- Title
- Characterizing changes in the orexin system in models of neuropsychiatric disease
- Creator
- Campbell, Erin Jane
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2016
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Hypothalamic dysfunction is a key feature of several neuropsychiatric disease states, including those involving reward-related deficits such as depression. Interestingly, exposure to early life adverse events, such as childhood trauma, typically precipitates the development of depression in adulthood. Most preclinical research regarding early life stress (ELS) has focussed on neuroendocrine cell populations. However, the lateral hypothalamus (LH) is also known to influence autonomic, neuroendocrine and behavioural responses to stress but its role in depressive-like behaviours such as low motivational drive is less well studied and was therefore the focus of this thesis. Within the LH there are several neuronal populations expressing GABA, and glutamate as well as neuropeptides such as orexin (hypocretin) and melanin-concentrating hormone (MCH). Notably, orexin has been implicated in reward-seeking pathways focussing on drug (cocaine) and natural reward-seeking behaviour (high fat and sugar foods). The overarching aim of my thesis was to assess the role of the hypothalamic orexin system in models of ELS in precipitating behaviours relevant to neuropsychiatric disease states such as suppressed reward-seeking behaviour. Using behavioural techniques and neural activity mapping, I first demonstrated that our model of ELS (maternal separation) suppressed motivated arousal in response to restraint stress in adulthood; an effect that was associated with a reduction in the percentage of Fos-positive orexin cells. Interestingly, voluntary wheel-running reversed both behavioural and neural deficits observed after ELS. A question that arose from these studies was whether these deficits in reward-seeking were produced by specific circuits within the LH. Further, given the difficulty in overcoming deficits in motivational drive, and in many cases an inability to exercise to beneficial levels in depressed individuals, I wanted to assess the feasibility of manipulating LH circuits pharmacologically to reverse ELS-induced deficits. To achieve my second aim, I applied for and received a prestigious travel grant from the Hunter Medical Research Institute to study at the National Institute on Drug Abuse (NIDA), Baltimore, USA to learn a novel technique termed chemogenetics. Professor Yavin Shaham’s lab at NIDA had recently employed chemogenetics to isolate specific circuits in the LH. At NIDA I used a dual-virus approach to inhibit ventral subiculum to nucleus acumbens shell projection neurons. Selective inhibition of this pathway decreased contextinduced relapse to alcohol seeking in rats. Upon returning to the University of Newcastle, I implemented these chemogenetic approaches to my model of ELS. I showed that chemogenetic activation of the LH reversed ELS-induced deficits in the motivation to lever press for a sucrose reward. Interestingly, this recovery of sucrose responding was associated with increases in the number of Fos-positive orexin neurons; but also a significant number of non-orexin, putative GABAergic neurons were recruited. In the final chapter of my thesis, I sought to determine if the orexin system was also altered following another type of ELS, exposure to an early life immune challenge lipopolysaccharide (LPS). LPS is an endotoxin bacterial cell wall product modelling the prevalence of bacterial immune stimuli in the perinatal human environment. Interestingly, early life LPS followed by formalin-induced inflammatory pain in adulthood resulted in an increase in the number of Fos-positive orexin cells. Together the data from my thesis indicate that that ELS rewires LH-orexin circuitry, as well as other LH projection pathways, and that these changes manifest as inappropriate behavioural responses to psychological and physical challenges in later life. Interestingly, exercise and chemogenetic activation of the LH is able to reverse the behavioural deficits produced by ELS. These data are important clinically because they suggest that capacity remains in LH circuitry, to overcome ELS-induced deficits in motivational drive.
- Subject
- hypothalamus; orexin; sex-differences; exercise; plasticity; alcohol; chemogenetics; nucleus accumbens; punishment; relapse; ventral subiculum; pain; stress; nociception; formalin; lipopolysaccharide; thesis by publication; anxiety; depression; cocaine; reinstatement; reward seeking; hypocretin; maternal separation
- Identifier
- http://hdl.handle.net/1959.13/1335688
- Identifier
- uon:27474
- Rights
- Copyright 2016 Erin Jane Campbell
- Language
- eng
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| View Details Download | ATTACHMENT01 | Thesis | 27 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 147 KB | Adobe Acrobat PDF | View Details Download |