Environmental enrichment rescues female-specific hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington's disease

Abstract

Huntington's disease (HD) has long been regarded as a disease of the central nervous system, partly due to typical disease symptoms that include loss of motor control, cognitive deficits and neuropsychiatric disturbances. However, the huntingtin gene is ubiquitously expressed throughout the body. We had previously reported a female-specific depression-related behavioural phenotype in the R6/1 transgenic mouse model of HD. One hypothesis suggests that pathology of the hypothalamic-pituitary-adrenal (HPA) axis, the key physiological stress-response system that links central and peripheral organs, is a cause of depression. There is evidence of HPA axis pathology in HD, but whether it contributes to the female R6/1 behavioural phenotype is unclear. We have examined HPA axis response of R6/1 mice following acute stress and found evidence of a female-specific dysregulation of the HPA axis in R6/1 mice, which we further isolated to a hyper-response of adrenal cortical cells to stimulation by adrenocorticotrophin hormone. Interestingly, the adrenal pathophysiology was not detected in mice that had been housed in environmentally enriching conditions, an effect of enrichment that was also reproduced in vitro. This constitutes the first evidence that environmental enrichment can in fact exert a lasting influence on peripheral organ function. Cognitive stimulation may therefore not only have benefits for mental function, but also for overall physiological wellbeing.

Disease stage, but not sex, predicts depression and psychological distress in Huntington's disease: A European population study

“…One body of research has identified depression to be associated with altered hypothalamic-pituitary-19 adrenal (HPA)-axis functioning (44)(45)(46)(47), and these mechanisms have been proposed for sex differences in depressive behaviours in rodents [48]. As yet, sex differences in HPA-axis functioning in human HD carriers have not been explored and this would be an interesting area for future research as sex differences in response to stress have been found to alter depending on the type of stressor and duration of exposure [48]; and a multitude of chemical, environmental and psychological stressors may affect individuals with HD.…”

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

“…Our laboratory and others have previously demonstrated that environmental enrichment can rescue the affective phenotypes and the abnormal physiological stress response in several disease models (Du et al, 2012;Li et al, 2014;Pang et al, 2013). However, there is growing evidence that the potential benefits of environmental enrichment extend beyond the exposed animal.…”

“…EE rescues the depression-like phenotype and corrects HPA-axis dysregulation in a mouse model of alcohol withdrawal . EE also has the capacity to influence peripheral stress-response as demonstrated by its correction of adrenal hyper-responsivity pathology in a mouse model of Huntington's disease (Du et al, 2012). In normal rodents, EE has consistently been shown to reduce anxiety-like behavior in the elevated-plus maze and the open-field test (Sztainberg et al, 2010), with recent evidence suggesting the requirement of a minimum 3-week enrichment period (Leger et al, 2015).…”

First use of creatine hydrochloride in premanifest Huntington disease

“…Upregulation or over-expression of BDNF can rescue some symptoms of Huntington's disease in animal models 71,[111][112][113] . Consistent with the expression patterns noted above, BDNF is associated with memory and learning 108,114 and with body weight and energy homeostastis at both central 115 and peripheral 116, 117 levels.…”

“…The paradigm of environmental enrichment employs increased mental, physical and social stimulation in animal models to enhance neurological input, thereby modulating brain activity and physical parameters to impact on disease progression [62][63][64][65][66][67] . A number of studies have shown the benefits of such an approach in Huntington's disease transgenic animal models, with evidence for it being able to delay the onset of motor abnormalities, slow disease progression, reduce impairments to weight loss, balance and physiological factors, and increase both neurogenesis and CNS levels of neurotransmitter receptors, neurotrophins and factors related to synaptic signal transduction pathways [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82] .…”