Quick Project Snapshot

Therapeutic approaches to dementia and depression in Huntington’s disease

Huntington’s disease (HD) is an inherited single-gene abnormality that causes neurons in the brain to become dysfunctional and eventually die. The condition involves cognitive deficits (culminating in dementia), psychiatric symptoms (the most common of which is depression), and a movement disorder (including the uncontrollable ‘dance-like’ symptoms called chorea). HD is one of the increasing numbers of fatal brain diseases known to be caused by DNA expansion (a ‘genetic stutter’) in the disease-causing gene.  In the case of HD, the gene mutation is translated into a toxic protein which slowly poisons subpopulations of cells in the brain.

Our previous research into Huntington’s disease (HD) has shown that we can use a mouse model of HD to understand the debilitating symptoms of depression and dementia. We have also identified key molecules involved in the depression and dementia that occurs in HD. The aim of this project is to identify key molecules associated with depression and dementia in HD, and to test a therapeutic intervention in a mouse model of HD.  We are using transgenic mice which express the gene mutation that causes HD in humans.  We are focusing on key molecules that we think may be involved in the disease process, including those located at synapses, the connections between neurons.   We use molecular biology and biochemistry approaches to measure changes in the candidate molecules in key brain regions, including the cerebral cortex and basal ganglia.  

Our first approach to therapy is to examine the effects of environmental enrichment (enhanced cognitive stimulation and physical activity).  We have previously demonstrated that environmental enrichment can delay onset of the depression and dementia in HD.  We will now examine the effect of the increased mental activity and physical exercise at the level of specific molecules in the brain.  Those molecules which are beneficially modulated by this intervention will be identified as candidate targets for ‘enviromimetics’, drugs which mimic or enhance the beneficial effects of environmental stimulation.

There are no effective disease-modifying treatments for this devastating disorder, so any new candidate therapeutic intervention we can identify has the potential to directly help HD families.  Furthermore, the disease processes in HD are highly relevant to other brain disorders including Parkinson’s disease, Alzheimer’s disease, other forms of dementia, and depression. Therefore this project will also have an impact outside of HD.

Profile
HEAD OF LAB
Dr Thibault Renoir

Genes Environment and Behaviour Laboratory

Our research includes models of specific neurological and psychiatric disorders which involve cognitive and affective dysfunction, investigated at behavioural, cellular and molecular levels so as to identify pathogenic mechanisms and novel therapeutic targets.

By integrating wide-ranging expertise (including animal behaviour, electrophysiology and molecular/cellular skills) and an extended network, the Genes Environment & Behaviour Laboratory explores how genes and environment combine via experience-dependent plasticity in the healthy and diseased brain. 

More specifically, our group has been focusing on projects related to the gene–environment interaction modulating the pathophysiology of Huntington’s disease publishing numerous papers on this topic. As a result, we recently attracted funding from the Brain Foundation and NHMRC.

Supported by my ARC DECRA Fellowship we have started the study of the environmental and pharmacological modulation of behavioural endophenotypes in relevant mouse models of psychiatric disorders (e.g. depression, anxiety, schizophrenia) as well as the investigation of the mechanisms mediating the effects of environmental enrichment and exercise. 

Recent publications include:

  1. Mo C, Hannan AJ, Renoir T. Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington's disease. Neurosci Biobehav Rev. 2015 May;52:178-92. (PMID: 25770041).

  2. Wright DJ, Renoir T, Smith ZM, Frazier AE, Francis PS, Thorburn DR, McGee SL, Hannan AJ, Gray LJ. N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease. Transl Psychiatry. 2015 Jan 6;5:e492. (PMID: 25562842).

  3. Mo C, Pang TY, Ransome MI, Hill RA, Renoir T, Hannan AJ. High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice. Neurobiol Dis. 2014 Sep;69:248-62. (PMID: 24825316).

  4. Renoir T, Hasebe K, Gray L. Mind and body: how the health of the body impacts on neuropsychiatry. Front Pharmacol. 2013 Dec 18;4:158. (PMID: 24385966).

  5. Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013 Apr 16;4:45. (PMID: 23596418).

  6. Wright DJ, Gray LJ, Finkelstein DI, Crouch PJ, Pow D, Pang T, 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 May 14. (PMID: 27179791)

  7. Rogers J, Vo U, Buret LS, Pang TY, Meiklejohn H, Zeleznikow-Johnston A, Churilov L, van den Buuse M, Hannan AJ, Renoir T. Dissociating the therapeutic effects of environmental enrichment and exercise in a mouse model of anxiety with cognitive impairment. Transl Psychiatry. 2016 Apr 26;6:e794. (PMID: 27115125)

 

All Projects by this Lab

Gene-environment interactions in the regulation of cellular plasticity, cognitive function and behaviourTherapeutic approaches to dementia and depression in Huntington’s disease

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