PROJECT 4: SEROTONIN RELATED TRANSCRIPTION FACTORS IN ANIMAL MODELS - DEPRESSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 下丘脑-垂体-肾上腺（HPA）轴的异常和下丘脑-垂体-肾上腺（HPA）系统的失调被认为在重性抑郁症的病理生理学中起作用。 压力通常被视为易受伤害的个体抑郁症的常见诱因。 慢性应激后对HPA轴的过度刺激导致皮质醇分泌过多，这是许多抑郁症患者常见的一种情况。 已发现抑郁症患者循环皮质醇水平的正常化与成功的临床治疗相关。 压力和不良生活事件与抑郁症的病因有关，妇女因压力性生活事件而患抑郁症的可能性是男子的三倍，这支持了妇女患抑郁症的可能性是男子的两倍的事实。 5-羟色胺（5-HT）系统似乎在重性抑郁症的病因学和抗抑郁药治疗的反应中起着重要作用。 经典以及最近的抗抑郁药物似乎调节5-HT神经传递。 本申请的中心假设是，应激诱导的胡萝卜素相关转录因子（NUDR、Freud-1和Pet-1）的变化在调节几种胡萝卜素特异性基因中起重要作用，所述胡萝卜素特异性基因控制应激暴露后的5-羟色胺生物合成和神经传递。 这一假设将通过以下具体目标进行评估：目标1。确定暴露于慢性束缚应激的雄性大鼠中缝背核和前额叶皮质中的胡萝卜素相关转录因子生物合成的特定变化。目标2.确定特定的变化，在生物合成的中缝背核和前额叶皮质的雌性大鼠暴露于约束压力的阿托宁相关的转录因子。目标3。 研究抗抑郁治疗对慢性束缚应激雌雄大鼠Pet-1、Freud-1和NUDR表达的影响。 我们的长期目标是阐明压力和性别差异如何调节5-羟色胺特异性转录因子的表达，以及这些转录因子如何反过来调节5-HT 1-A受体、色氨酸羟化酶2（TPH 2）和5-HT转运蛋白（5-HTT）的基因，这是开发新疗法的必要前提。这些研究将利用几种生物化学和分子生物学方法，包括原位杂交、Western印迹、真实的时间PCR和cDNA合成，来定量大鼠中脑中缝背核和前额叶皮层脑组织中各种多巴胺能分子和转录因子的蛋白质和基因表达。这一提议将是第一项研究，以检查这些新的阿托宁相关的转录因子在与抑郁症有关的应激动物模型中的表达。 总的来说，拟议的研究将阐明参与应激诱导的调节的降钙素相关转录因子和5-羟色胺神经传递的分子机制，并可能导致发现治疗应激相关抑郁症和精神疾病的新靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dysregulation of the serotonergic system and abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been suggested to play a role in the pathophysiology of major depression. Often stress is seen as a common precipitant of depression in vulnerable individuals. Excessive stimulation of the HPA axis following chronic stress results in the hypersecretion of cortisol, a common condition seen in many depressed patients. Normalization of circulating cortisol levels in depressed patients has been found to correlate with successful clinical treatment. Stress and adverse life events have been implicated in the etiology of depression and women are three times more likely than men to develop depression in relation to stressful life events, supporting the fact that women are twice as likely to suffer an episode of depression compared to men. The serotonin (5-HT) system appears to play a major role in the etiology of major depression and the response to antidepressant treatment. Classical as well as more recent antidepressant drugs appear to modulate 5-HT neurotransmission. The central hypothesis of this application is that stress-induced changes in serotonin-related transcription factors (NUDR, Freud-1 and Pet-1) play a significant role in regulating several serotonin-specific genes that control serotonin biosynthesis and neurotransmission following stress exposure. This hypothesis will be evaluated through the following specific aims: Aim 1. Determine specific alterations in the biosynthesis of the serotonin-related transcription factors in the dorsal raphe and prefrontal cortex of male rats exposed to chronic restraint stress. Aim 2. Determine specific alterations in the biosynthesis of serotonin-related transcription factors in the dorsal raphe and prefrontal cortex of female rats exposed to restraint stress. Aim 3. Study the effects of antidepressant treatment on the expression of Pet-1, Freud-1 and NUDR in male and female rats exposed to chronic restraint stress. Our long-term objectives are to elucidate how stress and gender differences modulate the expression of serotonin specific transcription factors and how these in turn regulate genes for the 5-HT1-A receptor, tryptophan hydroxylase 2 (TPH2) and the 5-HT transporter (5-HTT) as a necessary prerequisite to the development of novel therapeutics. The studies will utilize several biochemical and molecular biological procedures including in situ hybridization, Western blotting, real time PCR and cDNA synthesis to quantify protein and gene expression of the various serotonergic molecules and transcription factors in rat brain tissues from the midbrain dorsal raphe nucleus and prefrontal cortex. This proposal will be the first study to examine the expression of these novel serotonin-related transcription factors in an animal model of stress related to depression. Overall, the proposed research will elucidate the molecular mechanisms involved in the stress induced regulation of serotonin-related transcription factors and serotonin neurotransmission and may lead to the discovery of novel targets for the treatment of stress related depression and psychiatric illness.