Abstract
Two new large animal models of Huntington's disease (HD) have been developed recently, an old world monkey (macaque) and a sheep. Macaques, with their large brains and complex repertoire of behaviors are the ‘gold-standard’ laboratory animals for testing cognitive function, but there are many practical and ethical issues that must be resolved before HD macaques can be used for pre-clinical research. By contrast, despite their comparable brain size, sheep do not enjoy a reputation for intelligence, and are not used for pre-clinical cognitive testing. Given that cognitive decline is a major therapeutic target in HD, the feasibility of testing cognitive function in sheep must be explored if they are to be considered seriously as models of HD. Here we tested the ability of sheep to perform tests of executive function (discrimination learning, reversal learning and attentional set-shifting). Significantly, we found that not only could sheep perform discrimination learning and reversals, but they could also perform the intradimensional (ID) and extradimensional (ED) set-shifting tasks that are sensitive tests of cognitive dysfunction in humans. Their performance on the ID/ED shifts mirrored that seen in humans and macaques, with significantly more errors to reach criterion in the ED than the ID shift. Thus, sheep can perform ‘executive’ cognitive tasks that are an important part of the primate behavioral repertoire, but which have never been shown previously to exist in any other large animal. Sheep have great potential, not only for use as a large animal model of HD, but also for studying cognitive function and the evolution of complex behaviours in normal animals.
Highlights
The ability to learn associations between stimuli, actions and outcomes, and to adapt ongoing behavior to changes in the environment is arguably one of the fundamental determinants of survival
Discrimination learning, retention and reversal learning All of the sheep learned to discriminate between coloured buckets, reaching criterion in the simple discrimination (SD) within 7 sets of 8 discriminations (Fig. 2A)
The behavior of the sheep during simple discrimination reversal (SR) suggested that had they learned that the S+ was correct, but they had learned that the S- was incorrect
Summary
The ability to learn associations between stimuli, actions and outcomes, and to adapt ongoing behavior to changes in the environment is arguably one of the fundamental determinants of survival When such ‘executive’ function breaks down (as happens in disorders such as HD, Alzheimer’s disease (AD), and schizophrenia) the effect on the individual is devastating, but the distress it causes spreads beyond the affected individual to impact on both families and society. Most preclinical testing is conducted using rodents While undoubtedly these make useful and economical animal models, they have limitations, when the aim is to test cognitive function in neurodegenerative disorders. Rodents do not have the gyrencephalic cortex that is characteristic of the human brain These anatomical differences may be important when studying the functions of the brain regions (e.g. basal ganglia and cerebral cortex) involved in complex processes such as motor control and decision-making
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