Quick Project Snapshot

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

Huntington’s disease (HD) is a fatal neurodegenerative disorder with no known cure. HD is caused by a tandem repeat (CAG) expansion encoding an extended polyglutamine tract in the huntingtin protein.  The disease is characterised by progressive psychiatric symptoms, cognitive deficits and a movement 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.

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!

 

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.

Epigenetics and Neural Plasticity Laboratory

The Neural Plasticity Laboratory investigates gene-environment interactions and experience-dependent plasticity in the healthy and diseased brain, using a variety of experimental approaches.  This includes research using a model of Huntington’s disease (HD), a tandem repeat disorder, where we are following up our discoveries regarding the beneficial effects of environmental enrichment (enhanced cognitive stimulation and physical activity) and exercise, as well as depression and dementia-like symptoms associated with abnormalities of brain plasticity.  Furthermore, we recently discovered that chronic stress can accelerate onset of HD, and are investigating these neurotoxic effects of stress in HD and other brain disorders.

Many neurological and psychiatric disorders have their origins in abnormal maturation of the brain, including the billions of neurons exquisitely connected by trillions of synapses. We are also investigating how genetic and environmental factors combine to cause specific disorders of brain development and cognition, including schizophrenia and autism spectrum disorders (ASD).  We are interested in the mechanisms whereby specific genes regulate maturation of the brain and are dynamically regulated by interaction with the environment in conditions like ASD and schizophrenia. 

Our research links data at behavioural and cognitive levels to underlying cellular and molecular mechanisms.  We use a variety of behavioural tools, including automated touchscreen testing of cognition and high-throughput data analysis of vocalization and communication, that are directly translatable to clinical tests.  We are establishing the extent to which experience-dependent plasticity, including adult neurogenesis and synaptic plasticity, can modulate these behavioural and cognitive endophenotypes, in models with targeted genome editing.  This cellular level of understanding is linked, in turn, to molecular mechanisms, including epigenetics, transcriptomics and proteomics.

Based on this research, and the identification of key target molecules, we are also exploring the concept of ‘enviromimetics’, therapeutics that mimic or enhance the beneficial effects of cognitive stimulation and physical exercise.  One goal is to develop such therapeutic agents to help reduce the personal and societal burdens of devastating brain disorders such as schizophrenia, HD and dementia.

All Projects by this Lab

Investigation of paternal influence on offspring mental healthUtilising Touchscreen technology for preclinical modeling of attention in autism spectrum disorderInvestigating social communication in the Neuroligin 3 mouse model of AutismInvestigating the inherited paternal influence on offspring cognition and behaviourExperience-dependent plasticity modulating cognitive deficits in schizophreniaGene-environment interactions modulating dementia and depression in a tandem repeat disorder

Behavioural Neuroscience

The Division of Behavioural Neuroscience focuses on the use and development of models that reflect aspects of human disorders such as addiction, anxiety, depression, schizophrenia, autism and neurodegenerative conditions such as Huntington’s disease. The Cognitive Neuroscience group additionally studies cognitive disorders caused by diseases such as stroke (cerebrovascular disease), Alzheimer's disease and other dementias from a clinical perspective.

All Labs that operate in this Division

Addiction Neuroscience LaboratoryClinical Cognitive Neuroscience LaboratoryDevelopmental Psychobiology LaboratoryEpigenetics and Neural Plasticity LaboratoryGenes Environment and Behaviour LaboratoryInhalant Addiction LaboratoryMidbrain Dopamine Plasticity LaboratorySynapse Biology and Cognition LaboratoryVascular Neurodegeneration Research Laboratory