Reelin, neuroendocrinology, and behaviour

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The general purpose of my research program during the past 20 years has focussed on understanding the functional roles of the extracellular matrix protein Reelin and how they affect neural plasticity and behaviour: We demonstrated that Reelin was primarily expressed in GABAergic neurons in cortex and hippocampus, and how Reelin secretion in terminal dendritic fields regulated synaptic strength onto dendritic spines. We also showed how Reelin deficits in specific brain areas induced by chronic stress bring about specific behavioural and neurochemical alterations. During the past granting cycle (2015-2020) my work specifically focussed on the effects of central and peripheral Reelin in regulating the crosstalk between the immune and nervous systems. We showed that Reelin deficits bring about specific alterations not only in the brain but also in the immune system that may prime animals for the deleterious effects of chronic stress, and that some anti-inflammatory drugs rescue Reelin expression levels upon chronic stress. Recently, we observed that Reelin is differentially expressed in specific hypothalamic nuclei in the brain of male and female rats (particularly in oxytocin expressing cells in the paraventricular nucleus, but also in preoptic nuclei), that hippocampal Reelin is altered in females during pregnancy, and that these expression levels are differentially altered in the two sexes in response to chronic stress. This novel set of data allows us to hypothesize that Reelin expression in hypothalamic nuclei may differentially affect synaptic strength in specific hypothalamic circuits in male and female rodents that are directly involved in the regulation of the stress response. Our research program will examine this hypothesis at different levels. First, we will carry out a systematic evaluation of Reelin differences in male and female hypothalamus, this will include a proper identification and stereological counting of neuronal subtypes expressing Reelin. In the case of females, we will additionally study putative differences during the estrous cycle and pregnancy. Second, the effects of Reelin in hypothalamic synaptic plasticity and pituitary at the molecular level will be studied in hypothalamic synaptosomes in vitro and in cultured pituitary cells, by using a paradigm that involves adding exogenous Reelin or blocking Reelin actions by using specific anti-Reelin antibodies, and analyzing differences in the activation of Reelin signal transduction proteins, in membrane protein clustering, and in promoting protein translation in synaptosomes. Third, we will use an animal model of chronic stress to evaluate how it affects Reelin hypothalamic and pituitary expression in male and female rats, and how that relates to specific behavioural alterations, and will assay if intra-hypothalamic Reelin infusions or peripheral intravenous Reelin injections affect neurochemical and behavioural alterations induced by chronic stress.