Differences by Sex and Genotype in the Effects of Stress on Executive Functions

描述(申请人提供)：前额叶皮质(PFC)多巴胺(DA)系统的不同寻常的特性导致PFC及其依赖于它的认知功能对环境和遗传变异的异常敏感。(这些认知功能称为“执行功能”[EFS]，对推理、计划、解决问题和自我控制非常重要。)我们建议研究环境因素(轻度压力)对EFS的影响，测试我们的预测，即这些影响如何以及为什么会因生物因素(激素和基因)而不同。为了测试我们关于潜在机制的假设，我们将尝试从药理学的角度模拟轻度应激对EFS的影响。PFC中DA系统的不同寻常有两个方面：(1)它严重依赖儿茶酚-O-甲基转移酶(COMT)酶来清除释放的DA(其他大脑区域严重依赖多巴胺转运体)。(2)轻度应激可显著增加前额叶的DA含量(但对其他脑区无明显影响)。动物研究发现，性别差异在于，温和的压力有助于男性在需要PFC的认知任务中发挥作用，但会阻碍女性的PFC。我们建议(A)对此做出新的解释，(B)看看这种性别差异是否也适用于人类，以及(C)对我们的新解释进行检验。我们假设这是温和的 应激对认知产生影响，并在这方面通过增加DA而产生性别差异。 PFC(而不是仅仅通过增加皮质醇和影响海马体功能的机制)。如果我们是正确的，那么如果我们通过药物增加PFC中的DA来模拟这一点，我们应该能够复制性别差异。编码COMT酶的基因有两种常见的变体，一种编码的COMT酶比另一种慢得多，从PFC中清除DA的速度要慢得多。随着一种较慢的酶升高PFC中DA的水平，应激引起的PFC中DA的增加很可能导致PFC中过多的DA，从而损害EFS。因此，我们通过COMT基因预测了压力对认知的相反影响，并预测通过药物增加PFC中的DA，我们应该能够复制这一点(那些编码较快酶的基因的纯合子应该受益，但那些编码另一个版本的纯合子应该显示EFS受损)。因此，我们希望通过尝试在男性和女性中复制温和应激的相反影响，并通过不应激但仅通过增加PFC中的DA来检验我们的因果模型。如果我们的假设得到证实，在考虑帮助一个人自我控制和创造性解决问题的最佳环境和最佳药物剂量时，以及在试图预防或治疗与EFS和PFC中的DA系统有关的精神健康障碍(如成瘾)时，以及在教学或设计工作环境时，应该考虑性别和基因型。

DESCRIPTION (provided by applicant): The unusual properties of the prefrontal cortex (PFC) dopamine (DA) system contribute to the unusual sensitivity of PFC and the cognitive functions that depend on it to environmental and genetic variations. (Those cognitive functions are called 'executive functions' [EFs] and are important for reasoning, planning, problem-solving, and self-control.) We propose to study the effects of an environmental factor (mild stress) on EFs, testing our predictions of how and why those effects differ by biological factors (hormones and genotype). To test our hypotheses concerning the underlying mechanism, we will try to model the effects of mild stress on EFs pharmacologically. Two ways in which the DA system in PFC is unusual are: (1) It relies heavily on the catechol-O-methyltransferase (COMT) enzyme for clearing released DA (other brain regions rely heavily on the dopamine transporter). (2) Mild stress markedly increases DA in PFC (but not in other brain regions). Animal studies find a sex difference in that mild stress aids performance on cognitive tasks that require PFC in males, but hinders it in females. We propose (a) a new interpretation of that, (b) to see if this sex differene is also true in humans, and (c) to put our new interpretation to the test. We hypothesize that mild stress exerts its effect on cognition, and produces the sex difference in that, by increasing DA in PFC (rather than the mechanism being solely by increasing cortisol and affecting hippocampal functioning). If we are correct, then if we model this by pharmacologically increasing DA in PFC, we should be able to replicate the sex difference. There are two common variants of the gene that codes for the COMT enzyme, one codes for a much slower COMT enzyme than the other, clearing DA from PFC much more slowly. With a slower enzyme increasing the level of DA in PFC, the increase in PFC DA due to stress could well result in too much DA in PFC, impairing EFs. Thus we predict opposite effects of stress on cognition by COMT genotype, and we predict that by pharmacologically increasing DA in PFC, we should be able to replicate that (those homozygous for the gene coding for the faster enzyme should benefit, but those homozygous for the other version should show impaired EFs). We thus hope to put our causal model to the test by attempting to reproduce the opposing effects of mild stress in males and females and by genotype without stress but just by increasing DA in PFC. If our hypotheses are borne out, gender and genotype should be taken into account when considering the best environment and best drug dosage for aiding a person's self-control and creative problem-solving, and for minimizing a person's impulsive tendencies when trying to prevent or treat mental health disorders (such as addictions) in which EFs and the DA system in PFC are implicated and when teaching or designing a work environment.