Longitudinal characterization of cognitive and motor deficits in an excitotoxic lesion model of striatal dysfunction in non-human primates

Abstract

As research progresses in the understanding of the molecular and cellular mechanisms underlying neurodegenerative diseases like Huntington's disease (HD) and expands towards preclinical work for the development of new therapies, highly relevant animal models are increasingly needed to test new hypotheses and to validate new therapeutic approaches. In this light, we characterized an excitotoxic lesion model of striatal dysfunction in non-human primates (NHPs) using cognitive and motor behaviour assessment as well as functional imaging and post-mortem anatomical analyses. NHPs received intra-striatal stereotaxic injections of quinolinic acid bilaterally in the caudate nucleus and unilaterally in the left sensorimotor putamen. Post-operative MRI scans showed atrophy of the caudate nucleus and a large ventricular enlargement in all 6 NHPs that correlated with post-mortem measurements. Behavioral analysis showed deficits in 2 analogues of the Wisconsin card sorting test (perseverative behavior) and in an executive task, while no deficits were observed in a visual recognition or an episodic memory task at 6 months following surgery. Spontaneous locomotor activity was decreased after lesion and the incidence of apomorphine-induced dyskinesias was significantly increased at 3 and 6 months following lesion. Positron emission tomography scans obtained at end-point showed a major deficit in glucose metabolism and D2 receptor density limited to the lesioned striatum of all NHPs compared to controls. Post-mortem analyses revealed a significant loss of medium-sized spiny neurons in the striatum, a loss of neurons and fibers in the globus pallidus, a unilateral decrease in dopaminergic neurons of the substantia nigra and a loss of neurons in the motor and dorsolateral prefrontal cortex. Overall, we show that this robust NHP model presents specific behavioral (learning, execution and retention of cognitive tests) and metabolic functional deficits that, to the best of our knowledge, are currently not mimicked in any available large animal model of striatal dysfunction. Moreover, we used non-invasive, translational techniques like behavior and imaging to quantify such deficits and found that they correlate to a significant cell loss in the striatum and its main input and output structures. This model can thus significantly contribute to the pre-clinical longitudinal evaluation of the ability of new therapeutic cell, gene or pharmacotherapy approaches in restoring the functionality of the striatal circuitry.

Comparative test-retest variability of outcome parameters derived from brain [18F]FDG PET studies in non-human primates

“…Magnetic resonance imaging (MRI) acquisition procedure was previously described [1]. Briefly, MRI was performed on each NHP in order to delineate cerebral regions on co-registered PET images.…”

“…[ 18 F]FDG PET therefore provides a convenient tool to non-invasively monitor changes in neuronal activity in pathophysiological states. [ 18 F]FDG PET is a translational imaging method, which can be performed either in humans or in animals going from rodents to large animal species such as nonhuman primates (NHP) [1]. Though invasive in rodents, quantitative [ 18 F]FDG PET is only minimally invasive in NHPs, which facilitates its use as a close-human animal model.…”

Large Animal Models of Huntington’s Disease: What We Have Learned and Where We Need to Go Next

“…(For a review of the HD neurotoxin-based models in rodents and NHPs, see [ 60 ]). A more recent study [ 61 ] reported that in addition to spontaneous dyskinesias and increased perseverative behaviors on a set-shifting task, quinolinic acid-lesioned macaques also showed deficits in glucose metabolism and D2 receptor density in the lesioned putamen, as measured by positron emission tomography (PET), with a concomitant loss of neurons in the striatum and dorsolateral prefrontal cortex [ 61 ]. While the neurotoxin-based models do not replicate the genetic root cause of HD, they do recapitulate several key cardinal features of the disease.…”

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward

“…Animal models of HD remain an important experimental tool, in particular for assessing donor sources that may replace fetal‐derived cells, as outlined above, but it is important to understand their limitations and also to continue the quest for models that better represent the relevant elements of the human situation. Lesion models can reproduce the striatal, and sometimes even the cortical, cell loss seen in HD patients, as well as mimicking the behavioral and metabolic changes 77 . Such models in rodents have been essential for understanding the biology of grafts, but they do not replicate the progressive cell loss seen in HD, nor reliably replicate the extrastriatal damage 78 .…”

“…Lesion models can reproduce the striatal, and sometimes even the cortical, cell loss seen in HD patients, as well as mimicking the behavioral and metabolic changes. 77 Such models in rodents have been essential for understanding the biology of grafts, but they do not replicate the progressive cell loss seen in HD, nor reliably replicate the extrastriatal damage. 78 A variety of genetic models exist in mice, but these have so far proven problematic for assessing striatal grafts; they have substantially longer CAG repeat expansions than those seen in adult onset HD and do not accurately reflect the anatomy of changes of the CNS.…”