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Unmasking the functional anatomy of medial preoptic nucleus-influences on the hypothalamic-pituitary-adrenal axis Williamson, Martin Alexander


The hypothalamic-pituitary-adrenal (HPA) axis is a critical mediator of the stress response system. However, despite clear evidence for an inhibitory role of testosterone on stress-induced activation of the HPA axis, the routes and mechanisms have not been addressed. To first determine where testosterone acts in the brain to regulate stress-related input to the HPA axis, I used a combined retrograde transport and immunohistochemical procedure to characterize the anatomical nature by which androgen targets in the brain communicate with the paraventricular nucleus (PVN) of the hypothalamus, the initial point of the neuronally mediated stress response. The findings suggest that androgens could act throughout the brain, and on a large assortment of brain regions that innervate the PVN. Among the brain regions identified, neurons of the medial preoptic nucleus (MPN), highly express androgen receptors and project abundantly to the PVN, suggesting that the MPN stands out as a potential site of integration between testosterone and the HPA axis. To test the functional role of these cells, I tested whether lesions of the MPN alter the inhibitory effects of testosterone on the HPA axis. By selectively removing cells in the MPN, testosterone regulation of the PVN and HPA axis was eliminated. Together, these findings demonstrated that the integrity of the MPN is essential in maintaining the regulatory effects of testosterone on the brain's response to stress. Finally, to clarify whether the MPN is the seat of, or an obligatory relay for the central effects of testosterone, I tested the effects of implanting the androgen receptor antagonist hydroxyflutamide into the MPN, on the stress-induced activation of the PVN and HPA output. The differential effects of androgen exposure in the MPN on the biosynthetic capacity and activational responses of the PVN and its extended circuitries suggested that the MPN is capable of bridging converging limbic influences to the HPA axis with changes in gonadal status.

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