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.

Figure 1

Persistent elevation of corticosterone in female R6/1 mice following exposure to stress is rescued by environmental enrichment. Fluctuation of serum corticosterone levels in female (a) and male (b) mice at different intervals post-swim stress. ^*Significant difference in corticosterone, P<0.05; ^**significant difference in corticosterone, P<0.01; ^#significant difference in corticosterone at the specific time point sampled compared to baseline group, P<0.05 (n=5–8 per group).

Figure 2

Pharmacological examination of the hypothalamic-pituitary-adrenal (HPA) axis. Serum corticosterone levels were quantified in female (a) and male (b) mice treated with dexamethasone (DEX) alone or either corticotropin-releasing hormone (CRH) or adrenocorticotrophin hormone (ACTH) 6-h post-DEX administration. ACTH protein levels after DEX-CRH treatment was measured in female mice (c) as well as in vitro adrenal cellular response to ACTH stimulation (d). DEX administration suppressed corticosterone levels in all mice tested. CRH administration following DEX increased corticosterone levels in all mice. ACTH administration in DEX-treated mice also increased corticosterone levels in all mice, but levels in female Huntington's disease (HD) mice were 180% of wild-type (WT) levels. Normal pituitary function is reflected by similar [ACTH] levels in WT and HD mice following direct stimulation of the pituitary by CRH. ^**P<0.01, ^***P<0.001 (n=4–6 per group for a, 5–7 per group for b, 8 for WT and 7 for HD for c, and 4–5 per group for d).

Figure 3

Environmental enrichment changes the temporal dynamics of the stress response. (a) Environmental enrichment does not alter baseline corticosterone levels or peak stress response measured immediately following stress. However, the persistent increase in serum corticosterone in female Huntington's disease (HD) mice is corrected by enrichment. (b) Enriched female HD mice have the same dexamethasone-adrenocorticotrophin hormone (DEX-ACTH) response as wild-type (WT) mice. (c) Enrichment corrects hyperactivity of adrenal cells in vivo in response to ACTH. ^**P<0.01, ^***P<0.001 (n=8–10 per group for a and b, and 4–5 per group for c).

Figure 4

Expression patterns of genes involved in adrenal function and steroidogenesis in the adrenal glands of Huntington's disease (HD) and wild-type (WT) mice following environmental enrichment and exposure to stress. (a) The adrenocorticotrophin hormone (ACTH) receptor (mc2r), (b) cAMP response element modulator (crem) and (c) steroidogenic acute regulatory protein (StAR). (d) There is a significant reduction in glucocorticoid receptor (GR) expression in the adrenal glands of HD mice, which is completely rescued by environmental enrichment. Enriched HD mice also have greater adrenal GR expression than enriched WT under non-stress conditions. Expression levels were measured using quantitative reverse transcription-polymerase chain reaction (RT-PCR). ^*P<0.05, ^***P<0.001. (n=5–6 per group).