Elsevier

Behavioural Brain Research

Volume 301, 15 March 2016, Pages 63-71
Behavioural Brain Research

Research report
Assessments of cognitive abilities in a mouse model of Parkinson’s disease with a touch screen test

https://doi.org/10.1016/j.bbr.2015.12.016Get rights and content

Highlights

  • Touch screen test requires low motor output for Parkinson’s disease (PD) model mice to perform simple operant conditioning task.

  • Touch screen test can be used to investigate mechanisms of cognitive disabilities in PD model animals that cannot be tested by conventional cognition testing tools.

  • PD model mice showed impairment in location discrimination task.

Abstract

Patients with Parkinson’s disease (PD) experience both motor output deficits and cognitive disabilities. Various PD rodent models have been developed to investigate the genetic and brain circuit-related causes of PD and have contributed to the basic and clinical research and to therapeutic strategies for this disease. Most studies using PD rodent models have focused on the motor output deficits, rather than cognitive disabilities due to the lack of appropriate testing tools that do not require significant motor abilities. In this study, we assessed the cognitive disabilities of PD model mice using a touch screen test that required only little motor ability. We found that the PD model mice, which had motor deficits caused by unilateral striatal dopaminergic degeneration, successfully underwent operant conditioning with a touch screen test. Additionally, we found that the PD model mice demonstrated impaired location discrimination, but intact attention and reversal learning in the cognitive tests. Therefore, the touch screen test is useful for assessing hidden cognitive disabilities in disease model animals with decreased motor function.

Introduction

The main neurological feature of Parkinson’s disease (PD) is dopaminergic degeneration, which has long been considered the main cause of the symptoms that distress PD patients. PD rodent models have contributed to our understanding of the pathophysiology and therapeutics of PD [1]. One of the most common methods for generating PD model mice is to destroy dopaminergic circuits genetically or pharmacologically. For example, neurotoxins, such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are widely used to ablate dopaminergic neurons selectively, thereby reproducing the motor impairments that are observed in PD patients [2]. These neurotoxin-induced motor impairments can be ameliorated by pharmacological correction of the dopamine deficiency or optogenetic activation of striatal medium spiny neurons [3], [4].

Many studies on the importance of the dopaminergic circuit in cognition [5] and the cognitive disabilities of PD patients [6] suggest the need for studies of such disabilities in PD rodent models. However, the investigation of cognitive disabilities in PD rodent models is limited, because most cognitive tests require normal motor function for performing the given task [7]. Therefore, care should be taken about drawing conclusions on cognitive abilities in PD rodent models, as poor performance on cognitive tasks might be due to motor impairments rather than cognitive disabilities. However, to date, no tools for testing cognition in disease model animals with motor impairments have been available.

The touch screen test was recently developed to test complex cognitive abilities in mice and rats [8]. In the touch screen test, the animals are required to perform a cognitive task in order to obtain a reward by touching a visual stimulus that is shown on a LCD monitor located in the front of the chamber. The touch screen test has several advantages over conventional cognitive test tools for the testing the cognitive disabilities of PD rodent models. First, it requires relatively lower motor output [9], only ambulation in the small chamber and touching the LCD monitor in the front of the chamber. This low motor demand can reduce the possibility that poor performance in a cognitive task is due to motor impairments. Next, various types of cognition tasks can be tested with the touch screen test, and these include conventional cognition tasks [8], such as operant conditioning, delayed matched to position (DMTP), and 5-choice serial reaction time (5-CSRT) tasks, or novel complex tasks, such as paired associate learning (PAL), visual discrimination and its reversal learning, and trial-unique delayed non-matching-to-location (TUNL) tests. Because these complex tasks can also be used to test human cognition [10], the touch screen test is also useful for testing cognitive deficits in many human disease models.

In this study, we employed a touch screen test paradigm to assess cognitive disabilities in PD model mice, which were generated by unilateral injections of 6-OHDA into the dorsal striatum. We found that these mice did not show abnormal performance in a simple operant conditioning task in the touch screen test. However, they showed impairments in location discrimination, which may not be due to motor impairments, but rather to cognitive impairments. Therefore, the touch screen test can be used to test and investigate the mechanisms underlying cognitive disabilities that are concealed by motor impairments in many disease models.

Section snippets

Animals

C57BL/6N mice were purchased from Orient Bio Co. (Gyeonggi, Korea). The animals were housed in groups (3–4 mice) and maintained on a 12-h light/dark cycle as previously described [11]. Food and water were provided ad libitum except during the touch screen test. All of the animal procedures were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of Seoul National University.

Stereotaxic 6-OHDA injections

6-OHDA (Sigma − AldrichCo. LLC, St. Louis, MO, USA) was dissolved in

Motor output deficits in PD model mice

In order to ablate the dopaminergic neurons in the mesostriatal pathway selectively, we injected 6-OHDA into the dorsal striatum, which is known to be responsible for various types of cognition, as well as for motor output regulation [4], [15]. To reduce the mortality from the 6-OHDA injection, we chose a low dose of 6-OHDA (4 μg/μL) and unilateral injection (right hemisphere only) of 6-OHDA [4]. We observed that 6-OHDA injection, but not vehicle injection, caused substantial loss of

Discussion

In the present study, we showed that the touch screen test could be used to assess cognitive abilities of PD model mice. To generate the PD model mice, we injected a low dose of 6-OHDA into one side of the dorsal striatum (Fig. 1a), in order to reduce the mortality in the mice [21]. Consistent with a previous study, our PD model mice showed impairments in locomotion and rotational bias, while their motor coordination was not affected (Fig. 1) [4]. The rotational bias seemed to be the result of

Conflict of interest

The authors declare no conflict of interest.

Acknowledgement

This study was supported by the National Honor Scientist Program of Korea to BKK (2012R1A3A1050385).

References (27)

  • D. Muslimović et al.

    Cognitive profile of patients with newly diagnosed Parkinson disease

    Neurology

    (2005)
  • H.S. Lindgren et al.

    Cognitive dysfunction and depression in Parkinson’s disease: what can be learned from rodent models?

    Eur. J. Neurosci.

    (2012)
  • T.J. Bussey et al.

    The touchscreen cognitive testing method for rodents: How to get the best out of your rat

    Learn. Mem.

    (2008)
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