Short-term memory acquisition in female Huntington's disease mice is vulnerable to acute stress

Mo, Christina; Renoir, Thibault; Pang, Terence Y; Hannan, Anthony J.

doi:10.1016/j.bbr.2013.07.041

Cited by 26 publications

(14 citation statements)

References 34 publications

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“…Cognitive dysfunction, including impaired short-term memory, is a prominent symptom in HD (Meudell et al, 1978;Scholz and Berlemann, 1987). Short-term memory deficits in the Y-maze test develop at 8 weeks of age in male R6/1 HD mice (Mo et al, 2013) and we now report that 5 days of oral CORT treatment accelerated this deficit in male HD mice. The dose of CORT used in our study was moderate (Karatsoreos et al, 2010) and WT mice were spared from any CORT-induced Y-maze deficits.…”

Section: Corticosterone Treatment Accelerated the Onset Of Y-maze Memsupporting

confidence: 54%

“…We recently reported that male R6/1 mice display a Y-maze deficit from 8 weeks of age (Mo et al, 2013) and female R6/1 mice from 10 weeks of age (unpublished data). We therefore began CORT treatment at 6 weeks of age and tested mice at 7 weeks of age to assess whether the 5-day CORT treatment would accelerate the onset of the Y-maze deficit in HD animals.…”

mentioning

confidence: 83%

“…WT mice were unaffected (Mo et al, 2013). That was the first evidence that stress could be a key non-genetic modifier of HD symptom onset.…”

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confidence: 92%

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High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Mo¹,

Pang²,

Ransome³

et al. 2014

Neurobiology of Disease

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Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation in the huntingtin gene. Lifestyle factors, such as lack of activity may contribute to the variability in the age of disease onset. Therefore, better understanding of environmental modifiers may uncover potential therapeutic approaches to delay disease onset and progression. Recent data suggest that HD patients and transgenic mouse models show a dysregulated stress response. In this present study, we elevated stress hormone levels through oral corticosterone (CORT) treatment and assessed its impact on the development of motor impairment and cognitive deficits using the R6/1 transgenic mouse model of HD. We found that CORT consumption did not alter rotarod performance of R6/1 HD or wild-type (WT) littermates. However, the onset of hippocampal-dependent Y-maze deficits was accelerated in male R6/1 mice by 5days of CORT treatment, whereas short term memory of WT and female R6/1 mice was unaffected. We then further investigated the male HD susceptibility to CORT by measuring TrkB activation, BDNF and glucocorticoid receptor expression as well as the level of cell proliferation in the hippocampus. CORT treatment increased the levels of phosphorylated TrkB in male R6/1 mice only. There were no effects of CORT on hippocampal BDNF protein or mRNA levels; nor on expression of the glucocorticoid receptors in any group. Hippocampal cell proliferation was decreased in male R6/1 mice and this was further reduced in CORT-drinking male R6/1 mice. Female mice (WT and R6/1) appeared to be protected from the impacts of CORT treatment in all our hippocampal measures. Overall, our data demonstrate that treatment with corticosterone is able to modulate the onset of HD symptomatology. We present the first evidence of a male-specific vulnerability to stress impacting on the development of short-term memory deficits in HD. More generally, we found that female mice were protected from the detrimental effects of CORT treatment on a variety of hippocampus-based measures. Hippocampal plasticity and memory in HD may be more susceptible to the impacts of stress in a sex-dependent manner. We propose clinical investigations of stress as a key environmental modifier of HD symptom onset.

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Section: Corticosterone Treatment Accelerated the Onset Of Y-maze Memsupporting

confidence: 54%

mentioning

confidence: 83%

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High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Mo¹,

Pang²,

Ransome³

et al. 2014

Neurobiology of Disease

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“…Experimental elevation of CORT in the male R6/1 HD mouse exacerbates cognitive symptoms, reduces hippocampal neurogenesis, and slows weight gain (Mo et al , 2014a). Similarly, short-term stress in the R6/1 model exacerbates memory impairment in female HD mice (Mo et al , 2013), while long term stress reduces weight gain in male and female HD mice, reduces saccharine preference in female HD mice (a depressive-like measure of anhedonia), and reduces olfactory sensitivity (Mo et al , 2014b). In the series of experiments presented here, we extend these findings and demonstrate that elevated corticosterone in the R6/2 model dramatically exacerbates the weight loss phenotype in these mice and also shortens lifespan.…”

Section: Discussionmentioning

confidence: 99%

Corticosterone dysregulation exacerbates disease progression in the R6/2 transgenic mouse model of Huntington's disease

Dufour

McBride

2016

Experimental Neurology

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Huntington's disease (HD) is a genetic neurological disorder that causes severe and progressive motor, cognitive, psychiatric, and metabolic symptoms. There is a robust, significant elevation in circulating levels of the stress hormone, cortisol, in HD patients; however the causes and consequences of this elevation are largely uncharacterized. Here, we evaluated whether elevated levels of corticosterone, the rodent homolog of cortisol, contributed to the development of symptomology in transgenic HD mice. Wild-type (WT) and transgenic R6/2 mice were given either: 1) adrenalectomy with WT level corticosterone replacement (10ng/ml), 2) adrenalectomy with high HD-level corticosterone replacement (60ng/ml), or 3) sham surgery without replacement. R6/2 mice on HD-level replacement showed severe and rapid weight loss (p<.05) and a shorter latency to death (p<.01) relative to the HD mice on WT-level replacement. We further evaluated basal and stress-induced levels of circulating corticosterone in R6/2 mice throughout the course of their life. We found that R6/2 transgenic HD mice display a spontaneous elevation in circulating corticosterone levels that became significant at 10 weeks of age. Furthermore, we identified significant dysregulation of circadian rhythmicity of corticosterone release measured over a 24 hour period compared to wildtype controls. Unexpectedly, we found that R6/2 transgenic mice show a blunted corticosterone response to restraint stress, compared to wild-type mice. Together, this data provides further evidence that HPA-axis activity is abnormal in R6/2 mice, and highlights the important role that cortisol plays in HD symptom development. Our findings suggest that cortisol-reducing therapeutics may be of value in improving HD patient quality of life.

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“…Stress paradigms have been shown to exacerbate the phenotype of several mouse and rat models of Parkinson’s [71–76], yet there do not appear to be studies attempting to target stress pathways therapeutically within these models. Furthermore, early reports have shown that stress paradigms have a detrimental effect on the phenotype of the R6/1 mouse model of Huntington’s [77, 78]. Further investigation into the mechanisms of how stress signaling affects these proteinopathies is needed, and should also grow to include other neurodegenerative proteinopathies such as Amyotrophic Lateral Sclerosis (ALS) and FTD.…”

Section: Main Textmentioning

confidence: 99%

Targeting psychologic stress signaling pathways in Alzheimer’s disease

Futch

Croft

Truong

et al. 2017

Mol Neurodegeneration

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Alzheimer’s Disease (AD) is the most prevalent progressive neurodegenerative disease; to date, no AD therapy has proven effective in delaying or preventing the disease course. In the search for novel therapeutic targets in AD, it has been shown that increased chronic psychologic stress is associated with AD risk. Subsequently, biologic pathways underlying psychologic stress have been identified and shown to be able to exacerbate AD relevant pathologies. In this review, we summarize the literature relevant to the association between psychologic stress and AD, focusing on studies investigating the effects of stress paradigms on transgenic mouse models of Amyloid-β (Aβ) and tau pathologies. In recent years, a substantial amount of research has been done investigating a key stress-response mediator, corticotropin-releasing hormone (CRH), and its interactions with AD relevant processes. We highlight attempts to target the CRH signaling pathway as a therapeutic intervention in these transgenic mouse models and discuss how targeting this pathway is a promising avenue for further investigation.

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Short-term memory acquisition in female Huntington's disease mice is vulnerable to acute stress

Cited by 26 publications

References 34 publications

High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Corticosterone dysregulation exacerbates disease progression in the R6/2 transgenic mouse model of Huntington's disease

Targeting psychologic stress signaling pathways in Alzheimer’s disease

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