An intrinsic CRF signaling pathway in the optic tectum




Zhang, Sherry

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Corticotropin-releasing factor (CRF) is a 41 amino acid peptide that is best known as the principle hypophysiotropic hormone regulating the pituitary-adrenal axis during stress. CRF also regulates many stressors and anxiety related behaviors including food intake, and over-expression of CRF is thought to be the main causative agent in anxiety related eating disorders such as anorexia nervosa. Recent data collected in our laboratory using amphibian models indicate that, in addition to affecting appetite, CRF may modulate visual sensory pathways involved in detecting and responding to food. Here we examined the hypothesis that CRF directly modulates sensorimotor processing in the optic tectum of the African clawed frog, Xenopus laevis, the major site for integration of visually guided behavior in the non-mammalian brain. Previous studies in X. laevis using RT-PCR revealed that cells in the optic tectum express mRNA for CRF and the CRF R1 receptor but not the CRF R2 receptor. Furthermore, immunohistochemical studies by our laboratory indicate that CRF producing neurons are located strategically in tectal layers 6-8 to intercept retinal information. While these studies suggest that may be released by neurons in the tectum to act locally on CRF R1 receptors, whether or not CRF is actually released by tectal neurons and the existence of cognate CRF R1 receptors in the tectum has never been shown. In the current work, in vitro CRF-release studies revealed that both basal and depolarization-induced release of CRF, determined using a homologous radioimmunoassay, was greater from the optic tectum relative to the telencephalon, hypothalamus/midbrain or brainstem. These findings most likely reflected regional differences in the inhibitory regulation of CRF, as tectal content of CRF was actually lower than that of the hypothalamus in the two anuran species that have been studied to date. Depolarization-induced release of CRF from the optic tectum was calcium dependent. Radioligand binding studies indicated that specific binding of [125I-Tyr]-oCRF to tectal cell membranes could be displaced by the CRF R1 selective antagonists antalarmin or NBI 27914. CRF enhanced cAMP content in tectal slices in vitro, but the differences were not statistically significant. In order to figure out whether the control of CRF neurons is controlled by chemically defined pathways innervating the tectum we conducted in vitro studies with glutamate, the primary excitatory neurotransmitter in the tectum, neuropeptide Y (NPY) and the cholinergic agonist carbachol. The results showed that glutamate significantly inhibited basal and depolarization-induced CRF release from optic tectum. We conclude that the optic tectum possesses a CRF signaling system that may be involved in modulating communication between sensory and motor pathways involved in food intake.



Corticotropin-releasing factor (CRF), Xenopus laevis, Optic tectum, Stress, Corticotropin-releasing factor (CRF) receptor, Food intake