Terence Y. Pang

Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington’s disease transgenic mice

Huntingtons disease is a fatal neurodegenerative disorder caused by a mutation of the huntingtin gene and involves progressive motor abnormalities (including chorea), cognitive deficits (dementia) as well as psychiatric symptoms. We have previously demonstrated that environmental enrichment slows the onset and progression of Huntingtons disease in transgenic mice. Here, we investigated the effects of enhanced physical exercise on disease progression and brain-derived neurotrophic factor expression. Standard-housed Huntingtons disease mice developed phenotypic rear-paw clasping by 16 weeks of age, displayed abnormal rearing behavior, deficits in motor co-ordination and of spatial working memory. Huntingtons disease mice with access to running wheels exhibited delayed onset of rear-paw clasping, normalized levels of rearing behavior and amelioration of the cognitive deficits. However, in contrast to our previous environmental enrichment studies, there was no rescue of motor coordination deficits in wheel-running Huntingtons disease mice. An abnormal accumulation of brain-derived neurotrophic factor protein in the frontal cortex of Huntingtons disease mice was unaffected by running. Striatal and hippocampal brain-derived neurotrophic factor protein levels were unchanged. Brain-derived neurotrophic factor mRNA levels were reduced in the anterior cortex, striatum and hippocampus of Huntingtons disease mice, and only striatal deficits were ameliorated by running. Overall, we show that voluntary physical exercise delays the onset of Huntingtons disease and the decline in cognitive ability. In addition, our results reveal that some aspects of hippocampal dependent memory are not entirely reliant on sustained hippocampal brain-derived neurotrophic factor expression.

Altered serotonin receptor expression is associated with depression-related behavior in the R6/1 transgenic mouse model of Huntington's disease

Dysregulation of the serotonergic signaling system has been implicated in the pathology of mood disorders including depression, and various rodent models of disrupted serotonergic signaling display depression-related behavioral phenotypes. Depression is a common neuropsychiatric feature of preclinical Huntingtons disease (HD) but the underlying changes in the HD brain contributing to the development of depression are unknown. Using the R6/1 transgenic mouse model of HD, we show that pre-motor symptomatic HD mice display sex-specific depressive-related behaviors on the forced-swim (FST), tail-suspension (TST) and novelty-suppressed feeding (NSFT) tests while having muted responses to acute anti-depressant administration. The baseline behaviors of HD mice were similar to the behavioral phenotypes of serotonin (5-HT) receptor and transporter null mutants, and gene expression of specific serotonin receptors were subsequently found to be reduced in the hippocampus and cortex of HD mice. Female HD mice had an additional deficit in cortical expression of serotonin transporter (SerT). Environmental enrichment normalized the FST behavioral response of female HD mice corresponding with increased gene expression of specific 5-HT receptors in the hippocampus and cortex. Our findings implicate altered serotonergic signaling as the basis for the development of depression during the preclinical stages of HD.

Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington's disease mice

Brain‐derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5′ untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntingtons disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late‐stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre‐motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel‐running and environmental enrichment on wild‐type mice, in association with a proposed environment‐mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real‐time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel‐running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild‐type animals. Further quantification of BDNF exon‐specific transcripts revealed sex‐specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel‐running and environmental enrichment. The HD‐associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment‐induced changes in BDNF gene expression in the wild‐type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression.

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

Huntingtons disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.

Sexually dimorphic serotonergic dysfunction in a mouse model of Huntington's disease and depression

Depression is the most common psychiatric disorder in Huntingtons disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

Environmental enrichment rescues female-specific hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington's disease

Huntingtons disease (HD) has long been regarded as a disease of the central nervous system, partly due to typical disease symptoms that include loss of motor control, cognitive deficits and neuropsychiatric disturbances. However, the huntingtin gene is ubiquitously expressed throughout the body. We had previously reported a female-specific depression-related behavioural phenotype in the R6/1 transgenic mouse model of HD. One hypothesis suggests that pathology of the hypothalamic-pituitary-adrenal (HPA) axis, the key physiological stress-response system that links central and peripheral organs, is a cause of depression. There is evidence of HPA axis pathology in HD, but whether it contributes to the female R6/1 behavioural phenotype is unclear. We have examined HPA axis response of R6/1 mice following acute stress and found evidence of a female-specific dysregulation of the HPA axis in R6/1 mice, which we further isolated to a hyper-response of adrenal cortical cells to stimulation by adrenocorticotrophin hormone. Interestingly, the adrenal pathophysiology was not detected in mice that had been housed in environmentally enriching conditions, an effect of enrichment that was also reproduced in vitro. This constitutes the first evidence that environmental enrichment can in fact exert a lasting influence on peripheral organ function. Cognitive stimulation may therefore not only have benefits for mental function, but also for overall physiological wellbeing.

Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise

BACKGROUND AND PURPOSE Depression is the most common psychiatric disorder in Huntingtons disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5‐hydroxytryptaminergic (serotonergic) dysregulation.

Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring

Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.

Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic–pituitary–adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer’s, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies.

Differential effects of early environmental enrichment on emotionality related behaviours in Huntington's disease transgenic mice.

•  Clinical diagnosis of Huntingtons disease (HD) is determined on the basis of motor symptoms; however, the pre‐motor stages of the disease are commonly associated with psychiatric alterations including depression and anxiety. •  Using the R6/1 transgenic mouse model of HD, this study is the first report on the effects of environmental enrichment (EE) at a very early stage on a broad range of behavioural tests assessing stress‐related measures. •  Environmental enrichment did not prevent despair‐ and anhedonia‐like behaviours displayed by HD mice. However, EE reduced anxiety levels and corrected altered stress responses observed in HD mice. •  Despite the enhanced hypothermic response to the serotonin 5‐HT1A receptor agonist 8‐OH‐DPAT exhibited by HD mice, we found a reduction in 5‐HT1A receptor mediated stimulation of [35S]GTP‐γ‐S binding in the dorsal raphe nucleus and the hippocampus of HD animals. •  Our data suggest that early EE has beneficial effects on the anxiety‐like, but not on the depression‐like, behaviours in HD mice. We also provide evidence that 8‐OH‐DPAT induced hypothermia could be mediated by other targets besides the serotonin 5‐HT1A receptors.