections of AAV-injected animals were sampled throughout the striatum and for rats and monkeys transduction volume was calculated with Cavalieri's principle using the Mercator image analysis system (Explora Nova) (29,77).…”

Section: Animalsmentioning

confidence: 99%

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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113

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Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

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“…When β-gal levels are maximal, the inactive prodrug Daun02 (Farquhar et al, 2002) is injected directly into the brain area of interest. Daun02 is converted by β-gal into daunorubicin to reduce cellular excitability (Engeln et al, 2014) and induce apoptosis and cell death (Pfarr et al, 2015). Thus, activated β-gal expressing neurons are selectively and persistently silenced, while the surrounding neurons are unaffected.…”

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confidence: 99%

Daun02 Inactivation of Behaviorally Activated Fos‐Expressing Neuronal Ensembles

2016

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Learned associations about salient experiences (e.g. drug exposure, stress) and their associated environmental stimuli are mediated by a minority of sparsely distributed, behaviorally activated neurons coined 'neuronal ensembles'. For many years, it was not known whether these neuronal ensembles played causal roles in mediating learned behaviors. However, in the last several years the 'Daun02 inactivation technique' in Fos-lacZ transgenic rats has proved very useful in establishing causal links between neuronal ensembles that express the activity-regulated protein 'Fos' and learned behaviors. Fosexpressing neurons in these rats also express the bacterial protein b-galactosidase (b-gal) in strongly activated neurons. When the prodrug Daun02 is injected into the brains of these rats 90 min after a behavior (e.g. drug-seeking) or cue exposure, then the Daun02 is converted into daunorubicin by b-gal, which selectively inactivates the Fos and b-galexpressing neurons that were activated 90 min before the Daun02 injection. This unit presents protocols for breeding the Fos-lacZ rats and conducting appropriate Daun02 inactivation experiments. Significance StatementLearned behaviors are mediated by specific patterns of sparsely distributed neurons, called 'neuronal ensembles', that are selectively activated during behavior and cue exposures. For many years, neuroscientists observed that neural activity of specific neurons correlated with specific behaviors or cue exposures. However, they could not determine whether these selectively activated neurons play 'causal roles' in the learned behaviors because tools to selectively silence only the behaviorally activated neurons without affecting the surrounding neurons were unavailable. The Daun02 inactivation technique described in this protocol selectively inactivates neurons that were activated strongly enough during recent behavior to express the proteins b-galactosidase (b-gal) in Fos-lacZ transgenic rats. Researchers use this tool to establish whether specific neuronal ensembles directly mediate learned behaviors.

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Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA–Induced Dyskinesia

Cited by 72 publications

References 53 publications

Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex

Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Daun02 Inactivation of Behaviorally Activated Fos‐Expressing Neuronal Ensembles

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