Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson's disease: Evidence from rodent models.

Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons of the nigrostriatal pathway, which leads to the cardinal motor symptoms of the disease - tremor, rigidity and postural instability. A number of non-motor symptoms are also associated with PD, including cognitive impairment, mood disturbances and dysfunction of gastrointestinal and autonomic systems. Current therapies provide symptomatic relief but do not halt the disease process, so there is an urgent need for preventative strategies. Lifestyle interventions such as aerobic exercise have shown potential to lower the risk of developing PD and to alleviate both motor and non-motor symptoms. However, there is a lack of large-scale randomised clinical trials that have employed exercise in PD patients. This review will focus on the evidence from studies on rodent models of PD, for employing exercise as an intervention for both motor and non-motor symptoms.

Regulation of behaviour by the nuclear receptor TLX.

The orphan nuclear receptor Tlx (Nr2e1) is a key regulator of both embryonic and adult hippocampal neurogenesis. Several different mouse models have been developed which target Tlx in vivo including spontaneous deletion models (from birth) and targeted and conditional knockouts. Although some conflicting findings have been reported, for the most part studies have demonstrated that Tlx is important in regulating processes that underlie neurogenesis, spatial learning, anxiety-like behaviour and interestingly, aggression. More recent data have demonstrated that disrupting Tlx during early life induces hyperactivity and that Tlx plays a role in emotional regulation. Moreover, there are sex- and age-related differences in some behaviours in Tlx knockout mice during adolescence and adulthood. Here, we discuss the role of Tlx in motor-, cognitive-, aggressive- and anxiety-related behaviours during adolescence and adulthood. We examine current evidence which provides insight into Tlx during neurodevelopment, and offer our thoughts on the function of Tlx in brain and behaviour. We further hypothesize that Tlx is a key target in understanding the emergence of neurobiological disorders during adolescence and early adulthood.

Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators.

Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect on cognition may provide insight into why adolescence may be a vital period for correct conditioning of future hippocampal function.

Unlocking mechanisms in interleukin-1ß-induced changes in hippocampal neurogenesis--a role for GSK-3ß and TLX.

Glycogen synthase kinase-3ß (GSK-3ß) and the orphan nuclear receptor tailless homolog (TLX) are key regulators of hippocampal neurogenesis, which has been reported to be dysregulated in both neurodegenerative and psychiatric disorders. Inflammation is also implicated in the neuropathology of these disorders because of increased levels of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in the brain. At elevated levels, IL-1ß signaling through the IL-1 receptor type 1 has been shown to be detrimental to hippocampal neurogenesis. TLX is required to maintain neural stem/progenitor cells (NSPCs) in an undifferentiated state and is involved in NSPC fate determination, while GSK-3ß negatively regulates Wnt signaling, a vital pathway promoting neurogenesis. This study shows that GSK-3ß inhibition using a small-molecule inhibitor and the mood stabilizer lithium restores the IL-1ß-induced decrease in NSPC proliferation and neuronal differentiation of embryonic rat hippocampal NSPCs to control levels. The IL-1ß-induced effect on NSPCs is paralleled by a decrease in TLX expression that can be prevented by GSK-3ß inhibition. The present results suggest that GSK-3ß ameliorates the anti-proliferative and pro-gliogenic effects of IL-1ß, and that TLX is vulnerable to inflammatory insult. Strategies to reduce GSK-3ß activity or to increase TLX expression may facilitate the restoration of hippocampal neurogenesis in neuroinflammatory conditions where neurogenesis is impaired.