Gonadal Hormones and Depression:The Role of Mood Disorder Risk Gene CACNA1C

描述（由申请人提供）：很明显，性别差异是理解心境障碍病理生理学的关键因素。虽然人们假设易感基因和激素可能相互作用以改变情绪障碍的发展，但目前支持这一点的实验证据有限。最近的许多人类遗传学研究表明，CACNA1C（一种编码CaV1.2 L型钙通道11亚基的基因）多态性与双相情感障碍或抑郁症的诊断之间存在强有力的关联。我们最近发现了人类和小鼠的性别差异，这共同表明CACNA1C基因型主要影响女性对情绪相关行为变化的适应力，但这些性别差异的潜在因素尚不清楚。本申请的目的是使用我们的小鼠模型，以进一步评估性别和Cacna1c基因型之间的相互作用，导致抑郁症相关行为的发展，并确定激素机制，确定女性特定的行为影响Cacna1c单倍不足的小鼠。成年人大脑的性别差异可以在发育早期建立，这是性腺激素介导的组织过程的结果。同样的性腺激素作用于成年人的大脑，它们的行为可能受到早期组织过程的限制，或者可能独自介导生理和行为上的性别差异。我们的中心假设是，性腺激素与Cacna1c基因型在新生儿早期组织期相互作用，以调节成年期抑郁相关的行为，Cacna1c表达减少将导致雌性小鼠对慢性应激的影响具有弹性。我们的具体目标是：1）确定性腺激素的激活效应在确定Cacna1c单倍不足中女性特异性习得性无助行为中的作用，2）确定性腺激素的组织效应在确定Cacna1c单倍不足中女性特异性习得性无助行为中的作用，和3）在慢性不可预测的应激模型中，定义Cacna1c单倍不足和性别在改变行为和大脑可塑性方面的相互作用，萧条我们的研究将提高对Cacna1c基因在情绪障碍的病理生理学相关背景下调节行为和其他大脑功能的作用的理解。本申请中描述的实验的完成将为性腺激素和遗传风险因素在敏感的发育时间段相互作用以调节发展情绪障碍的风险的假设提供关键支持。公共卫生相关性：一旦我们完成这些实验，就有可能将我们的发现转化为其他动物模型，并最终转化为人类，阐明机制和可能的药物靶点，以及对患有情绪障碍和可能携带CACNA1C风险等位基因的患者进行干预的发育时间点。 公共卫生相关性：最近的人类遗传学研究表明，CACNA1C（一种编码CaV1.2 L型钙通道11亚基的基因）多态性与双相情感障碍或抑郁症的诊断之间存在强有力的关联。我们最近发现了人类和小鼠的性别差异，这共同表明CACNA1C基因型主要影响女性的情绪相关行为变化，但这些性别差异的潜在因素尚不清楚。本申请中描述的实验的完成将为性腺激素和遗传风险因素在敏感的发育时间段相互作用以调节发展情绪障碍的风险的假设提供关键支持。

DESCRIPTION (provided by applicant: It is clear that sex differences are a critical consideration to understanding the pathophysiology of mood disorders. While it is hypothesized as likely that susceptibility genes and hormones interact to modify the development of mood disorders, there exists limited current experimental evidence to support this. Numerous recent human genetic studies indicate a robust association between polymorphisms in CACNA1C, a gene that codes for the 11 subunit of the CaV1.2 L-type calcium channel, and a diagnosis of bipolar disorder or depression. We have recently identified sex differences in both humans and mice, which collectively indicate that CACNA1C genotype influences resilience to mood-related behavioral changes primarily in females, but the factors underlying these sex differences are unknown. The objective of this application is to use our mouse model to further assess the interaction between sex and Cacna1c genotype leading to the development of depression-related behavior, and to define the hormonal mechanisms that determine female-specific behavioral effects in Cacna1c haploinsufficient mice. Sex differences in the adult brain can be established early in development as a result of an organizational process mediated by gonadal hormones. The same gonadal hormones act on the adult brain and their actions may be constrained by earlier organizational processes or may, on their own, mediate sex differences in physiology and behavior. Our central hypothesis is that gonadal hormones interact with Cacna1c genotype during the early neonatal organizational period to modulate depression-related behavior at adulthood, and that decreased expression of Cacna1c will result in female mice that are resilient to the effects of chronic stress. Our specific aims are to: 1) Identify the role of activational effects of gonadal hormones in determining female-specific learned helplessness behavior in Cacna1c haploinsufficiency, 2) Identify the role of organizational effects of gonadal hormones in determining female-specific learned helplessness behavior in Cacna1c haploinsufficiency, and 3) Define the interaction between Cacna1c haploinsufficiency and sex in modifying behavior and brain plasticity in the chronic unpredictable stress model of depression. Our studies will improve understanding of the role of the Cacna1c gene in regulating behavior and other brain functions in a context relevant to the pathophysiology of mood disorders. Completion of the experiments describe in this application will provide critical support for the hypothesis that gonadal hormones and genetic risk factors interact at sensitive developmental time periods to modulate the risk to develop a mood disorder. Public Health Relevance: Once we complete these experiments it will then be possible to translate our findings to additional animal models and ultimately to humans, elucidating mechanisms and possible drug targets, and developmental time points for intervention in patients who suffer from mood disorders and who may carry CACNA1C risk alleles. PUBLIC HEALTH RELEVANCE: Recent human genetic studies indicate a robust association between polymorphisms in CACNA1C, a gene that codes for the 11 subunit of the CaV1.2 L-type calcium channel, and a diagnosis of bipolar disorder or depression. We have recently identified sex differences in both humans and mice, which collectively indicate that CACNA1C genotype influences mood-related behavioral changes primarily in females, but the factors underlying these sex differences are unknown. Completion of the experiments described in this application will provide critical support for the hypothesis that gonadal hormones and genetic risk factors interact at sensitive developmental time periods to modulate the risk to develop a mood disorder.