Stress is defined as a challenge to homeostatic equilibrium by physical or psychological events, generating a coping response consisting of central and peripheral changes, with the aim of exerting control over the threatening events. Corticotropin-releasing factor (CRF) is well known as a hypothalamic factor which controls the hypothalamic-pituitary-adrenocortical (HPA) axis during basal activity and stress. CRF also serves a neurotransmitter function in the brain, where it is implicated in a range of stress-related behaviours. The measurement of local cerebral glucose utilisation (LCGU) using radiolabelled 2-deoxy-D-glucose (2DG) provides an estimate of cellular activity in the brain. 2DG competes with glucose in its metabolic pathway, but is not fully metabolised, instead accumulating within astrocytes where it can be quantified. After consideration of available modifications to the LCGU technique, the effect of manipulating the CRF system on LCGU was studied, in order to test the hypothesis that CRF and other endogenously expressed CRF-related peptides would induce different patterns of LCGU, and to examine the involvement of CRF receptors in any response. The CRF1 receptor has been implicated in the mediation of stress- and anxiety-related behaviour, while recent evidence has suggested a role for CRF2 in mediating the delayed effects of stress, although it has previously been postulated that CRF2 may be involved in the attenuation of stress-related behaviour. CRF and the endogenous CRF-related peptide Urocortin 1 both induced increases in LCGU in a number of brain regions associated with the CRF system, with concomitant activation of the HPA axis. CRF induced increases in LCGU in the dissected hypothalamus, thalamus, cerebellum and hippocampus, while Urocortin 1 induced a significant increase in LCGU in a dissected hindbrain region, with trend-like effects in frontal cortex and hippocampus. These regions contain components of the CRF system, or receive projections from regions involved in the CRF system, and have been implicated in stress-related function. The effects of CRF on LCGU appear to be mediated by the CRF2 receptor, as they were abolished by the selective CRF2 antagonist antisauvagine-30, but persisted in mice lacking CRF1 and were unaffected by a selective CRF1 antagonist. However, neither of the endogenous CRF-related peptides selective for CRF2, Urocortin 2 and Stresscopin, affected LCGU, which may indicate ligand-specific effects within the CRF system. In contrast to the effects of CRF, restraint stress reduced LCGU, while activating the HPA axis, and this response was unaffected by a selective CRF1 antagonist. This data suggests that the role of CRF receptors in restraint-induced LCGU changes may be overshadowed by effects on other neurotransmitter systems. These studies support the hypothesis that CRF and other endogenously expressed CRF-related peptides would induce different patterns of LCGU, and highlight the involvement of particular brain regions in the response to CRF receptor stimulation. Furthermore, these studies provide evidence suggesting ligand-specific effects within the CRF system.
|Date of Award||1 Dec 2007|
|Supervisor||Roland Jones (Supervisor)|
- glucose metabolism