Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain.

Overexpression of human alpha-synuclein (alpha-syn) using recombinant adeno-associated viral (rAAV) vectors provides a novel tool to study neurodegenerative processes seen in Parkinson's disease and other synucleinopathies. We used a pseudotyped rAAV2/5 vector to express human wild-type (wt) alpha-syn, A53T mutated alpha-syn, or the green fluorescent protein (GFP) in the primate ventral midbrain. Twenty-four adult common marmosets (Callithrix jacchus) were followed with regular behavioural tests for 1 year after transduction.

Neglect of memory after dopaminergic lesions in monkeys.

Crossed unilateral dopaminergic lesions of the nigrostriatal bundle and unilateral inferotemporal cortex ablations (DA x IT lesions) in marmoset monkeys produced impaired retention of object discriminations first learnt before, or after, the DA lesion but no impairment on new learning of the same type of task. Retention testing of a pre-operatively learned task was given after new learning of a different task so impairment cannot be attributed to improvement with practice or spontaneous recovery. We argue that the DA lesion produces a form of intentional neglect, a defect of volition, which is the mnemonic counterpart of the volitional neglect of directional hypokinesia, which animals with this lesion also exhibit.

Mild topographical memory impairment following crossed unilateral lesions of the mediodorsal thalamic nucleus and the inferotemporal cortex.

Monkeys with crossed unilateral lesions of the dorsomedial thalamus and contralateral ablations of the inferotemporal cortex were mildly impaired on acquisition and retention of visual conditional tasks requiring the integration of information about objects and their positions in space. They were not impaired on other conditional and nonconditional tasks. This impairment pattern resembles, qualitatively, that found following crossed unilateral lesions of the anterior thalamus and the inferotemporal cortex or bilateral lesions of the anterior and mediodorsal thalamic nuclei.

Further analysis of the effects of immunotoxic lesions of the basal nucleus of Meynert reveals substantial impairment on visual discrimination learning in monkeys.

In this paper we undertake a combined analysis of several studies in which marmoset monkeys received immunotoxic lesions of the cortical cholinergic projections from the basal nucleus of Meynert (NBM) bilaterally and/or in combination with immunotoxic lesions of other parts of the cholinergic system or ablations of the target inferotemporal neocortical area. Analysis of the mean learning scores across all visual discriminations learning tasks for each lesion combination revealed highly significant impairments where the NBM was lesioned bilaterally or where an NBM lesion in one hemisphere was crossed with an inferotemporal cortical ablation in the other hemisphere. This demonstrates that the cholinergic projection from the NBM to the major target area of neocortex involved in visual discrimination learning, i.

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

The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) for Parkinson's disease is likely to depend on sustained delivery of the appropriate amount to the target areas. Recombinant adeno-associated viral vectors (rAAVs) expressing GDNF may be a suitable delivery system for this purpose. The aim of this study was to define a sustained level of GDNF that does not affect the function of the normal dopamine (DA) neurons but does provide anatomical and behavioral protection against an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in the common marmoset.

Analysis of infant carrying in large, well-established family groups of captive marmosets (Callithrix jacchus).

To assess the pattern of infant carrying across time and family members, we counted which animals in 13 well-established family groups of captive-bred marmosets (Callithrix jacchus) carried neonates during the first 8 weeks of life. The neonates were carried almost continuously for the first 3 weeks and then spent progressively more time independently. The mother did most of the carrying for the first 2 weeks, her contribution rising from day 1 to day 3 and declining thereafter.

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

Glial cell line-derived neurotrophic factor (GDNF) has shown potential as a treatment for Parkinson's disease. Recombinant adeno-associated viral vectors expressing the GDNF protein (rAAV-GDNF) have been used in rodent models of Parkinson's disease to promote functional regeneration after 6-OHDA lesions of the nigrostriatal system. The goal of the present study was to assess the anatomical and functional efficacy of rAAV-GDNF in the common marmoset monkey (Callithrix jacchus).

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

Animal studies investigating the efficacy of neurotrophic factors as treatments for Parkinson's disease (PD) ideally require partial dopamine (DA) lesion models. The intrastriatal 6-hydroxydopamine (6-OHDA) lesion model may be suitable for this purpose. Although this model has been well characterized in rodents, it has not previously been used in monkeys.

Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion.

Background And Purpose: NXY-059 has substantial protective effects when administered immediately after the onset of ischemia in a primate model of stroke. This study examined the efficacy of this drug when administered 4 hours after onset, a more clinically relevant time point.

Methods: Before surgery, marmosets were trained and tested on a number of neurological tests, which assessed general neurological function, motor ability, and spatial awareness.

What would T. H. Huxley have made of prion diseases?

T. H. Huxley was "Darwin's bulldog," and took the offensive in championing the cause of evolution against skeptical scientists and outraged theologians.

Comparison of the neuroprotective effect of clomethiazole, AR-R15896AR and NXY-059 in a primate model of stroke using histological and behavioural measures.

Three experimental neuroprotective agents (clomethiazole, AR-R15896AR and NXY-059) have recently been tested in a primate model of acute ischaemic stroke. As the experimental techniques used in all three studies were similar and the compounds were administered at clinically relevant doses, a comparative analysis of the functional benefits of these drug-treatments has now been performed. Furthermore a more detailed histological analysis of the neuroprotection afforded by the drugs has also been made.

Unilateral hippocampal and inferotemporal cortex lesions in opposite hemispheres impair learning of single-pair visual discriminations as well as visuovisual conditional tasks in monkeys.

Monkeys with unilateral ablations of the inferotemporal (IT) cortex were not impaired on learning or retention of single-pair object discriminations or visuovisual conditional tasks. Addition of an excitotoxic hippocampal lesion to the hemisphere opposite to the IT ablation impaired retention and acquisition of single-pair object discriminations and visuovisual conditional tasks. Histology revealed no areas of bilaterally symmetrical damage.

Assessment of cognitive and motor deficits in a marmoset model of stroke.

The Stroke Therapy Academic Industry Roundtable noted the need for standardized, well-accepted primate models of stroke to help develop both neuroprotective and restorative therapies. One primate model has been developed using the marmoset, a small New World species of monkey, in which long-term functional deficits can be assessed. The surgery and postoperative care of the animals is described, as well as the behavioral tests used to quantify the postoperative disability.

Learning impairments in monkeys with combined but not separate excitotoxic lesions of the anterior and mediodorsal thalamic nuclei.

Clinical studies in humans and experiments in macaques suggest that damage to the anterior and the mediodorsal thalamus can induce a moderate amnesia, but a more dense impairment may result from substantial damage within the temporal lobes or their subcortical connections. Lesions of the anterior thalamus in macaques produce impairments which resemble those seen after lesions of the fornix-mamillary pathway, which carries projections from the hippocampus to the anterior thalamus, while lesions of the mediodorsal thalamus, which receives inputs from frontal and temporal cortex, produce moderate impairments on a wider range of memory tasks. In the present study, we have made bilateral excitotoxic lesions of either the anterior or the mediodorsal thalamus, or both, in marmoset monkeys.