Abstract
Environmental enrichment (EE) is a therapeutic paradigm that consists of complex combinations of physical, cognitive, and social stimuli. The mechanisms underlying EE-mediated synaptic plasticity have yet to be fully elucidated. In this study, we investigated the effects of EE on synaptic vesicle-associated proteins and whether the expression of these proteins is related to behavioral outcomes. A total of 44 CD-1® (ICR) mice aged 6 weeks were randomly assigned to either standard cages or EE (N = 22 each). Rotarod and ladder walking tests were then performed to evaluate motor function. To identify the molecular mechanisms underlying the effects of EE, we assessed differentially expressed proteins (DEPs) in the striatum by proteomic analysis. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were conducted to validate the expressions of these proteins. In the behavioral assessment, EE significantly enhanced performance on the rotarod and ladder walking tests. A total of 116 DEPs (54 upregulated and 62 downregulated proteins) were identified in mice exposed to EE. Gene ontology (GO) analysis demonstrated that the upregulated proteins in EE mice were primarily related to biological processes of synaptic vesicle transport and exocytosis. The GO terms for these biological processes commonly included Synaptic vesicle glycoprotein 2B (SV2B), Rabphilin-3A, and Piccolo. The qRT-PCR and western blot analyses revealed that EE increased the expression of SV2B, Rabphilin-3A and Piccolo in the striatum compared to the control group. Immunohistochemistry showed that the density of Piccolo in the vicinity of the subventricular zone was significantly increased in the EE mice compared with control mice. In conclusion, EE upregulates proteins associated with synaptic vesicle transport and exocytosis such as SV2B, Rabphilin-3A and Piccolo in the striatum. These upregulated proteins may be responsible for locomotor performance improvement, as shown in rotarod and ladder walking tests. Elucidation of these changes in synaptic protein expression provides new insights into the mechanism and potential role of EE.
Highlights
Environmental enrichment (EE) has the potential to elicit neurorestorative effects using complex combinations of physical, cognitive, and social stimuli [1]
The rotarod performance was increased after 4 weeks intervention (135.30 ± 26.23 s) compared to baseline (69.28 ± 19.52 s; p = 0.002) in EE group, while this locomotive activity was not improved over the time in control group by multiple pairwise comparison (Figure 2A)
EE mice exhibited lower forelimb slip rate (1.18 ± 0.39%) at 8 weeks post-intervention, compared to controls (4.13 ± 0.62%; p < 0.01) by independent t-test (Figure 2B). These results identified from the rotarod test and the ladder walking test suggest that EE can improve locomotor function and fine motor function
Summary
Environmental enrichment (EE) has the potential to elicit neurorestorative effects using complex combinations of physical, cognitive, and social stimuli [1]. EE can induce brain plasticity and enhance motor and cognitive function in the animal brain through biochemical and morphological changes such as neurogenesis, axonal sprouting, and dendritic branching [3,4,5]. We observed alterations in levels of synaptic activity regulating genes including dopamine transporters (DAT) [6, 7]. Genes associated with presynaptic neurotransmitter transporters such as DAT were down-regulated, suggesting that EE elicits efficient neurotransmitter reuptake and presynaptic plasticity. Synaptic plasticity involves changes to these molecular components, which are present at synapses, and the efficiency with which synapses can communicate [8]
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