CIRCUITS MEDIATING BEHAVIORAL CONSEQUENCES OF STEROID SENSATION

描述(申请人提供)：类固醇激素调节哺乳动物生理的许多方面。类固醇穿过细胞膜，与核受体/转录因子结合，启动基因转录的改变。尤其是在神经系统中，类固醇的作用速度太快，不能归因于这种机制。最近，我的实验室发现了一种新的类固醇作用模式：驻留在犁鼻器官中的神经元可以检测到硫酸类固醇，这些神经元为副嗅觉系统提供感觉输入。这些感觉神经元表达数百种不同类型的G蛋白偶联受体，不同的神经元检测不同的硫化类固醇。硫化类固醇存在于自然的身体分泌物中，如尿液中，是组织哺乳动物社会行为的主要候选者。在小鼠中，由副嗅觉系统介导的行为或生理反应经常涉及多个线索的整合；特别是，有几个例子表明，男性来源的刺激与女性来源的刺激相反，这些线索的整合导致了单一的行为反应。我们假设这些行为的产生是处理有关硫化类固醇的感觉数据的神经元回路的直接结果。为了验证这一假设，我们提出了电生理和行为学实验，以阐明该电路在分析复杂的类固醇混合物中的功能。在目标1中，我们将确定副嗅球的二尖瓣细胞如何编码有关个别硫化类固醇的信息，并测试电路处理如何改变从感觉神经元继承的表征。在目标2中，我们将检验男性和女性类固醇线索在混合抑制中的作用，这可能是男性/女性对手行为过程的生理关联。在目标3中，我们将研究嗅觉检测到的硫化类固醇在抑制发情周期中的作用，特别是糖皮质激素的作用。在目标4中，我们将研究硫化类固醇在防止陌生男性尿液引发的受孕障碍方面的作用。这些目的将阐明类固醇在哺乳动物生殖行为的嗅觉调节中的新作用。 公共卫生相关性：更好地了解类固醇在神经系统中的作用为治疗压力、焦虑和情绪障碍带来了希望，并阐明了神经元发育中的性别差异。大多数关于类固醇效应的实验都是在啮齿动物身上进行的，但由于啮齿动物和人类之间的差异，对结果的解释变得复杂。嗅觉检测可能代表了类固醇在小鼠中作用的一个以前未知的主要机制；了解这一现象将为解释改变类固醇环境的研究提供关键的新见解。

DESCRIPTION (provided by applicant): Steroid hormones regulate many aspects of mammalian physiology. Steroids pass through membranes and bind to nuclear receptor/transcription factors, initiating a change in gene transcription. Particularly in the nervous system, steroids also exert effects that are too rapid to be attributed to this mechanism. Recently, my laboratory discovered a novel mode of steroid action: sulfated steroids are detected by neurons residing in the vomeronasal organ, which provide sensory input to the accessory olfactory system. These sensory neurons express several hundred different types of G protein-coupled receptors, and different neurons detect different sulfated steroids. Sulfated steroids are present in natural bodily secretions, such as urine, and represent a prime candidate for organizing mammalian social behavior. In mice, behavioral or physiological responses mediated by the accessory olfactory system frequently involve integration of multiple cues; in particular, there are several examples in which male-derived stimuli act in opposition with female-derived stimuli, and the integration of these cues leads to a single behavioral response. We hypothesize that these behaviors arise as a direct consequence of the neuronal circuitry that processes sensory data about sulfated steroids. To test this hypothesis, we propose both electrophysiological and behavioral experiments that will elucidate the functions of this circuitry in analyze complex steroidal blends. In aim 1, we will determine how mitral cells of the accessory olfactory bulb encode information about individual sulfated steroids, and test how circuit processing changes the representation inherited from the sensory neurons. In aim 2, we will examine the role of male and female steroidal cues in mixture suppression, a likely physiological correlate of male/female opponent behavioral processes. In aim 3, we will examine the role of olfactory-detected sulfated steroids in estrous cycle suppression, focusing in particular on the role of glucocorticoids. In aim 4, we will examine the role of sulfated steroids in protecting against pregnancy block triggered by the urine of strange males. These aims will illuminate the novel role of steroids in the olfactory regulation of mammalian reproductive behaviors. PUBLIC HEALTH RELEVANCE: A better understanding of steroid effects in the nervous system offers hope for treatment of stress, anxiety, and mood disorders, as well as to shed light on sex differences in neuronal development. Most experiments on steroid effects are performed in rodents, but interpretation of the results is complicated by differences between rodents and humans. Olfactory detection may represent a major, previously-unrecognized mechanism for steroid action in mice; understanding this phenomenon will provide critical new insights for interpreting studies that alter the steroid milieu.