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• W1921515037 abstract "Article8 November 2011free access Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions Pierre F Durieux Pierre F Durieux Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium Search for more papers by this author Serge N Schiffmann Serge N Schiffmann Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium Search for more papers by this author Alban de Kerchove d'Exaerde Corresponding Author Alban de Kerchove d'Exaerde Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium Search for more papers by this author Pierre F Durieux Pierre F Durieux Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium Search for more papers by this author Serge N Schiffmann Serge N Schiffmann Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium Search for more papers by this author Alban de Kerchove d'Exaerde Corresponding Author Alban de Kerchove d'Exaerde Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium Search for more papers by this author Author Information Pierre F Durieux1, Serge N Schiffmann1,‡ and Alban de Kerchove d'Exaerde 1,‡ 1Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, ULB, Brussels, Belgium ‡These authors contributed equally to this work *Corresponding author. Laboratory of Neurophysiology, School of Medicine, Université Libre de Bruxelles, Campus Erasme, C.P. 601, Route de Lennik, 808, Brussels 1070, Belgium. Tel.: +32 2 555 41 20; Fax: +32 2 555 41 21; E-mail: [email protected] The EMBO Journal (2012)31:640-653https://doi.org/10.1038/emboj.2011.400 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info The dorsal striatum is critically involved in a variety of motor behaviours, including regulation of motor activity, motor skill learning and motor response to psychostimulant and neuroleptic drugs, but contribution of D2R-striatopallidal and D1R-striatonigral neurons in the dorsomedial (DMS, associative) and dorsolateral (DLS, sensorimotor) striatum to distinct functions remains elusive. To delineate cell type-specific motor functions of the DMS or the DLS, we selectively ablated D2R- and D1R-expressing striatal neurons with spatial resolution. We found that associative striatum exerts a population-selective control over locomotion and reactivity to novelty, striatopallidal and striatonigral neurons inhibiting and stimulating exploration, respectively. Further, DMS-striatopallidal neurons are involved only in early motor learning whereas gradual motor skill acquisition depends on striatonigral neurons in the sensorimotor striatum. Finally, associative striatum D2R neurons are required for the cataleptic effect of the typical neuroleptic drug haloperidol and for amphetamine motor response sensitization. Altogether, these data provide direct experimental evidence for cell-specific topographic functional organization of the dorsal striatum. Introduction The striatum represents the main input nucleus of the basal ganglia, a system of subcortical nuclei critically involved in motor control and motivational processes and altered in several conditions such as Parkinson's and Huntington's diseases or drug addiction and schizophrenia (Nestler, 2005; Kreitzer and Malenka, 2008). The projection neurons of the striatum are GABAergic medium-sized spiny neurons (MSNs) subdivided into two sub-populations, the striatonigral and striatopallidal neurons (Gerfen et al, 1990; Schiffmann et al, 2007) that form two main efferent pathways. The striatonigral MSNs (direct pathway) co-express dopamine D1 receptor (D1R) and substance P (SP), while striatopallidal MSNs (indirect pathway) co-express dopamine D2 receptor (D2R), adenosine A2A receptor (A2AR) and enkephalin (Enk) (Schiffmann and Vanderhaeghen, 1993). MSNs in the direct and indirect pathways are equal in number and shape, mosaically distributed throughout the striatum (Gerfen, 1992), and are not dissociable with techniques such as surgical or excitotoxic lesions. The striatum can be functionally divided into dorsal and ventral subregions based on the origin of cortical glutamatergic and midbrain dopaminergic (DA) afferents. The dorsal striatum is thought to be involved mostly in motor behaviours, while ventral striatum is crucial for motivational processes (Robbins and Everitt, 1996; Groenewegen, 2003). The dorsal striatum is often subdivided into an external portion (the dorsolateral striatum (DLS) corresponding to the primate putamen, predominantly innervated by the sensorimotor cortex) and an internal part (the dorsomedial striatum (DMS) homologous to primate caudate nucleus, receiving projections from prefrontal and other association cortices) (Voorn et al, 2004; Graybiel, 2008). Cell-specific functions of the DMS or DLS in motor control and learning or in basal ganglia-related disorders (such as schizophrenia or drug addiction) remain poorly understood. While the DMS seems more engaged during initial stages of motor skill learning, when the task is more dependent on attention and susceptible to interference (Jueptner and Weiller, 1998; Luft and Buitrago, 2005), the DLS seems required for progressive skill automatization and habit learning (Miyachi et al, 2002; Yin et al, 2004). Treatment of schizophrenia-positive symptoms with typical antipsychotics, such as haloperidol, often induces a dramatic rigidity and locomotor immobility, called catalepsy (Lieberman et al, 2008). While striatal D2R antagonism is a common characteristic of antipsychotic drugs (Karam et al, 2010), a cell type-specific involvement of dorsal striatum subregions in the haloperidol-induced catalepsy remains elusive. Behavioural sensitization to psychostimulants provides a model of addictive behaviours such as those associated with craving and relapse (Robinson and Berridge, 1993; Hyman et al, 2006), but involvement of D1R- and D2R-neuron pathways in this process remains controversial (Mattingly et al, 1996; Chen et al, 2003; Karlsson et al, 2008). To date, to the best of our knowledge, no in-vivo approach has unravelled respective functions of D1R and D2R MSNs in the DMS and DLS. We selectively ablated each class of neurons in adult mice using an inducible diphtheria toxin receptor (DTR)-mediated cell targeting strategy (Durieux et al, 2009) and delineated distinct roles of D1R and D2R MSNs in associative and sensorimotor striatum during novelty- or drug-induced locomotor behaviours and motor skill learning. Results We bred lines of Drd1a-EY262-cre+/− (Gong et al, 2007; founder EY262) or Adora2a-cre+/− (Durieux et al, 2009) mice to inducible DTR+/+ (iDTR+/+) (Buch et al, 2005) mice, leading to mice that selectively expressed the DTR in D1R or D2R MSNs (Drd1a-EY262-cre+/− iDTR+/− (D1-DTR+ mice) or Adora2a-cre+/− iDTR+/− (A2A-DTR+ mice), respectively); and control mice (Drd1a-EY262-cre−/− iDTR+/− (D1-DTR− mice) or Adora2a-cre−/− iDTR+/− (A2A-DTR− mice)). This approach allows inducible ablation of D1R or D2R neurons in striatum of adult mice with high spatial resolution, avoiding neuronal ablation in other brain areas or potential developmental adaptations (Drago et al, 1998; Gantois et al, 2007; Durieux et al, 2009). All animal procedures were approved by the Université Libre de Bruxelles School of Medicine Ethical Committee. Diphtheria toxin (DT) was stereotaxically injected into the striatum to ablate the class of neurons throughout the entire striatum (full ablation) or to restrict the ablation to DMS (DMS ablation) or DLS (DLS ablation). Selective ablation of D1R-striatonigral neurons We first characterized full ablation of D1R-striatonigral neurons by DT injections in the entire striatum of D1-DTR mice (Figures 1 and 2). Bilateral full DT-injected D1-DTR+ mice showed specific loss of D1R and SP mRNAs (Figure 1A) as well as D1R binding (Figure 1B) with full preservation of D2R-striatopallidal neurons markers as D2R, A2AR and Enk mRNAs (Figure 1A) and A2AR binding (Figure 1B). The four sub-populations of striatal interneurons were spared in full D1R MSN ablated striatum (Figure 2). We also demonstrated that DT injections in the entire striatum of D1-DTR+ or A2A-DTR+ animals lead to a reduction of nearly 45% of dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32, a protein expressed in both MSN sub-populations)-positive cells in each model (Figure 3), confirming that striatal D1R and D2R neurons are approximately equal in number (Bertran-Gonzalez et al, 2008). Altogether, these results indicate that striatal DT injections in D1-DTR+ and, as previously described (Durieux et al, 2009), in A2A-DTR+ mice lead to selective elimination of D1R-striatonigral and D2R-striatopallidal neurons, respectively. Figure 1.Characterization of D1R-striatonigral neuron ablation after full striatum DT injections in D1-DTR+ mice. (A) In-situ hybridization autoradiograms (coronal sections, level +1.2 mm relative to bregma) of D1R-striatonigral (D1R, SP) and D2R-striatopallidal (D2R, Enk and A2AR) neuron mRNAs and respective levels in the striatum of D1-DTR− and D1-DTR+ mice 2 weeks after bilateral full DT injections (n=6 per group). (B) Autoradiograms (coronal sections, level +1.2 mm relative to bregma) of D1 and A2A receptors and respective striatal binding levels of D1-DTR− and D1-DTR+ mice 2 weeks after bilateral full striatum DT injections (n=5–6 per group). Scale bars=1 mm. Data are reported as mean±s.e.m. ***P<0.001. Download figure Download PowerPoint Figure 2.Preservation of striatal interneurons after ablation of striatonigral neurons in D1-DTR+ mice. (A–D) Immunostaining and quantitative analysis of (A) choline acetyltransferase (ChAT), (B) parvalbumin (PV), (C) neuropeptide Y (NPY) and (D) calretinin (CR)-positive cells in full DT-injected striatum as compared with uninjected striatum of D1-DTR+ mice (day 22 after unilateral full DT injections). Scale bars=100 μm. Columns represent the mean±s.e.m. (n=7). Download figure Download PowerPoint Figure 3.Reduction of striatal DARPP-32-positive neurons in DT-injected D1-DTR+ or A2A-DTR+ mice. (A, B) DARPP-32 immunostaining 1 month after unilateral DT injection in the entire striatum showing a 44.5±2.5 and 42.9±2.62% reduction of DARPP-32-positive cells in the injected striatum as compared with the uninjected striatum of D1-DTR+ (A) (6870±244 cells versus 3807±40 cells, n=2) and A2A-DTR+ (B) (6046±1094 cells versus 3481.5±783.5 cells, n=2) mice, respectively. Scale bars=200 μm. Download figure Download PowerPoint Motor activity and rotarod learning after D1R- or D2R-neuron removal in the entire striatum We next compared the respective functions of D1R or D2R MSNs during locomotion and motor skill learning following full ablation of D1-positive or D2-positive MSNs (Figure 4) that was verified by quantitative in-situ hybridization after completion of behavioural observations (Figure 4A and B). As shown in A2A-DTR+ mice (Durieux et al, 2009), the reduction of striatopallidal A2AR binding and behavioural abnormalities appear 1 week after DT injections. For that reason, all the behavioural experiments were conducted after a minimum delay of 1 week post DT injections. Spontaneous locomotion was recorded in a videotracked open field and mice were trained in a motor skill learning task (accelerating rotarod). In this task, mice have to learn a novel sequence of movements to maintain balance on a rotating rod in constant acceleration and receive several trials per day for consecutive days (Buitrago et al, 2004). While A2A-DTR+ mice exhibited persistent hyperactivity as previously described (Durieux et al, 2009) (Figure 4E, genotype: F(1,12)=208.55, P<0.001; time × genotype: F(11,12)=2.48, P=0.007), D1-DTR+ mice showed reduced locomotion (Figure 4C, genotype: F(1,14)=12.88, P=0.003; time × genotype: F(11,14)=2.60, P=0.005) that was still present 2 weeks after DT injections (39±8.9% of D1-DTR− distance moved in 60 min, P=0.03, data not shown). Full ablation of D2-positive MSN resulted in early impairments in the rotarod task, but progressive improvement of performance and finally performance equivalent to control level (Figure 4F, genotype: F(1,12)=16.45, P=0.002; trials × genotype: F(33,12)=3.13, P<0.001). In contrast, full DT-injected D1-DTR+ mice were unable to learn the task and displayed a permanent deficit (Figure 4D, genotype: F(1,14)=206.446, P<0.001; trials × genotype: F(33,14)=4.30, P<0.001). Figure 4.Motor activity and rotarod learning in D1R and D2R MSN full ablation mice. (A, B) In-situ hybridization for substance P (SP) (A) and enkephalin (Enk) (B) mRNA and respective quantitation, in rostral (bregma +1.2 mm) and caudal (bregma −0.1 mm) coronal brain sections of full striatum DT-injected D1-DTR−/D1-DTR+ (A) and A2A-DTR−/A2A-DTR+ (B) mice. Data are expressed as optical density values of the injected striatum in DTR+ as a percentage of the respective DTR− mice. Scale bars represent 1 mm. (C, E) Locomotor activity over 60 min in an open field of D1-DTR+ (C) and A2A-DTR+ (E) mice, and respective controls, 1 week after full DT injections. (D, F) Rotarod performance in D1-DTR−/D1-DTR+ (D) and A2A-DTR−/A2A-DTR+ (F) mice 1 week after full DT injections (n=6–10 per group). (G, H) Ten days of rotarod training and three days of performance recall one week after full DT injections in D1-DTR−/D1-DTR+ (G) and A2A-DTR−/A2A-DTR+ (H) mice (n=6–8 per group). Data are reported as mean±s.e.m. Statistical comparisons were made between DTR+ and respective DTR− control mice. *P<0.05, **P<0.01, ***P<0.001. Download figure Download PowerPoint In view of these cell type-specific deficits during the rotarod acquisition, we investigated impact of D1R- or D2R-MSN removal after extensive rotarod training. D1-DTR and A2A-DTR mice were overtrained on the rotarod for 10 days before receiving full DT injections (Figure 4G and H). One week after DT injections, these mice were retested on the rotarod. While D1R neuron-ablated mice displayed profound rotarod impairments (Figure 4G, genotype: F(1,12)=12.57, P=0.004; time × genotype: F(53,12)=18.82, P<0.001), mice lacking D2R neurons showed similar performances as compared with controls (Figure 4H, genotype: F(1,12)=0.55, P=0.472; time × genotype: F(53,12)=1.65, P=0.003). Thus, after extensive training, D2R MSNs from the entire striatum are not required for rotarod task execution while D1R neurons are still necessary for performance. D1R and D2R MSNs in the DMS or DLS oppositely regulate locomotor activity and novelty exploration To further investigate the roles of D2R and D1R MSNs in functionally distinct portions of the dorsal striatum, A2A-DTR+ and D1-DTR+ mice were bilaterally injected with DT in either the DMS or the DLS (Figures 5, 6, 7, 8, 9 and 10). The cell-type ablation was characterized (Figure 5) and its regional location measured and topographically represented after behavioural observations were completed (see respective figures). Elimination of D1R-striatonigral neurons in the DMS (Figure 6A and B) induced a reduction in ambulation (genotype: F(1,38)=14.096, P=0.001) that was not observed following the DLS lesion (Figure 6E and F, genotype: F(1,49)=1.38, P=0.245). In contrast, DMS D2R-striatopallidal neuron-ablated mice displayed hyperlocomotion over the trial (Figure 6D, genotype: F(1,40)=48.78, P<0.001; time: F(11,40)=3.01, P=0.001) while D2R-striatopallidal neuron loss in the DLS did not produce any locomotor activity increase (Figure 6H, genotype: F(1,41)=3.18, P=0.082). It is worth to note that the increased locomotor activity observed in DMS D2R-striatopallidal neuron ablated mice exhibited an incremental kinetics in contrast to the decremental locomotor activity observed in all other groups (Figure 6B, time: F(11,38)=24.1, P<0.001; Figure 6F, time: F(11,49)=16.85, P<0.001; Figure 6H, time: F(11,41)=9.11, P<0.001, see also histograms on each figure). Figure 5.Ablation of D1R and D2R MSNs in the dorsomedial (DMS) or dorsolateral (DLS) striatum. (A–D) In-situ hybridization and quantitation of substance P (SP) (A, C) and enkephalin (Enk) (B, D) mRNA in rostral (bregma +1.2 mm) and caudal (bregma −0.1 mm) coronal brain sections of DMS (A, B) or DLS (C, D) DT-injected D1-DTR−/D1-DTR+ (A, C) and A2A-DTR−/A2A-DTR+ (B, D) mice (topographical representation of lesions can be found on Figure 6A, C, E and G). Data are expressed as optical density values of the injected striatum in DTR+ as a percentage of respective DTR− mice. Scale bars represent 1 mm. Data are reported as mean±s.e.m. (n=7–9 per group). Statistical comparisons were made between DTR+ and respective DTR− control mice. *P<0.05, ***P<0.001. Download figure Download PowerPoint Figure 6.Locomotor behaviour after ablation of D1R or D2R MSNs in the dorsomedial (DMS) or dorsolateral (DLS) striatum. (A, C, E, G) Topographic representation of the lesioned areas in D1-DTR+ (A, E) and A2A-DTR+ (C, G) DT-injected mice into the DMS (A, C) or the DLS (E, G). Colours represent percent of superimposed lesioned areas. (B, D, F, H) Locomotion of DMS DT-injected D1-DTR+ (B) and A2A-DTR+ (D) or DLS DT-injected D1-DTR+ (F) and A2A-DTR+ (H) mice, and respective controls over 60 min in an open field; histograms represent mean ambulation during the first 10 min and the 10 last minutes of the open field. Data are reported as mean±s.e.m. (n=19–28 per group). Statistical comparisons were made between DTR+ and respective DTR− control mice (dot chart) or between first and last open field 10 min for the same genotype (histograms). *P<0.05, **P<0.01, ***P<0.001. Download figure Download PowerPoint Figure 7.Object recognition task of DMS or DLS D1R- and D2R-MSN ablated mice. (A) Decoupled delayed spontaneous object recognition task, in which time spent in an open field core zone (dot line) is recorded without object, with novel object or repeated object. (B, F, J, N) Topographic representation of the lesioned areas in D1-DTR+ (B, J) and A2A-DTR+ (F, N) DT-injected mice into the DMS (B, F) or the DLS (J, N). Colours represent percent of superimposed lesioned areas. (C–E, G–I, K–M, O–Q) Time spent in the open field core in the absence of object (C, G, K, O), time spent in open field core in the presence of novel objects divided by the time spent in the open field core without object (D, H, L, P) and time spent in the open field core during the test phase divided by time spent in the open field core during the study phase in novel or repeated conditions (F, I, M, Q) of DMS D1-DTR (C–E) and A2A-DTR (G–I) or DLS D1-DTR (K–M) and A2A-DTR (O–Q) DT-injected mice. Data are reported as mean±s.e.m. (n=6–10 per group). Statistical comparisons were made as described in Materials and methods. *P<0.05, **P<0.01, ***P<0.001. Download figure Download PowerPoint Figure 8.Rotarod performance after ablation of D1R and D2R MSNs in the DMS or DLS. (A, C, E, G) Topographic representation of the lesioned areas in D1-DTR+ (A, E) and A2A-DTR+ (C, G) DT-injected mice into the DMS (A, D) or the DLS (E, G). Colours represent percent of superimposed lesioned areas. (B, D, F, H) Rotarod performance of DMS D1-DTR+ (B) and A2A-DTR+ (D) and DLS D1-DTR+ (F) and A2A-DTR+ (H) DT-injected mice and respective controls. (I, J) Ten days of rotarod training and three days of performance recall one week after DT injections in DLS of D1-DTR (I) and DMS of A2A-DTR (J) mice; respective topographic representation of the lesioned areas can be found on Figure 5F and J. Data are reported as mean±s.e.m. (n=7–9 per group). Statistical comparisons were made between DTR+ and respective DTR− control mice. *P<0.05, **P<0.01, ***P<0.001. Download figure Download PowerPoint Figure 9.Haloperidol-induced immobility and catalepsy in mice lacking D1R or D2R MSNs in the DMS or DLS. (A, B, D, E, G, H, J, K) Locomotor activity in a 60-min open field after saline or haloperidol (1.5 mg/kg) administration in DMS D1-DTR (A, B) and A2A-DTR (D, E) or DLS D1-DTR (G, H) and A2A-DTR (J, K) DT-injected mice. (C, F, I, L) Catalepsy score (latency to move) 30 min after haloperidol (1.5 mg/kg) administration in D1-DTR+ (C, I) and A2A-DTR+ (F, L) DT-injected mice into the DMS (C, F) or the DLS (I, L). Respective topographic representation of the lesioned areas can be found on Figure 5B, F, J and N. Data are reported as mean±s.e.m. (n=6–11 per group). Statistical comparisons were made between haloperidol and saline treatment (dot chart) or DTR+ and respective DTR− control mice (histograms). *P<0.05, **P<0.01, ***P<0.001. Download figure Download PowerPoint Figure 10.Amphetamine locomotor sensitization after D1R or D2R MSN ablation in the DMS or DLS. (A, D, G, J) Topographic representation of the lesioned areas in D1-DTR+ (A, G) and A2A-DTR+ (D, J) DT-injected mice into the DMS (A, D) or the DLS (G, J). Colours represent percent of superimposed lesioned areas. (B, C, E, F, H, I, K, L) Locomotor activity in a 60-min open field after repeated d-amphetamine (3 mg/kg) administration in DMS D1-DTR (B, C) and A2A-DTR (E, F) or DLS D1-DTR (H, I) and A2A-DTR (K, L) DT-injected mice. Histograms represent ambulation following first and last d-amphetamine administration. Data are reported as mean±s.e.m. (n=10–17 per group). Statistical comparisons were made between DTR+ and respective DTR− control mice (dot chart) or between first and last amphetamine injection (histograms). *P<0.05, **P<0.01. Download figure Download PowerPoint In view of this impairment in novel environment habituation, we tested whether or not novel object exploration and recognition (Hughes, 2007) were also altered (Figure 7). Each ablated group was tested in a decoupled delayed spontaneous object recognition task (McTighe et al, 2010; see Materials and methods) in which mice have to explore an object placed in the middle of an open field. DMS D2R neuron-ablated mice spent less time in the open field core in the absence of object (Figure 7G, P=0.0497), but exhibited a dramatic increase in novel object exploration (Figure 7H, P<0.001) and were unable to reduce their exploratory behaviour when an object was repeatedly presented (Figure 7E, I, M and Q, condition: F(1,57)=5.211, P=0.026; condition × group: F(7,57)=3.284, P=0.005; Figure 7I, group: P=0.027). On the other hand, DMS D1R neuron-ablated mice showed no difference in exploring the open field core without object (Figure 7C, P=0.899), but displayed a reduced novel object exploration (Figure 7D, P=0.033). These effects were specific of the associative striatum, since neither DLS D2R neuron (Figure 7O, P=0.833; Figure 7P, P=0.90) nor DLS D1R neuron (Figure 7K, P=0.386; Figure 7L, P=0.912) ablations altered the task. Thus, DMS-specific ablations, but not the DLS lesions, demonstrate a cell type-specific modulation of locomotor activity and novel object exploration in which D2R MSNs and D1R MSNs inhibit and stimulate locomotion and novelty exploration, respectively. DMS D2R neurons and DLS D1R neurons are required for early motor learning and progressive skill acquisition, respectively Evaluation of involvement of DLS and DMS D1R and D2R neurons in motor skill learning by the accelerating rotarod (Figure 8) showed that DMS D2R neuron-ablated mice (Figure 8D, genotype: F(1,14)=1.17, P=0.297; trials × genotype: F(25,14)=2.87, P<0.001) were impaired during initial trials but gradually improved their performances to reach control levels from the second learning day, while D2R-neuron elimination in the DLS did not affect the task (Figure 8H, genotype: F(1,14)=0.32, P=0.58; trials × genotype: F(25,14)=1.51, P=0.06). On the other hand, mice lacking D1R-expressing neurons in the DLS (Figure 8F) showed rotarod impairments until 6 days of learning (genotype: F(1,16)=39.96, P<0.001; trials × genotype: F(33,16)=2.50, P<0.001), an effect totally absent in DMS D1R neuron-ablated mice (Figure 8B, genotype: F(1,14)=0.16, P=0.69; trials × genotype: F(25,14)=1.19, P=0.244). Importantly, after extensive rotarod training, ablation of DMS D2R neurons (Figure 8J, genotype: F(1,14)=0.285, P=0.602) or DLS D1R neurons (Figure 8I, genotype: F(1,18)=0.308, P=0.586) did not induce performance deficit, indicating that rotarod learning impairments (see Figure 8D and F) are not due to task execution disruption. Distinct contribution of DMS and DLS direct or indirect pathways in haloperidol-induced catalepsy and amphetamine sensitization Treatment of schizophrenia-positive symptoms with typical neuroleptic drugs is often associated with motor side effects such as catalepsy (Lieberman et al, 2008). We then evaluated involvement of each neuronal population in motor responses to neuroleptic drugs (Figure 9). Investigation of these locomotor responses revealed that D2R-striatopallidal neuron removal selectively in the associative striatum completely abolished haloperidol-induced immobility (Figure 9E, treatment: F(1,12)=0.127, P=0.728) and catalepsy (Figure 9F, P<0.001). Neither ablation of D2R neurons in the DLS (Figure 9K, treatment: F(1,10)=11.81, P=0.006; Figure 9L, P=0.17) nor D1R-neuron ablations in both dorsal striatum subregions (Figure 9B, treatment: F(1,10)=99.26, P<0.001; Figure 9C, P=0.32; Figure 9H, treatment: F(1,16)=56.15, P<0.001; Figure 9I, P=0.59) altered haloperidol responses, indicating that D2R antagonism in striatopallidal neurons of the DMS is crucial for the motor effects of haloperidol. Locomotor sensitization to psychostimulants is produced by repeated drug administration and is defined as an increase in the locomotor effect of the drug upon readministration. We evaluated involvement of each neuronal population in these motor responses to psychostimulant (Figure 10). Mice lacking D1R neurons in the DMS (Figure 10B, genotype: F(2,24)=4.56, P=0.043), but not in the DLS (Figure 10H, genotype: F(1,29)=1.3, P=0.26) showed a reduced acute amphetamine-induced hyperlocomotion as compared with controls; but repeated amphetamine injections sensitized this locomotor response (Figure 10B, repeated injections: F(2,24)=13.47, P<0.001; repeated injections × genotype: F(2,24)=1.45, P=0.246; Figure 10C, P=0.003). In contrast, ablation of DMS D2R neurons totally disrupted amphetamine locomotor sensitization (Figure 10E, repeated injections × genotype: F(2,24)=4.345, P=0.018; Figure 10F, P=0.995). On the other hand, DLS lesions of D2R neurons induced an increase in amphetamine acute locomotor activation (Figure 10K, genotype: F(1,21)=5.926, P=0.024) but sensitization was preserved in these mice (Figure 10K, repeated injections: F(2,21)=12.085, P<0.001; repeated injections × genotype: F(2,21)=0.482, P=0.621; Figure 10L, P=0.026). Discussion While it is currently accepted that dorsal striatum plays an important role in locomotor behaviours and motor learning (Graybiel, 1991; Mink and Thach, 1993; Groenewegen, 2003), MSN-type and dorsal striatum subregion involvement in these behaviours remains difficult to decipher without cell-type targeting tools. In the present work, we produced selective and inducible D2R and D1R MSN ablation in Drd1a-cre+/− iDTR+/− and Adora2a-Cre+/− iDTR+/− mice with a spatial resolution allowing their functional dissection selectively in the DMS and DLS (see Table I for a synthetic view of the observed behaviours in the different ablation subtypes). Table 1. Summary of the observed behaviours in each ablation model DMS ablation DLS ablation Entire striatum ablation D1 neurons D2 neurons D1 neurons D2 neurons D1 neurons D2 neurons Open field Total locomotion ↓ ↑ ↔ ↔ ↓ ↑ Habituation ↔ Inverted ↔ ↔ ↔ Absent Rotarod Learning curve ↔ Initial ↓ ↓ ↔ ↓ Initial ↓ Performance after learning ND ↔ ↔ ND ↓ ↔ Novel object Exploration of novel object ↓ ↑ ↔ ↔ ND ND Exploration of old object ↔ ↑ ↔ ↔ ND ND Object memory ↔ ↔ ↔ ↔ ND ND Haloperidol-induced catalepsy ↔ ↓ ↔ ↔ ND ND Amphetamine-induced locomotion Acute effect ↓ ↔ ↔ ↑ ND ND Sensitization ↔ ↓ ↔ ↔ ND ND ND, not determined. First, the selective loss of D1R and SP in D1-DTR+, taken together with the previously described loss of D2R, A2AR and Enk in A2A-DTR+ DT-injected mice (Durieux et al, 2009), confirms that expression of these receptors and neuropeptides is largely segregated in the two MSN populations (Gerfen and Young, 1988; Gerfen et al, 1990; Lobo et al, 2006; Bateup et al, 2008; Bertran-Gonzalez et al, 2008; Heiman et al, 2008). Full D2R-MSN ablation produced hyperlocomotion in contrast to the reduction of ambulation observed in D1R neuron full ablated mice. These data provide direct experimental evidence for an opposite control of the two populations over motor activity in freely moving animals, showing that D2R and D1R MSNs inhibit and stimulate motor activity respectively. Moreover, this modulatory influence on locomotion was partially recapitulated in DMS, but not in DLS, restricted ablations, indicating that associative striatum area exerts an MSN population-dependent control over spontaneous lo" @default.
• W1921515037 created "2016-06-24" @default.
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• W1921515037 date "2011-11-08" @default.
• W1921515037 modified "2023-10-07" @default.
• W1921515037 title "Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions" @default.
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• W1921515037 doi "https://doi.org/10.1038/emboj.2011.400" @default.
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