Molecular regulators of mood and mood disorders

心境障碍，如双相情感障碍和重度抑郁症在美国和世界范围内的患病率非常高。对于很大比例的患者，结局指标相当差，自杀、复发和残留症状（认知和功能障碍、心理社会残疾和幸福感下降）的发生率很高。情绪障碍的现有治疗方法远非理想--显然需要为这些毁灭性的疾病开发新的治疗方法。该项目的重点是发现基因，基因表达水平，基因表达调节因子，蛋白质和分子级联被认为影响与情绪调节相关的神经网络的活动。使用综合基因组学、蛋白质组学、神经化学和行为学方法进行分析。 1)microRNA在性别特异性应激诱导的抑郁样行为中的作用 压力会引发抑郁症，抑郁症在女性中比男性更普遍。 我们的研究解决了可能的基础上的基因调控水平的压力效应和性别差异。 调节相关基因表达的新候选物是microRNAs（miRNAs）。 MicroRNA是一类小的非肽编码RNA，其以序列选择性方式与靶信使RNA（mRNA）结合并引起蛋白质翻译抑制和mRNA降解。已知MiRNAs在细胞应激和早期发育中起关键作用。 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。这提出了一个有趣的可能性，即它们可能在压力应对的生物机制中发挥作用，或者相反，适应不良。 我们发现，小鼠的慢性束缚应激上调了几种miRNAs，而慢性锂处理下调了几种microRNAs。其中两种常见于压力和锂治疗。我们还发现这两个miRNA的启动子区含有多个糖皮质激素受体（GR）结合位点，其中一个位于X染色体上。因此，我们怀疑这些miRNAs之一通过GR介导的机制调节男性和女性对压力的不同行为反应。我们将进行实验来检验这一假设。 2)双相情感障碍患者CACAN 1C功能异常 CACNA 1C是最有希望的双相风险基因之一，涉及几项遗传研究。我们发现GluR 6敲除（KO）小鼠缺乏谷氨酸受体亚基，是躁狂症的遗传部分模型（Mol Psychiatry，2009）。 这些小鼠表现出截短形式的CACNA 1C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，长期锂治疗降低了截短的CACNA 1C水平。我们进一步发现，尼莫地平，CACNA 1C选择性阻断剂，迅速减轻行为异常的GluR 6基因敲除小鼠，包括多动，增加侵略，增加冒险活动，增加享乐活动。仍然存在一些关键问题。我们将调查是否截短CACNA 1C本身导致与躁狂症相关的行为异常。我们还将研究GluR 6消融和锂治疗调节截短CACNA 1C水平的机制。

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.