Behavioral Characterization of Quinolinate-Induced Lesions of the Medial Striatum: Relevance for Huntington's Disease

Furtado, Joarez; Mazurek, Michael F.

doi:10.1006/exnr.1996.0054

Cited by 75 publications

(31 citation statements)

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“…The cognitive deficits in H D are associated with frontostriatal pathology, however striatal dysf unction and cognitive deficits in the absence of cell death are seen in early stage H D (Myers et al, 1988). Interestingly, animal models of HD with frontostriatal lesions display cognitive deficits, attributed to the selective striatal damage, which are similar to those reported here (Divac et al, 1967;Furtado and Mazurek, 1996;Palfi et al, 1996;Emerich et al, 1997;Shear et al, 1998a,b). The present data are consistent with a frontostriatal basis for the deficit.…”

Section: Possible Mechanisms Underlying Cognitive Dysfunctionsupporting

confidence: 76%

“…Several animal models for HD have been described, including lesions of the striatum induced by excitotoxins (e.g., quinolinic acid) and metabolic poisons (e.g., 3-nitropropionic acid). These models show striatal pathology similar to that seen in H D (Coyle and Schwarcz, 1976;McGreer and McGreer, 1976;Beal et al, 1986Beal et al, , 1993Bossi et al, 1993;Brouillet et al, 1993Brouillet et al, , 1995, and also replicate some of the motor and cognitive symptoms of the disease (Borlongan et al, 1995;Brouillet et al, 1995;Furtado and Mazurek, 1996;Palfi et al, 1996;Emerich et al, 1997;Kodsi and Swerdlow, 1997;Shear et al, 1998a,b). However, a major disadvantage of these neurotoxic models is that they lack the genetic pathogenesis and the progressive nature of HD.…”

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confidence: 71%

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Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation

Lione

Carter²,

Hunt³

et al. 1999

J. Neurosci.

355

241

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Cognitive decline is apparent in the early stages of Huntington's disease and progressively worsens throughout the course of the disease. Expression of the human Huntington's disease mutation in mice (R6/2 line) causes a progressive neurological phenotype with motor symptoms resembling those seen in Huntington's disease. Here we describe the cognitive performance of R6/2 mice using four different tests (Morris water maze, visual cliff avoidance, two-choice swim tank, and T-maze). Behavioral testing was performed on R6/2 transgenic mice and their wild-type littermates between 3 and 14.5 weeks of age, using separate groups of mice for each test. R6/2 mice did not show an overt motor phenotype until ∼8 weeks of age. However, between 3.5 and 8 weeks of age, R6/2 mice displayed progressive deterioration in specific aspects of learning in the Morris water maze, visual cliff, two-choice swim tank, and T-maze tasks. The age of onset and progression of the deficits in the individual tasks differed depending on the particular task demands. Thus, as seen in humans with Huntington's disease, R6/2 mice develop progressive learning impairments on cognitive tasks sensitive to frontostriatal and hippocampal function. We suggest that R6/2 mice provide not only a model for studying cognitive and motor changes in trinucleotide repeat disorders, but also a framework within which the functional efficacy of therapeutic strategies aimed at treating such diseases can be tested.

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Section: Possible Mechanisms Underlying Cognitive Dysfunctionsupporting

confidence: 76%

mentioning

confidence: 71%

Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation

Lione

Carter²,

Hunt³

et al. 1999

J. Neurosci.

355

241

View full text Add to dashboard Cite

show abstract

“…Woolley and colleagues [10] reported increased activation of dorsomedial striatum (DMS) in mice during the first three days of training, and lesion studies showed that rats with DMS damage needed more time to acquire the hidden platform position [5,6,11,12]. Impaired performance in these animals might be, at least partly, attributed to disinclination or inability to acquire spatial search strategies.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the spatial-cognitive functions of dorsomedial striatum and anterior cingulate cortex in mice

et al. 2017

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Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a corticostriatal circuit with putative roles in learning and other cognitive functions. In the present study, the spatial-cognitive importance of aCC and DMS was assessed in the hidden-platform version of the Morris water maze (MWM). Brain lesion experiments that focused on areas of connectivity between these regions indicated their involvement in spatial cognition. MWM learning curves were markedly delayed in DMS-lesioned mice in the absence of other major functional impairments, whereas there was a more subtle, but still significant influence of aCC lesions. Lesioned mice displayed impaired abilities to use spatial search strategies, increased thigmotaxic swimming, and decreased searching in the proximity of the escape platform. Additionally, aCC and DMS activity was compared in mice between the early acquisition phase (2 and 3 days of training) and the over-trained high-proficiency phase (after 30 days of training). Neuroplasticity-related expression of the immediate early gene Arc implicated both regions during the goal-directed, early phases of spatial learning. These results suggest the functional involvement of aCC and DMS in processes of spatial cognition that model associative cortex-dependent, human episodic memory abilities.

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“…Quinolinic acid (QA) could induce lesions similar as the behavioral, morphological and neurochemical alterations in HD patients, including hyperactivity [2] , cognitive impairment [3] , depletion of spiny neuron markers [1,4] , and reduction in GABAergic and cholinergic neurotransmission [5,6] . Hyperstimulation of NMDA receptors [7] leads to massive Ca 2+ influxes that would then activate other cellular processes, such…”

Section: Introductionmentioning

confidence: 99%

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

Kalonia

Kumar

et al. 2009

Neurosci. Bull.

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Objective The neuroprotective roles of cyclooxygenase (COX) and lipooxygenase (LOX) inhibitors have been well documented. Quinolinic acid (QA) is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington's disease (HD), by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid (a specific inhibitor for LOX), rofecoxib (a specific inhibitor for COX-2), and their combination in ameliorating QAinduced neurotoxicity in rats. Methods QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity. Results Intrastriatal QA administration (300 nmol) not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status (decreased glutathione and increased oxidized glutathione level) in striatum, as compared to the sham group.Moreover, chronic treatment with caffeic acid (5 mg/kg and 10 mg/kg, respectively, p.o.) or rofecoxib (10 mg/kg, p.o.) could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib (10 mg/kg) and caffeic acid (5 mg/kg) could significantly protect against QA neurotoxicity. Conclusion The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.

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Behavioral Characterization of Quinolinate-Induced Lesions of the Medial Striatum: Relevance for Huntington's Disease

Cited by 75 publications

References 0 publications

Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation

Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation

Comparison of the spatial-cognitive functions of dorsomedial striatum and anterior cingulate cortex in mice

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

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