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Intrastriatal dopamine D1 antagonism dampens neural plasticity in response to motor cortex lesion.

ABSTRACT: Motor cortex lesions in rats partially denervate the striatum, producing behavioral deficits and inducing reactive neuroplasticity. Plastic responses include changes in growth-associated protein marker expression and anatomical restructuring. Corticostriatal plasticity is dependent on dopamine at the striatal target, where D1 receptor signaling reinforces behaviorally relevant neural activity. To determine whether striatal dopamine D1 receptor signaling is important for the growth-associated protein responses and behavioral recovery that follow unilateral motor cortex aspiration, the dopamine D1 receptor antagonist SCH23390 was intrastriatally infused in cortically lesioned animals. After a cortical aspiration lesion in Long Evans rats, the growth-associated proteins SCG10 and GAP-43 were upregulated in the cortex contralateral to the lesion at 30 days post-lesion. However, continuous unilateral intrastriatal infusion of SCH23390 prevented this aspiration-induced upregulation. Furthermore, lesioned rats demonstrated spontaneous sensorimotor improvement, in terms of limb-use symmetry, about 1 month post-lesion. This improvement was prevented with chronic intrastriatal SCH23390 infusion. The D1 receptor influence may be important to normalize corticostriatal activity (and observable behavior), either in a long-term manner or temporarily until other more permanent means of synaptic regulation, such as sprouting or synaptogenesis, may be implemented.

SUBMITTER: Davis EJ

PROVIDER: S-EPMC1955381 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Intrastriatal dopamine D1 antagonism dampens neural plasticity in response to motor cortex lesion.

Davis E J H EJ Coyne C C McNeill T H TH

Neuroscience 20070227 2

Motor cortex lesions in rats partially denervate the striatum, producing behavioral deficits and inducing reactive neuroplasticity. Plastic responses include changes in growth-associated protein marker expression and anatomical restructuring. Corticostriatal plasticity is dependent on dopamine at the striatal target, where D1 receptor signaling reinforces behaviorally relevant neural activity. To determine whether striatal dopamine D1 receptor signaling is important for the growth-associated pro ...[more]

PMID: 17331653

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Project description:IntroductionDespite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound's long-term therapeutic effects.Materials and methodsIn the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.ResultsOur results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH+ cells and TH+ fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.ConclusionIn summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.

Project description:The present study in rats was conducted to identify brain regions affected by the interruption of vestibular transmission and to explore selected aspects of their functional connections. We analyzed, by positron emission tomography (PET), the regional cerebral glucose metabolism (rCGM) of cortical, and subcortical cerebral regions processing vestibular signals after an experimental lesion of the left laterodorsal thalamic nucleus, a relay station for vestibular input en route to the cortical circuitry. PET scans upon galvanic vestibular stimulation (GVS) were conducted in each animal prior to lesion and at post-lesion days (PLD) 1, 3, 7, and 20, and voxel-wise statistical analysis of rCGM at each PLD compared to pre-lesion status were performed. After lesion, augmented metabolic activation by GVS was detected in cerebellum, mainly contralateral, and in contralateral subcortical structures such as superior colliculus, while diminished activation was observed in ipsilateral visual, entorhinal, and somatosensory cortices, indicating compensatory processes in the non-affected sensory systems of the unlesioned side. The changes in rCGM observed after lesion resembled alterations observed in patients suffering from unilateral thalamic infarction and may be interpreted as brain plasticity mechanisms associated with vestibular compensation and substitution. The second set of experiments aimed at the connections between cortical and subcortical vestibular regions and their neurotransmitter systems. Neuronal tracers were injected in regions processing vestibular and somatosensory information. Injections into the anterior cingulate cortex (ACC) or the primary somatosensory cortex (S1) retrogradely labeled neuronal somata in ventral posteromedial (VPM), posterolateral (VPL), ventrolateral (VL), posterior (Po), and laterodorsal nucleus, dorsomedial part (LDDM), locus coeruleus, and contralateral S1 area. Injections into the parafascicular nucleus (PaF), VPM/VPL, or LDDM anterogradely labeled terminal fields in S1, ACC, insular cortex, hippocampal CA1 region, and amygdala. Immunohistochemistry showed tracer-labeled terminal fields contacting cortical neurons expressing the ?-opioid receptor. Antibodies to tyrosine hydroxylase, serotonin, substance P, or neuronal nitric oxide-synthase did not label any of the traced structures. These findings provide evidence for opioidergic transmission in thalamo-cortical transduction.

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Intrastriatal dopamine D1 antagonism dampens neural plasticity in response to motor cortex lesion.

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Intrastriatal dopamine D1 antagonism dampens neural plasticity in response to motor cortex lesion.

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