Whilst these models lack genetic construct validity, they exhibit partial face validity with respect to motor symptoms and neuropathology, and are gradually

being complemented by genetically targeted animal models of PD [85,86]. As PD models with better genetic and environmental construct validity are developed, in vitro models such as inducible pluripotent stem cells (IPSCs) will allow genetic and molecular mechanisms to be explored in parallel, in the context of human genomes and cells [87]. Furthermore, both preclinical and clinical studies are providing evidence for environmental modifiers and associated gene-environment interactions in the pathogenesis and progression of PD [88]. EE was first shown to have beneficial effects in an animal model of PD through the use of 6-hydroxy-dopamine (6-OHDA) lesioned rats [89,90]. Cilomilast This has since been followed up in other models [91] and with varied timing of EE interventions [92]. There is evidence suggesting that EE and physical exercise can regulate the generation of neural precursors in the substantia nigra (SN) of adult mice [93]. However, the evidence for adult neurogenesis is controversial and therefore more work needs Pexidartinib datasheet to be done to demonstrate the potential of EE in promoting SN neurogenesis. Exercise

interventions have also been demonstrated to exert beneficial effects in animal models of PD [94–96]. The translation of EE and exercise studies in animal models of PD remains in its infancy. However, epidemiological and interventional clinical data suggests that cognitive stimulation and physical exercise are promising approaches to facilitate neuroprotection and brain repair [97]. An ongoing approach being developed for brain repair is that of stem cell transplantation, which may be particularly suited to neurodegenerative diseases involving localized cell loss, such as PD [98]. EE has been found to improve the survival, integration and functional impact of transplanted cells, particularly in models of PD and stroke [99–103]. Models of brain disorders where the lesion is experimentally

Fludarabine molecular weight initiated, such as stroke [104] and traumatic brain injury [105], provide unique opportunities to assess the effects of EE on brain repair. A diverse range of molecular, cellular and behavioural effects of EE have been described in wild-type mice and rats, as reviewed previously [1,5,6,106,107]. Behavioural effects encompass alterations to sensory, cognitive, affective and motor function, which may depend on the timing, quality and duration of EE, as well as the genetic background, age and sex of the animals [5–7,108–119]. The molecular effects include selective changes in gene expression with spatiotemporal and cellular specificity across a variety of different gene ontology classes [120–123].