Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions

Miyoshi, Edmar; Wietzikoski, Samantha; Camplessei, Milton; Silveira, Ricardo dos Reis; Takahashi, Reinaldo Ν.; Cunha, Cláudio Da

doi:10.1016/s0361-9230(02)00754-2

Cited by 141 publications

(85 citation statements)

References 63 publications

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“…On the basis of recent evidence, visuo-spatial memory impairments seem to be the most constantly reported cognitive deficit in Parkinson's disease (PD) patients (Berger et al, 2004;Cools et al, 2002Cools et al, , 2007Giraudo et al, 1997;Lewis et al, 2003;Owen et al, 1998;Pillon et al, 1997Pillon et al, , 1998. Consistently, extensive DA lesions, obtained through either medial forebrain bundle or dorsal striatum 6-hydroxydopamine (6-OHDA) administrations, have been found to impair memory in the spatial version of the Morris water maze in rats (Miyoshi et al, 2002;Mura and Feldon, 2003;Whishaw and Dunnett, 1985). Furthermore, it has been recently shown that partial bilateral DA depletion of the dorsal striatum impairs spatial discrimination in the object-place association task in mice, and that this effect is specific for spatial information (De Leonibus et al, 2007), thus providing an useful animal model of cognitive deficit in the early stages of PD.…”

Section: Introductionmentioning

confidence: 82%

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Leonibus

Managò

Giordani

et al. 2008

Neuropsychopharmacol

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Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudateputamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.

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Section: Introductionmentioning

confidence: 82%

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Leonibus

Managò

Giordani

et al. 2008

Neuropsychopharmacol

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“…A selective lesion in the SNpc (Miyoshi et al 2002;Da Cunha et al 2003;Tadaiesky et al 2008), which mainly projects to the striatum, or the systemic MPTP treatment (Pothakos et al 2009) selectively impaired the learning process as well as the memory test performance of rodents in the cued, but not in the spatial, version of MWM. Those behavioral observations were accompanied by a reduction of dopamine levels in the striatum and prefrontal cortex, but not in the hippocampus (Miyoshi et al 2002;Da Cunha et al 2003). Conversely, the bilateral injection of 6-OHDA into the dorsal and ventral subiculum and adjacent CA1 hippocampus area (Gasbarri et al 1996) selectively affected the test performance in the spatial, but not in the cued, version of MWM.…”

Section: -Ohda-and Mptp-based Rodent Modelsmentioning

confidence: 99%

Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

et al. 2013

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Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet clinical condition. At the preclinical level, the large majority of studies aiming at defining mechanisms and testing novel therapies have similarly focused on the motor aspects of PD. Unfortunately, deterioration of the executive functions, such as attention, recognition, working memory, and problem solving, often appear in an early, premotor phase of the disease and progressively increase in intensity, negatively affecting the quality of life of 50% -60% of PD patients. At present, the cellular mechanisms underlying cognitive impairments in PD patients are largely unknown and an adequate treatment is still missing. The preclinical research has recently developed new animal models that may open new perspectives for a more integrated approach to the treatment of both motor and cognitive symptoms of the disease. This review will provide an overview on the cognitive symptoms occurring in early PD patients and then focus on the rodent and nonhuman primate models so far available for the study of discriminative and spatial memory attention and learning abilities related to this pathological condition. Cognitive deficits in Parkinson's diseaseParkinson's disease (PD) is a chronic neurodegenerative disorder affecting over four million people worldwide (Dorsey et al. 2007). It is classically characterized by the emergence of motor symptoms such as rigidity, tremor, postural unbalance, and bradykinesia/akinesia (Braak et al. 2003;Jankovic 2008). However, PD also involves nonmotor symptoms (NMS) (Chaudhuri et al. 2006;Jankovic 2008) that appear in the early, often premotor, phase of the disease (Abbott et al. 2005;Abbott 2007;Claassen et al. 2010) and significantly contribute to the impairment of the quality of life of 50%-60% of PD patients (Aarsland et al. 2012). Among others, NMS include olfactory dysfunction, REM sleep disorder, neuropsychiatric disturbances, and cognitive deficits (Schrag et al. 2004;Chaudhuri and Odin 2010). All these symptoms develop independently from each other in the early phase of the disease, and progressively increase in intensity, often leading to dementia in the late phase (Cools et al. 2001;Goetz et al. 2008).Neuropsychiatric mood-related disorders are rather common in PD (Cummings 1992;Schrag et al. 2004) with a prevalence of 20% (Reijnders et al. 2008), and manifest as apathy, depression, and anxiety.On the other hand, cognitive impairments associated with PD are mainly related to the executive functions, resulting in a phenotype resembling that of frontal lobe patients (Robbins and Arnsten 2009), with deficits in attention (Ballard et al. 2002), planning, concept formation, and working memory (Kehagia et al. 2010). In particular, memory deterioration aff...

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“…Following important early demonstrations of dopamine (DA)-dependent memory (Williams and Goldman-Rakic 1995), it is now clear that DA is implicated in both spatial (e.g. Miyoshi et al 2002) and phonological (Jacobsen et al 2006) WM (though, owing to the more substantial literature, our focus will be on visuospatial tasks). Experimental pharmacological lesions of the DA system lead to impaired spatial WM performance (Miyoshi et al 2002).…”

Section: Working Memorymentioning

confidence: 99%

“…Miyoshi et al 2002) and phonological (Jacobsen et al 2006) WM (though, owing to the more substantial literature, our focus will be on visuospatial tasks). Experimental pharmacological lesions of the DA system lead to impaired spatial WM performance (Miyoshi et al 2002). In contrast, lower doses lead to an enhancement (e.g.…”

Section: Working Memorymentioning

confidence: 99%

Attractor models of working memory and their modulation by reward

2007

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This work reports an empirical examination of two key issues in theoretical neuroscience: distractibility in the context of working memory (WM) and its reward dependence. While these issues have been examined fruitfully in isolation (e.g. Macoveanu et al. in Biol Cybern 96(4): 407-19, 2007), we address them here in tandem, with a focus on how distractibility and reward interact. In particular, we parameterise an observation model that embodies the nonlinear form of such interactions, as described in a recent neuronal network model (Gruber et al. in J Comput Neurosci 20:153-166, 2006). We observe that memory for a target stimulus can be corrupted by distracters in the delay period. Interestingly, in contrast to our theoretical predictions, this corruption was only partial. Distracters do not simply overwrite target; rather, a compromise is reached between target and distracter. Finally, we observed a trend towards a reduced distractibility under conditions of high reward. We discuss the implications of these findings for theoretical formulations of basal and dopamine (DA)-modulated neural bumpattractor networks of working memory.

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Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions

Cited by 141 publications

References 63 publications

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

Attractor models of working memory and their modulation by reward

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