Sensorimotor deficits in a unilateral intrastriatal 6-OHDA partial lesion model of Parkinson's Disease in marmoset monkeys

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Nigrostriatal a-synucleinopathy induced by recombinant AAV vector-mediated overexpression of human a-synuclein: a new primate model of Parkinson's disease

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Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant AAV vectors provides neuroprotection and induces behavioural recovery in a primate model of Parkinson's disease

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Recombinant adeno-associated viral vector (rAAV) delivery of GDNF provides anatomical and behavioural protection against 6-OHDA lesions in the common marmoset monkey (Callithrix jacchus)

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Behavioural analysis of unilateral monoamine depletion in the marmoset

Original article can be found at: http://brain.oxfordjournals.org/archive/ Copyright Guarantors of Brain. DOI: 10.1093/brain/115.3.825 [Full text of this article is not available in the UHRA]Unilateral stereotaxic injections of 6-hydroxydopamine (6-OHDA) into the nigrostriatal bundle of marmosets (Callithrix jacchus) produced substantial losses of tyrosine hydroxylase immunoreactive neurons from the substantia nigra, and mean dopamine (DA) depletions of 98–99% in the caudate nucleus, putamen and nucleus accumbens, and of 91-97% in frontal cortex, on the side of the lesion. Noradrenaline (NA) and 5-hydroxytryptamine (5-HT) levels were also affected. Behavioural tests conducted pre-operatively and at regular intervals during the 6mths following surgery revealed persistent deficits in the lesioned marmosets as a group compared with sham-lesioned controls, although individual marmosets sometimes recovered or showed no initial deficit on some tests. The main behavioural effects of the lesions were as follows: (i) an increase in the time spent with the head positioned ipsilaterally with respect to the rest of the body; (ii) ipsilateral spontaneous and amphetamine-induced rotation, although occasional intermittent periods of contralateral rotation and head biases were also recorded; (iii) contralateral apomorphine-induced rotation; (iv) reduced spontaneous activity; (v) ipsilateral hand preference on a conveyor belt task, although hand skill (measured as percentage errors when the speed of the belt was increased) was not affected; (vi) neglect of contralateral stimuli, both at the conveyor belt where lesioned monkeys often failed to respond on trails on which apple pieces arrived from the contralateral side, and on a test of sensorimotor neglect in which adhesive labels were placed around both feet. Comparisons of biochemical measures of the lesion with behavioural scores in individual monkeys suggest that DA depletions in excess of 95% are essential for long-term behavioural deficits.Peer reviewe

Behavioural effects of subthalmic nucleus lesions in the hemiparkinsonian marmoset.(Callithrix jacchus)

" The definitive version is available at www.blackwell-synergy.com " Copyright Blackwell Publishing. DOI: 10.1046/j.1460-9568.1998.00077.x [Full text of this article is not available in the UHRA]Recent studies in non-human primates support a role for the subthalamic nucleus in the expression of parkinsonian symptomatology, and it has been proposed that subthalamic lesions may provide a surgical treatment for the symptoms of Parkinson’s disease in humans. We have applied a broad range of behavioural tests to characterize the effects of lesions of the subthalamic nucleus on parkinsonian symptoms in the unilateral 6-hydroxydopamine (6-OHDA) lesioned marmoset (Callithrix jacchus). Thirteen marmosets were trained on a battery of behavioural tasks that were conducted at regular intervals before and after surgery. All received unilateral 6-OHDA lesions to the medial forebrain bundle. Seven animals were then given an additional N-methyl-d-aspartate lesion of the ipsilateral subthalamic nucleus, whereas the remaining six animals received a variety of control or sham lesions to the nucleus. The 6-OHDA lesions induced a strong ipsilateral bias in head position; mild–moderate ipsilateral rotation spontaneously and after injection of saline or amphetamine; and contralateral rotation after injection of apomorphine. Hemineglect was evident as delayed initiation of reaches on the contralateral side on the staircase reaching task. Additional subthalamic lesions significantly reversed the bias in head position from ipsilateral to contralateral and decreased neglect as evidenced by improved latencies to initiate reaching on the contralateral side at the staircase. However, deficits in skilled movements persisted in the subthalamic nucleus lesion group in that they did not complete the staircase task any faster than the control group and remained impaired on another task which required reaching into tubes. These behavioural effects demonstrate that excitotoxic lesioning of the subthalamic nucleus can ameliorate some, but not all, parkinsonian-like deficits in the unilateral 6-OHDA lesioned marmoset.Peer reviewe

A comparison of the behavioural effects of embryonic nigral grafts in the caudate nucleus and in the putamen of marmosets with unilateral 6-OHDA lesions

" The original publication is available at www.springerlink.com " Copyright Springer. DOI: 10.1007/BF00241495 [Full text of this article is not available in the UHRA]The behaviour of marmosets with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle and grafts of embryonic mesencephalon in either the caudate nucleus or the putamen was compared with that of lesion-alone and unoperated controls. The grafts comprised injections of cell suspensions prepared from marmoset ventral mesencephalon (i.e. allografts) targeted at four sites either entirely within the caudate nucleus or entirely within the putamen. Behavioural tests, including measures of amphetamine-induced rotation, neglect and use of each arm to retrieve food from inside tubes, were given before and after the 6-hydroxydopamine lesion and at regular intervals for 6 months after transplantation surgery. Grafts in the caudate nucleus reduced the ipsilateral rotation induced by amphetamine, whereas grafts in the putamen did not. Despite the absence of an effect on rotation, the putamen grafts were effective in reducing lesion-induced deficits on the task in which the marmosets were required to reach into tubes. In this latter task, the caudate grafts were also effective when the monkeys were given a free choice of which hand to use. However, when constrained to use the hand contralateral to the lesion and graft, the performance of the marmosets with caudate grafts was not significantly improved compared with that of lesion-alone controls. Neither the grafts in the caudate nucleus nor the grafts in the putamen abolished the contralateral somatosensory neglect induced by the lesion, although there was a trend for the marmosets with putamen grafts to contact the label on the contralateral side more quickly than those with caudate grafts or the lesion-alone controls. These results demonstrate that the location of embryonic nigral grafts within the primate striatum influences the profile of functional recovery.Peer reviewe

Behavioural assessment of the effects of embryonic nigral grafts in marmosets with unilateral OHDA lesions of the nigrostriatal pathway

Original article can be found at: http://www.sciencedirect.com/science/journal/00144886 Copyright Elsevier Inc. DOI: 10.1006/exnr.1994.1026 [Full text of this article is not available in the UHRA]Grafts of embryonic nigral tissue were made into the striatum of marmosets (Callithrix jacchus) which had previously received a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal bundle. The grafts comprised injections of cell suspensions prepared from embryonic (74 day) marmoset ventral mesencephalic tissue targeted at multiple striatal sites in the caudate nucleus, the putamen, and the nucleus accumbens on the same side as the initial lesion. A series of behavioral tests was used to assess the monkeys prior to surgery, following the 6-OHDA lesion, and at regular intervals for 6 months after transplantation surgery. Lesioned and grafted (n = 6) or lesion alone (n = 4) monkeys were matched as far as possible with respect to their scores prior to transplantation so that explicit graft-derived recovery could be distinguished from any spontaneous recovery that might occur. Shamlesioned or unoperated monkeys served as further controls (n = 5). The grafts were functionally effective as measured by a reduction, and in some cases a reversal, of spontaneous, amphetamine- and apomorphine-induced rotation. The reversal of amphetamine-induced rotation correlated with the number of dopaminergic neurons in the grafts visualized by tyrosine hydroxylase immunohistochemistry. Successful use of the hands was restored by the grafts on tasks in which the monkeys reached into tubes to retrieve food. However, functional recovery was not seen on some other behavioral tests. In particular, grafts did not influence ipsilateral biases induced by the lesion, including the position of the head with respect to the rest of the body, hand preference while reaching for food at a conveyor belt, and neglect of contralateral stimuli either at the conveyor belt or of adhesive labels placed around the feet. Indeed, the graft group was impaired compared with the lesion group in the accuracy of reaches at the conveyor belt. Overall, these results indicate that embryonic nigral grafts can yield a partial recovery from the symptoms induced by unilateral nigrostriatal lesions in a primate model of hemiparkinsonism.Peer reviewe

Subthalamic nucleus lesions induce deficits as well as benefits in the hemiparkinsonian rat

" The definitive version is available at www.blackwell-synergy.com " Copyright Blackwell Publishing. DOI: 10.1046/j.1460-9568.1999.00692.x [Full text of this article is not available in the UHRA]Lesions of the subthalamic nucleus can restore some imbalances in motor output of the basal ganglia induced by nigrostriatal dopamine depletion, and have been proposed as a potential therapy for Parkinson’s disease. Although there is substantial supporting evidence from experimental studies in both rats and primates, there is less information on the effects of subthalamic lesions alone. In order to characterize potential side effects, the present study evaluates the behavioural effects of unilateral excitotoxic lesions of the subthalamic nucleus in rats that have previously received either unilateral saline or 6-hydroxydopamine injections into the nigrostriatal bundle on the same side. The 6-hydroxydopamine lesions induced ipsilateral orientation asymmetries in head position and body axis bias, rotational asymmetries following injections of direct or indirect dopamine agonists, neglect of contralateral stimuli, and a reduction in the numbers of pellets retrieved with the contralateral paw in a skilled reaching task. Subsequent excitotoxic lesions of the subthalamic nucleus reduced (but did not abolish) rotational asymmetries, had no effects on the measures of neglect and skilled paw-reaching, and produced contralateral orientation biases in head turning and body axis curling. Rats that received subthalamic lesions alone exhibited de novo impairments comprising contralateral biases in the orientation tests. These results support a neuromodulatory role of the subthalamic nucleus in regulating motor outputs of the basal ganglia, and caution that there may be distinct side effects of the lesion by itself. Whereas some impairments attributable to dopamine depletion may be alleviated by subthalamic manipulations, other symptoms are not, or may even be aggravated.Peer reviewe

Characterization of Patient-Derived GNAQ Mutated Endothelial Cells from Capillary Malformations

Capillary malformations (CM) (port-wine stains) are congenital skin lesions that are characterized by dilated capillaries and postcapillary venules. CMs are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cells of CMs, providing an opportunity for the development of targeted therapies. However, there is currently limited in-depth mechanistic insight into the pathophysiology and a lack of preclinical research approaches. In a monocenter exploratory study of 17 adult patients with CMs, we found somatic sequence variants in the GNAQ (p.R183Q, p.R183G, or p.Q209R) or GNA11 (p.R183C) genes. We applied an endothelial-selective cell isolation protocol to culture primary endothelial cells from skin biopsies from these patients. We successfully expanded patient-derived cells in culture in 3 of the 17 cases while maintaining endothelial specificity as demonstrated by vascular endothelial-cadherin immunostainings. In addition, we tested the angiogenic capacity of endothelial cells from a patient with a GNAQ (p.R183G) sequence substitution. These proof-of-principle results reveal that primary cells isolated from CMs may represent a functional research model to investigate the role of endothelial somatic mutations in the etiology of CMs, but improved isolation and culture methodologies are urgently needed to advance the field