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Abstract
Hypocretin (Hcrt, also known as orexin) is a neuropeptide produced exclusively by neurons located in the dorsal tuberal hypothalamus. Hcrt has been implicated in a range of functions associated with high arousal states including feeding, wakefulness, motor activity, autonomic function and stress. This thesis investigated the role of Hcrt in two forms of psychological stress, conditioned fear to context and restraint. Three complementary techniques were used in rats. (i) Lesions of Hcrt containing neurons and surrounding cells were made with a Hcrt-saporin toxin and the cardiovascular and behavioural response to stress investigated using radiotelemetry. (ii) Fos was used as an indicator of Hcrt neuronal activity during stress in both the day and night time. (iii) Radioimmunoassay was used to determine the release of the Hcrt peptide into the CSF during stress.
The lesions reduced the cardiovascular and behavioural response to contextual fear but did not affect the response to restraint. Similarly, the activity of Hcrt neurons and the release of the Hcrt peptide were greater after contextual fear than after restraint. These results suggest that Hcrt neurons are involved in specific forms of stress, which are likely to include stressors that are purely psychological (contextual fear) rather than stressors that have an additional physical component (restraint). Most importantly it was also shown that Hcrt's involvement was not determined by the degree of stress, as increased stress did not result in more Hcrt neuronal activity or Hcrt peptide release than exploratory activity in a non-feared context. This was demonstrated during both day and night when baseline Hcrt and arousal levels were low and high, respectively.
It is proposed that Hcrt contributes to the increased attention and arousal that is required to interact with the environment during some stressful and non-stressful conditions. Importantly, this idea integrates the many previously proposed but poorly linked functions of Hcrt.