Reelin, neuroendocrinology, and behaviour

Reelin、神经内分泌学和行为

• 批准号: RGPIN-2020-04600
• 负责人: Caruncho, Hector
• 金额: $ 2.04万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760796
• 关键词: Reelin; neuroendocrinology; behaviour

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.

在过去的20年里，我的研究计划的总体目的是了解细胞外基质蛋白Reelin的功能作用及其如何影响神经可塑性和行为：我们证明Reelin主要在皮质和海马区的GABA能神经元中表达，以及Reelin在终末树突域如何调节树突棘上的突触强度。我们还展示了慢性应激引起的特定大脑区域的Reelin缺陷如何导致特定的行为和神经化学变化。在过去的授予周期中(2015-2020)，我的工作主要集中在中枢和外周Reelin在调节免疫和神经系统之间的串扰方面的影响。我们发现，Reelin缺陷不仅会在大脑中带来特定的变化，还会在免疫系统中引起特定的变化，这可能会使动物适应慢性应激的有害影响，而且一些抗炎药物可以在慢性应激时挽救Reelin的表达水平。最近，我们观察到Reelin在雄性和雌性大鼠脑内特定的下丘脑核团(特别是在室旁核和视前核团的催产素表达细胞)中有差异表达，在雌性大鼠的海马区Reelin在怀孕期间发生变化，并且这些表达水平在雌性大鼠对慢性应激的反应中存在差异。这组新的数据使我们可以假设，Reelin在下丘脑核团的表达可能对雄性和雌性啮齿动物特定下丘脑回路中的突触强度产生不同的影响，这些啮齿动物直接参与应激反应的调节。我们的研究计划将在不同的层面上检验这一假设。首先，我们将对男性和女性下丘脑的Reelin差异进行系统的评估，这将包括对表达Reelin的神经元亚型进行适当的鉴定和体视学计数。在雌性的情况下，我们还将研究发情周期和怀孕期间的假定差异。其次，将在分子水平上研究Reelin在下丘脑突触体内和培养的垂体细胞中的作用，通过使用特定的抗Reelin抗体添加外源Reelin或阻断Reelin作用的范式，分析Reelin信号转导蛋白在激活Reelin信号转导蛋白、膜蛋白聚集和促进突触体内蛋白质翻译方面的差异。第三，我们将使用慢性应激的动物模型来评估它如何影响雄性和雌性大鼠的Reelin下丘脑和垂体的表达，以及这种影响如何与特定的行为改变有关，并将测试下丘脑内注射Reelin或静脉注射Reelin是否会影响慢性应激诱导的神经化学和行为改变。