Molecular regulators of mood and mood disorders

情绪和情绪障碍的分子调节剂

• 批准号: 8158159
• 负责人: MILES A. HERKENHAM
• 金额: $ 43.51万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158159
• 关键词: Molecular; Mood Disorders; Moods

Mood disorders such as bipolar disorder and major depressive disorder have remarkably high prevalence rates in the United States and worldwide. For a large percentage of patients, outcome measures are quite poor, with high rates of suicide, relapse, and residual symptoms (cognitive and functional impairment, psychosocial disability, and diminished well being). Available treatments for mood disorders are far from ideal -- there is a clear need to develop novel treatments for these devastating disorders. This project is focused on discovering genes, gene expression levels, regulators of gene expression, proteins, and molecular cascades thought to influence the activity of neuronal networks associated with mood regulation. The analyses are done using integrated genomic, proteomic, neurochemical, and behavioral approaches. 1) Roles of microRNAs in gender-specific, stress-induced depression-like behaviors Stress can trigger depression, and depression is more prevalent in woman than men. Our studies address the possible bases at the level of gene regulation for the stress effects and for the sex differences. A novel candidate for regulation of relevant gene expression is microRNAs (miRNAs). MicroRNAs are a class of small, non-peptide-coding RNAs, which bind to target messenger RNAs (mRNAs) in a sequence-selective manner and cause protein translation suppression and mRNA degradation. MiRNAs are known to play critical roles in cellular stress and early development. Accumulating data indicate that miRNAs influence the molecular regulation underlying neuronal development and dendritic spine morphogenesis, synaptic and circuitry plasticity, and circadian rhythms. This raises the intriguing possibility that they may play a role in the biological mechanisms of stress coping, or conversely, maladaptation. We found that chronic restraint stress in mice upregulated several miRNAs, and chronic lithium treatment down regulated several microRNAs. Two of them are common for stress and lithium treatments. We also found that the promoter regions of these two miRNAs contain several glucocorticoid receptor (GR) binding sites and one of the two miRNA genes is located on chromosome X. Therefore, we suspect that one of these miRNAs modulates differential behavioral responses to stress in male and female through a GR-mediated mechanism. We will conduct experiments to examine this hypothesis. 2) A plausible CACAN1C dysfunction in Bipolar Disorder CACNA1C is one of the most promising bipolar risk genes, implicated in several genetic studies. We found that GluR6 knockout (KO) mice, lacking a subunit of the glutamate receptor, are a genetic partial model of mania (Mol Psychiatry, 2009). The mice showed increased levels of a truncated form of CACNA1C. It is known that this truncated form has 10-15 fold increases in calcium current due to lack of c-terminal regulatory domain. We also found that chronic lithium treatment decreased levels of truncated CACNA1C. We further found that Nimodipine, a CACNA1C selective blocker, rapidly alleviated behavioral abnormities of GluR6 KO mice including hyperactivity, increased aggression, increased risk-taking activity, and increased hedonic activity. There are key questions that remain. We will investigate whether truncated CACNA1C per se causes the behavioral abnormalities related to mania. We will also investigate the mechanisms by which GluR6 ablation and lithium treatment regulate levels of truncated CACNA1C.

情绪障碍，如双相情感障碍和严重抑郁障碍，在美国和世界各地的患病率都非常高。对于很大比例的患者来说，结果衡量标准相当差，自杀率、复发率和残留症状(认知和功能障碍、心理社会残疾和幸福感降低)很高。情绪障碍的现有治疗方法远不理想--显然需要为这些毁灭性的疾病开发新的治疗方法。这个项目的重点是发现基因，基因表达水平，基因表达的调节器，蛋白质，以及被认为影响与情绪调节相关的神经网络活动的分子级联。这些分析是使用综合基因组、蛋白质组、神经化学和行为方法完成的。 1)microRNAs在性别特异的应激诱导的抑郁样行为中的作用 压力会引发抑郁，而抑郁在女性中比男性更普遍。我们的研究从基因调控的角度探讨了压力效应和性别差异的可能基础。MicroRNAs(MiRNAs)是调控相关基因表达的一个新的候选基因。MicroRNAs是一类小的、非肽编码的RNA，它以序列选择性的方式与靶信使RNAs结合，导致蛋白质翻译抑制和mRNA降解。已知miRNAs在细胞应激和早期发育中发挥关键作用。越来越多的数据表明，miRNAs影响神经元发育和树突棘形态发生、突触和回路可塑性以及昼夜节律的分子调控。这提出了一种有趣的可能性，即它们可能在压力应对的生物机制中发挥作用，或者相反，在适应不良中发挥作用。 我们发现，小鼠的慢性束缚应激上调了几个miRNAs，而慢性锂治疗下调了几个microRNAs。其中两种是常见的压力和锂治疗方法。我们还发现，这两个miRNAs的启动子区域含有几个糖皮质激素受体(GR)结合位点，其中一个位于X染色体上。因此，我们怀疑其中一个miRNAs通过GR介导的机制调节男性和女性对应激的不同行为反应。我们将进行实验来检验这一假设。 2)双相情感障碍患者可能存在CACAN1C功能障碍 CACNA1C是最有前景的双相情感障碍基因之一，与多项遗传学研究有关。我们发现，GluR6基因敲除(KO)小鼠，缺乏谷氨酸受体的一个亚单位，是躁狂症的遗传部分模型(Mol Squchiatry，2009)。这些小鼠表现出截短形式的CACNA1C水平增加。已知这种截短形式由于缺乏c-末端调节结构域而使钙电流增加10-15倍。我们还发现，慢性锂治疗降低了截短的CACNA1C水平。我们进一步发现，CACNA1C选择性阻滞剂尼莫地平能迅速缓解GluR6 KO小鼠的行为异常，包括多动、攻击性增加、冒险活动增加和享乐活动增加。还有一些关键问题仍然存在。我们将调查CACNA1C截短本身是否会导致与躁狂症相关的行为异常。我们还将研究GluR6消融和锂治疗调节CACNA1C截断水平的机制。