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Gene-environment interactions modulating dementia and depression in a tandem repeat disorder

Using a transgenic mouse model of HD, our group has made progress in understanding molecular and cellular mediators that lead to behavioural abnormalities, as well as environmental and pharmacological modulators.

We were the first group to demonstrate depression-like behaviors in an animal model of HD, and the first to relate cognitive dysfunction to in vivo deficits of experience-dependent neocortical plasticity. We were also the first to show that environmental factors, including environmental enrichment, exercise and stress, can modify onset and progression of HD.

Aims

In this project, transgenic mice will be used to investigate mechanisms whereby pre-existing vulnerability to dementia and depression/anxiety may interact with specific environmental/pharmacological factors to modulate disease states, with a focus on modelling dementia and depression.

Cognitive deficits in HD, which culminate in dementia, create a major burden of disease. Furthermore, depression is the most common psychiatric symptom of HD and is estimated to develop in around half of all patients. Some changes to the brain of HD patients during the early stages of the disease are similar to changes that have been described in clinical dementia and depression.

Further studies are required to better understand the molecular and cellular pathogenesis of dementia and depression in HD. This could be YOU!

Key References:

van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Delaying the onset of Huntington's in mice. Nature 2000;404:721-2.

Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A, Blakemore C, Hannan AJ. Environmental enrichment rescues protein deficits in a mouse model of Huntington's disease, indicating a possible disease mechanism. J. Neurosci. 2004;24:2270-6.

Mazarakis NK, Cybulska-Klosowicz A, Grote H, Pang T, Van Dellen A, Kossut M, Blakemore C, Hannan AJ. Deficits in experience-dependent cortical plasticity and sensory-discrimination learning in presymptomatic Huntington's disease mice. J. Neurosci. 2005;25:3059-66.

Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nature Rev. Neurosci. 2006;7:697-709.

Pang TY, Du X, Zajac MS, Howard ML, Hannan AJ. Altered serotonin receptor expression is associated with depression-related behavior in the R6/1 transgenic mouse model of Huntington's disease. Hum. Mol. Genet. 2009;18:753-66.

Hannan AJ. Tandem repeat polymorphisms: modulators of disease susceptibility and candidates for 'missing heritability'. Trends Genet. 2010;26:59-65.

Du X, Leang L, Mustafa T, Renoir T, Pang TY, Hannan AJ. Environmental enrichment rescues female-specific hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington's disease. Transl. Psychiatry 2012;2:e133.

Wright DJ, Gray LJ, Finkelstein DI, Crouch PJ, Pow D, Pang TY, Li S, Smith ZM, Francis PS, Renoir T, Hannan AJ. N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease. Hum. Mol. Genet. 2016;25:2923-2933.

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