Huntington's disease (HD) is caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD patients exhibit cognitive deficits (culminating in dementia), psychiatric symptoms (the most common of which is depression) and motor abnormalities (e.g. chorea). In a transgenic mouse model of HD we have correlated early deficits of hippocampal neurogenesis with onset of cognitive and affective (depression-like) abnormalities, and identified potential molecular mechanisms mediating this ‘pathological plasticity’. We have also demonstrated that altered sensory, cognitive and motor stimulation can dramatically modify the disease process in HD mice. A more specific component of environmental enrichment, voluntary physical exercise, was found to delay the onset of hippocampal-dependent cognitive and affective symptoms, in a similar fashion to chronic administration of selective serotonin reuptake inhibitors (SSRIs). Together with parallel BrdU labeling, immunohistochemistry and stereology, these findings suggest that the cellular mechanisms mediating this delayed onset of hippocampal-dependent behavioural deficits involve enhancement of adult neurogenesis. Our findings indicate that the modulatory effects of various environmental stimuli are mediated by experience-dependent changes in transcription of specific genes implicated in adult hippocampal neurogenesis and synaptic plasticity. Transcription of brain-derived neurotrophic factor (BDNF) is disrupted by the HD mutation at an early stage in both the hippocampus and neocortex, associated with onset of the depressive-like signs. Furthermore this transcriptional dysregulation is exon-specific, sex-specific, results in abnormal levels of BDNF protein, and is differentially modulated by environmental enrichment (which enhances both mental and physical activity levels) compared to voluntary exercise alone.