Neurotrophins in Neuroendocrine Control: Brain Derived-neurotrophic Factor (BDNF) and Somatostatin Involvement in the Stress Response and Reproductive Physiology

Abstract

Some neurohormonal secretions, other than Gn-RH, are also sensitive to gonadal steroid influences. Thus, we have recently shown that somatostatin (SRIH) is a hypothalamic hormone whose mRNA, peptide content and release are affected by the sexual cycle in vitro and in vivo. Furthermore, the in vivo interaction between stress application (cold exposure) and steroid status determines the subsequent response to a depolarizing concentration of K + analyzed in hypothalamic ex-vivo fragments. Such interaction between stress and sex steroids suggests that a kind of neuronal plasticity occurs to ensure this coupling process. We therefore focused on the brain derived-neurotrophic factor (BDNF), a conspicuous member of the neurotrophin NGF family that has been associated with synaptic plasticity and whose concentration is particularly important in the hypothalamus. In this region, we have shown that BDNF mRNA levels exhibit very rapid up-regulation following stress application and that protein translation also occurs rapidly. Under acute stress immobilization conditions, somatostatin expressing neurons are subjected to plasticity processes since somatostatin mRNA levels, measured by in situ hybridization (ISH), are increased in spite of a significant decrease in the number of cells expressing the messenger. In this connection, we observed that in the periventricular nucleus BDNF mRNA is likely localized in the same cells expressing somatostatin mRNA and are reactive to stress stimulus. Furthermore, in primary cultures of hypothalamic neurons, BDNF is able to stimulate both the synthesis and release of somatostatin. In addition, acute icv microinjections of BDNF are able to rapidly decrease somatostatin content in the hypothalamus, and this is also observed after acute stress application. This phenomenon could be explained by a concomitant increase in somatostatin release as estimated with push-pull cannula. The median eminence (ME) is another hypothalamic region where we have detected BDNF protein by immunohistochemical methods, particularly in astrocytes. In this structure, tanycytes (long considered to be indirect regulators of neurohormonal secretion in processes such as lactation and ovulation), appear to be a novel target of BDNF, since we detected the specific trkB receptor on the podia of these specialized glial cells. Furthermore, in this structure, BDNF content and release as well as TrkB receptors are sensitive to immobilization stress. Taken as a whole, these data indicate that there are close relationships between stress and sexual status, with hypothalamic somatostatin neurons being new cellular targets whose metabolism seems to be modulated by neurotrophins.