Centre for Neuroscience - Theses
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ItemRelaxin-3 systems in brain: effects on feeding, anxiety, depression and addiction( 2012)The neuropeptide, relaxin-3 (RLN3), and its major endogenous receptor, RXFP3 (relaxin family peptide receptor 3), have been postulated to modulate feeding, anxiety- and depressive-like behaviour, and reward based on neuroanatomical and neurochemical data. The major aim of the research described in this thesis, therefore, was to determine the effect of centrally administered RXFP3-selective peptides on these functions in the adult rat. Intracerebroventricular (icv) administration of the RXFP3-selective agonist peptides, R3/I5 and RXFP3-A2, and native rat/mouse relaxin-3 (rmRLN3) significantly increased acute food intake in male Sprague-Dawley rats, and this effect was prevented by prior icv injection of the RXFP3-selective antagonist peptides, RXFP3-A3 and R3(B1-22)R. Icv injection of RXFP3-A2 decreased anxiety-like behaviour in male Sprague-Dawley rats in a range of behavioural tests, including the light-dark box and elevated plus maze, and produced antidepressant-like effects in the repeat forced swim test, but notably only in rats that had previously been tested in anxiety-like paradigms. Icv injection of RXFP3-selective agonists had no significant effect on general activity assessed quantitatively in automated locomotor cells. Icv administration of an RXFP3 antagonist (R3(B1-22)R) decreased alcohol but not sucrose self-administration in male inbred alcohol-preferring (iP) rats in a dose-related manner, and decreased cue-induced reinstatement (a model of relapse) for alcohol but not sucrose, suggesting a possible role for relaxin-3/RXFP3 signalling in alcohol-seeking. In addition, endogenous relaxin-3 mRNA expression in the hindbrain nucleus incertus correlated with daily alcohol and sucrose intake in the two-bottle choice paradigm, suggesting a role for endogenous relaxin-3 in modulating intake of ‘rewarding’ substances. Overall, the results from this research suggest that the endogenous relaxin-3/RXFP3 system promotes ‘motivated’ or ‘goal-seeking’ aspects of behaviour. These studies contribute to a deeper understanding of the neurobiology underlying clinical disorders such as obesity, anxiety, depression and addiction, which may in turn lead to novel diagnostics and therapeutic approaches. These important findings are therefore predicted to have a significant impact within the fields of neuropeptide biology and behavioural neuroscience, and are associated with several published or submitted scientific journal articles and reviews. In addition, the data have helped stimulate interest in this research area, with several major pharmaceutical companies expressing interest in the relaxin-3/RXFP3 system as a possible target for the development of therapeutic treatments for individual and co-morbid psychiatric and metabolic disorders.
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ItemDepression in Huntington's disease: Modulation of environment and gender( 2012)Of the plethora of symptoms that arise in HD, depression is the most diagnosed psychiatric symptom, with 30-50% of patients developing depression. This makes depression far more prevalent in the HD population than in the general populace and indeed, significantly more conspicuous compared to other neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease. Due to depression’s ubiquity, impact and also the fact that it can appear decades before crippling motor symptoms, treatment and management of depression would significantly prolong the symptom-free period of patients’ lives. The overrepresentation of depression is most likely an endemic reflection of pathophysiology caused by the HD mutation. However, the aetiology of depression in the context of HD has not been well understood. The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine system responsible for stress adaptation and its dysfunction has been implicated in clinical depression. Few studies have examined the HPA-axis in HD to date. Our group has previously found, using the R6/1 mouse model of HD, a female-specific depression-like behavioural phenotype. In this thesis, examining the HPA-axis in these animals, it was found that female, but not male, R6/1 mice displayed a hyperactive HPA-axis in response to stressors. Further pharmacological challenges, gene expression analyses and in vitro studies discerned the source of the abnormality to a hypersensitive adrenal gland; a novel finding of a peripheral source for what has been largely seen as a centrally mediated pathology. Environmental factors have been found to produce significant modulation to the progression of HD. Previously, our lab has shown that environmental enrichment is able to delay the onset of various symptoms in the R6/1 mice, including depression-like behavioural phenotype in the female mice. In this thesis, environmental enrichment was also found to be able to rescue the abnormalities of the HPA-axis both in vivo and in vitro. One possible mechanism of such rescue by environmental enrichment is mediated through increased glucocorticoid receptor gene expression in the adrenal gland. Furthermore, experiments were carried out to dissect the influences of sex hormones toward explaining the sexually-dimorphic manifestation of this phenotype. Abnormality of the hypothalamic-pituitary-gonadal axis was found in both male and female R6/1 mice. Ovariectomy altered HPA-axis response in female mice, correlating with female R6/1 specific increases in estrogen receptor α gene expression in the adrenal gland. The findings in this thesis are the first to establish a peripheral origin of the HPA-axis dysfunction. It is also a first in showing that environmental enrichment can exert peripheral specific benefits. Sex-specificity of this phenotype is also a novel observation and may be due to female-specific adrenal alterations of estrogen receptor α gene expression. Clinical implications of these findings include prospective new biomarkers as well as opening up the way for potentially new targets for future treatments. Furthermore, these findings raise the consciousness regarding the importance of peripheral changes in HD and the importance of sex dimorphism in the disease progression of HD, two areas that have not been well studied.