Accelerate your path to proof of concept
Explore the most appropriate preclinical strategy for evaluating your therapeutic candidate in CNS disorders.
Integrated models of motor and cognitive function
Translational preclinical models for evaluating the interactions between motor and cognitive systems and their disorders.
Macaque Model of Psychosis
Description
Aged animals are ideal for evaluating cognition-enhancing strategies and are particularly relevant for developing cognitive performance enhancers targeting Alzheimer’s disease or mild cognitive impairment (MCI). We have recently shown that this model is superior to rodent models in terms of predicting outcomes from studies of potential cognition-enhancing drugs in human Alzheimer’s disease (Schneider et al., 2013).
Method
Evaluation of the test item in the apomorphine-induced psychosis-like behaviour model.
Assessment of the severity of psychosis is classically performed for 30 min before and 60 min post apomorphine administration in 6 animals videotaped in a dedicated observation enclosure.
Endpoints
A battery of behavioural tests is performed that includes recording of locomotor activity and clinical rating of the psychosis-like behaviour based on rating of the level of agitation, stereotypies, other abnormal behaviours not classically displayed by healthy animals.
Chronic Low-Dose MPTP Model
Description
Chronic low-dose MPTP-treated monkeys develop impairments of attention, working memory and executive functioning similar in scope to the cognitive deficits described in Parkinson’s disease patients. We now offer a model in which animals express these cognitive deficits as well as typical parkinsonian motor deficits. This model is invaluable for drug discovery efforts: for the first time, potentially positive drug effects on motor function and cognition can be assessed simultaneously. This model can also be used to detect potentially negative effects on cognition for drugs that may have a positive effect on motor functioning.
Method
Animals are initially trained to perform a variety of cognitive tasks. MPTP is then administered at low doses over an extended period of time, until cognitive deficits appear (in advance of parkinsonian motor impairment). MPTP administration is then continued until stable motor deficits characteristic of Parkinson’s disease develop. Measurement of cognitive performance is by a computer-controlled touch-screen battery of tests that have been validated in this model. Motor functioning can be assessed using a rating scale (developed and validated by us) that quantifies various components of the parkinsonian syndrome and through automated measurement of locomotor activity.
Endpoints
Variable Delayed Response. This is a spatial working memory task with attentional and memory components.
Attentional Set Shifting/Cognitive Flexibility Task. This task is based on the principle of the Wisconsin Card- Sorting Test. It assesses aspects of executive function including cognitive flexibility, set shifting ability and concept formation.
Continuous Performance Task. This task assesses selective and sustained attention.
Other cognitive/behavioural assays are available upon request.
References
D. Charvin, T. Di Paolo, E. Bezard, L. Gregoire, A. Takano, G. Duvey, E. Pioli, C. Halldin, R. Medori, F. Conquet, An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. Mov Disord 33, 1619-1631 (2018).
W. K. Ko, S. M. Camus, Q. Li, J. Yang, S. McGuire, E. Y. Pioli, E. Bezard, An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models.
Neuropharmacology 110, 48-58 (2016).
J. S. Schneider, E. Y. Pioli, Y. Jianzhong, Q. Li, E. Bezard, Levodopa improves motor deficits but can further disrupt cognition in a macaque Parkinson model. Mov Disord 28, 663-667 (2013).
Object Retrieval Task in Macaques
Description
This simple cognitive/motor task is sensitive to dysfunction of prefronto-striatal circuits and can be applied to both normal and parkinsonian animals. The task can detect impulsivity, deficits in motor planning, and decreased ability to inhibit certain behaviours, as has been described following frontal lobe lesions, in attention deficit hyperactivity disorder (ADHD) and in patients with Parkinson’s disease. We have adapted procedures to allow this task to be performed by advanced parkinsonian animals, thus allowing simultaneous examination of drug effects on motor symptoms and cognition. This task can easily be incorporated into studies examining anti-Parkinson or anti- dyskinesia drugs to provide a valuable readout of potential positive or negative effects on cognition. Additional advantages of this task are that animals can learn to perform the task in a very short time and, when applied to normal animals, the task can detect the cognitive/motor disrupting effects of drug candidates.
Method
The animal is required to retrieve a food reward by reaching into a clear Plexiglass box having one open side. The orientation of the opening and the location of the reward are varied, in order to adjust the difficulty of the motor and cognitive demands of the task. A testing session typically is 30 trials consisting of a predetermined sequence of presentations.
Endpoints
The measures recorded are task completion time (time between presentation and correct response), the number of successfully completed trials (reward retrieved on first attempt) and the number of correctly performed trials (reward retrieved but not on first attempt). If the reward is not retrieved on the first attempt, the type of error is recorded, such as barrier reaches (animal hits a closed side of the box rather than making a detour reach), other types of cognitive errors (e.g. perseverative errors, hesitation errors, no response errors) and motor errors (e.g. reaching into the open side of the box but failing to retrieve the reward or dropping a reward that is retrieved).
References
D. Charvin, T. Di Paolo, E. Bezard, L. Gregoire, A. Takano, G. Duvey, E. Pioli, C. Halldin, R. Medori, F. Conquet, An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. Mov Disord 33, 1619-1631 (2018).
W. K. Ko, S. M. Camus, Q. Li, J. Yang, S. McGuire, E. Y. Pioli, E. Bezard, An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models. Neuropharmacology 110, 48-58 (2016).
J. S. Schneider, D. P. Roeltgen, Delayed matching-to-sample, object retrieval, and discrimination reversal deficits in chronic low dose MPTP-treated monkeys. Brain Res 615, 351-354 (1993).
J. S. Schneider, M. Van Velson, F. Menzaghi, G. K. Lloyd, Effects of the nicotinic acetylcholine receptor agonist SIB- 1508Y on object retrieval performance in MPTP-treated monkeys: comparison with levodopa treatment. Ann Neurol 43, 311-317 (1998).
Stereotactic Neurosurgery in Rodents, Pigs and Non-human Primates
Description
Stereotactic neurosurgery is a fundamental methodology for the precise targeting of brain structures with hundreds-of-micrometre accuracy. It is essential for:
- The production of animal models of neurodegenerative diseases by local delivery of neurotoxins (e.g. 6-OHDA), viral vectors (e.g. AAV-synuclein or AAV-Abeta) or pathologic peptides (e.g. purified or synthetic synuclein or Abeta).
- The delivery of therapeutic biologics (e.g. growth factors, viral vector, cells) or pharmacological agents into specific brain areas.
- The targeting of deep brain structures for biomedical solutions (e.g., deep brain stimulation). These can be achieved by acute injection/sampling or chronically, after implantation of indwelling cannulae.
- The in vivo sampling of brain chemicals (e.g. by microdialysis) or fluid (ventricular cerebrospinal fluid).
These can be achieved by acute injection/sampling or chronically, after implantation of indwelling cannulae.
Method
Rodents, pigs or non-human primates (NHPs) are immobilised in a stereotactic headframe under general anaesthesia and aseptic conditions. Accurate stereotaxy relies upon the use of reference atlases of brain anatomy, consisting of sections prepared in the three orthogonal planes. In rodents, intracerebral structures can be accurately and reliably targeted by using animals of the same strain, sex and weight.
In pigs and primates there is considerable variation in intracerebral anatomy between individuals. For this reason, it is important to image the brain of each individual and use this to correct the stereotactic coordinates provided by standard atlases. This is achieved by stereotactic ventriculography. Briefly, a small craniotomy is performed, and a needle is inserted into the anterior horn of the lateral ventricle. In brain structures with a recognisable “signature” of neural activity, electrophysiological recording can be used to further refine targeting. Motac staff have refined these techniques over many years to deliver numerous projects and probably have more experience of stereotactic surgery in pigs and NHPs than any other group worldwide.
