Introduction

Parkinson’s disease (PD) is a common neurodegenerative disease in the elderly. Its main feature is gradual loss of dopaminergic neurons in the substantia nigra, accompanied by motor symptoms and cognitive impairments and sometimes dementia (Wirdefeldt et al., 2011). PD affects 1–2% of the population over the age of 60 years (Ohashi et al., 2006; Wood et al., 2010; Pringsheim et al., 2014). Motor impairments and cognitive dysfunction are usual symptoms of PD (Wood et al., 2010) that result from extended death of dopaminergic neurons in the substantia nigra pars compacta and a 70–80%reduction in dopamine levels in the striatum (Bergman and Deuschl, 2002; Galvan and Wichmann, 2008). PD is considered a multi-factor disorder that results from the combined effects of multiple factors, including genetic and environmental factors and aging (Elbaz et al., 2016), with aging being the most prominent risk factor (Collier et al., 2007).

The senescence-accelerated mouse prone 8 (SAMP8) inbred mouse line has early onset senility and a short life span(Flood and Morley, 1998) and is characterized by learning and memory impairments, and affective disturbance during the aging process (Kawamata et al., 1997; Takeda et al., 1997). In our previous studies, we have used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-SAMP8 model of PD (Liu et al., 2008; Yuan et al., 2008), which has non-motor symptoms (Liu et al., 2010).

With an aging population, the number of people with PD is increasing (LaHue et al., 2016). Although several studies have suggested that combinations of pharmacological and non-pharmacological therapies can alleviate PD symptoms(Mo et al., 2015; Chang et al., 2016), all therapeutic options to date have failed to halt the progression of degeneration(Kakkar and Dahiya, 2015). Some experimental data indicate that the environment can change behavior and molecular indicators in some animal models (Laviola et al., 2008).These changes can induce plastic brain changes and promote beneficial effects on the progression of neuronal impairment related to PD (Campêlo et al., 2017). Physical activity and experience of novelty have been shown to improve both motor and cognitive functions in PD patients (Benka Wallén et al., 2015; Hindle et al., 2016).

A previous study has shown that enriched environments(EEs) can protect dopaminergic neurons from MPTP-induced neuronal injury (Yuan et al., 2009a). What are the underlying mechanisms for this effect? In the past few years,many studies have focused on neural plasticity. Growth associated protein-43 (GAP-43) is strongly associated with neurite growth and axon regeneration during neural development (Aigner and Caroni, 1993). GAP-43 is also regarded as a molecular marker of neural plasticity (Gorup et al.,2015). To investigate the possible protective effects of EEs,this study examined the cognitive ability of MPTP-treated SAMP8 mice in the Morris water maze (MWM), and determined mRNA and protein levels of GAP-43 in the substantia nigra pars compacta.

Materials and Methods

Animals

Ninety-six 3-month-old female SAMP8 mice weighing 20–23 g were obtained from the Animal Center of Hebei Medical University of China (No. SCXK (Ji) 2008-1-003).All mice were randomly and equally assigned to EE and standard environment (SE) groups. The EE cages (52 cm ×37 cm × 22 cm) consisted of a platform, several tunnels, two running wheels, a variety of toys and nesting material. There were 10–12 mice per cage. The SE cages (32 cm × 20 cm × 15 cm) only contained nesting material and 5–6 mice per were housed in a room at 22–25°C with 55 ± 5% humidity and a 12-hour light/dark cycle. Mice had free access to water and food and these conditions were maintained for 3 months. All experimental procedures were performed according to the Guidance Suggestions for the Care and Use of Laboratory Animals, issued by the Ministry of Science and Technology of China. This study was approved by the Animal Ethics Committee of the First Hospital of Hebei Medical University of China (approval No. ).

MPTP injection

Mice were equally and randomly divided into an MPTP group and a 0.9% normal saline solution (NS) group. The MPTP mice were subcutaneously injected in the abdomen with MPTP (14 mg/kg) four times from 8 am at 2-hour intervals. The mice in the NS group received an equal volume(14 mL/kg) of 0.9% saline solution at the same time experiments were conducted for 5 days. The following day, mice were euthanized for immunohistochemistry,and reverse-transcription polymerase chain reaction (RTPCR) and western blot assays.

MWM test

The day after MPTP and NS injection, 96 mice were tested in the MWM for 5 consecutive days using apparatus from Anhui Huaibei Zhenghua Biological Equipment (Anhui,China). The swimming pool, 50 cm in height and 120 cm in diameter, had four quadrants. A hidden platform, 20 cm in height and 14 cm in diameter, was fixed 1.5 cm under the surface of the water and was defined as the target quadrant. The water temperature was maintained at 22 ± 2°C and was made opaque with black non-toxic dye to prevent the mice from seeing the platform. A place navigation test was performed for four days. Mice were put into the pool facing the wall of the pool and allowed to swim randomly until the platform was found or for up to 120 seconds. If a mouse could not find the platform, they were guided to the platform. All mice were allowed to stay on the platform for 10 seconds. Escape latency(the time taken to find the platform) was recorded. This was repeated three more times with the mice being placed in a different quadrant each time. On day 5, the probe test was performed; the hidden platform was removed and each mouse was allowed to swim for 120 seconds. The swim paths were automatically recorded with a video tracking system (Anhui Huaibei Zhenghua Biological Equipment) and the time spent in each quadrant was recorded.