Mediating role of corticotropin-releasing hormone (CRH) in anxiety and ischemia: Behavioural and physiological correlates

Corticotropin-releasing hormone (CRH) has been considered the quintessential 'stress' neuropeptide, as it mediates stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and produces behavioural and autonomic responses analogous to natural stressors. However, the role of CRH in mediating the behavioural response to psychological stressors, also termed anxiety, is unclear due to inconsistent anxiolytic effects for CRH antagonists in processive stress models, and the central activation of CRH by non-anxiogenic stimuli. The first half of the current thesis examined the role of CRH, and amygdala CRH in particular, in the behavioural response to anxiety. The first experiment standardized the use of a neophobia-based feeding model for use as a behavioural index of anxiety. Using this model, the second experiment demonstrated that while exposure to an unfamiliar environment activates stress-relevant neural circuitry, activation of CRH receptors is not necessary for the expression of anxiety-like behavioral responses. In addition, amygdala CRH activation by novel stimuli is unaffected by changes in the organism's anxiety state. The second half of the current thesis focused on the role of CRH in neurotoxicity and behavioural deficits produced by global ischemic insults. It was demonstrated that global ischemic insults of 10--15 min duration produced short-term CRH increases in hypothalamic and amygdalar regions as well as the piriform cortex, perhaps mediating stress, inflammatory and/or epileptiform activity. This was followed by widespread CRH depletions throughout the brain at 24 h post-ischemia. However, by 72 h post-ischemia, just prior to the onset of cell death, CRH concentrations had normalized throughout the brain. Furthermore, there were no short or long term CRH changes at the CA1 hippocampal region, the area most vulnerable to cell death. Both selective and non-selective CRH antagonists failed to confer neuroprotection when administered before or shortly after an ischemic insult, and failed to protect against ischemia-induced spatial memory deficits. However, CRH1 antagonists did significantly attenuate ischemia-induced hyperactivity in the open field and in the elevated plus maze. Thus while ischemia-induced CRH activation does not appear to mediate subsequent neuronal degeneration, it may play a role in anxiety-related behavioural changes