- Title
- Drug-induced changes to lateral hypothalamic circuits and downstream projection targets
- Creator
- Yeoh, Jiann Wei
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2015
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The lateral hypothalamus (LH) contains a large number of neuropeptide transmitter-expressing neurons that act to co-ordinate consummatory and reward-seeking behaviours. My thesis focuses on two classes of these neuropeptides; orexins, of which I generally classified as ‘pro’ reward-seeking and cocaine and amphetamine reward transcript (CART) peptides, commonly considered to be ‘anti’ reward-seeking. For example, in the context of drug addiction, activation of the orexin system generally promotes the reinstatement of cocaine-seeking behaviour, whereas the majority of the studies have demonstrated that increased CART signalling negatively regulates drug-motivated behaviours. Critically, it remains unclear how these systems interact and modulate the output of key nodes of the reward seeking circuitry. Therefore, in this thesis I address a number of outstanding questions regarding how changes in the activity of orexin or CART neurons might behavioural output controlled by the reward-seeking circuit. First, using ex vivo slice electrophysiology, I assessed how orexin circuitry in the LH is modified by cocaine exposure in rats that were passively exposed to cocaine or were trained to self-administer cocaine in operant boxes. Immunohistochemical detection of markers of glutamatergic versus GABAergic synapses was used to estimate and identify changes in presynaptic inputs onto orexin neurons after cocaine. I found evidence of increased presynaptic drive and excitatory terminals onto orexin neurons irrespective of whether animals self-administered or injected passively with cocaine. In Chapter 2, I determined if similar changes occur in orexin neurons from transgenic mice where the reporter gene (green fluorescent protein, GFP) was driven by the orexin promoter. These studies are important in order to take advantage of the expanding transgenic approaches in mice in the future. Further, I also tested the longevity of presynaptic drive to orexin neurons produced by cocaine and examined whether activation of group III metabotropic glutamate receptors could reverse any of the changes induced by cocaine. These studies showed that presynaptic drive to LH orexin neurons persists for at least two weeks after animals were withdrawn from cocaine. Further, activation of GP-III mGluRs curtailed the cocaine-induced increase in glutamate release onto orexin neurons. Previous work in our lab has identified that CART peptide injections but not orexin receptor antagonism in the PVT negatively regulates drug seeking behaviour. Therefore I assessed in Chapter 3 how cocaine influences the normal firing properties of PVT neurons and whether, as predicted by our previous behavioural studies, CART reduces PVT neuron activity. In the final chapter of my thesis, I summarise and integrate my results in the context of the wider literature and attempt to present a synthesis of LH based changes with relevance to addiction and other psychiatric conditions such as depression and anxiety.
- Subject
- lateral hypothalamus; addiction; electrophysiology; cart; orexin; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1309854
- Identifier
- uon:21950
- Rights
- Copyright 2015 Jiann Wei Yeoh
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 487 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 13 MB | Adobe Acrobat PDF | View Details Download |