Early Life Stress-- Effects On A Model Of Learned Safety

指导该项目研究的主要假设是，早期生活压力导致对安全信号做出反应的能力降低。尽管有大量的轶事证据支持这一假设，但使用良好控制的行为范式在人类或动物中进行的直接测试仍然有限。在啮齿动物和人类，我们已经开发出一种歧视的程序，被称为AX+，BX-，允许独立评估的兴奋和抑制的恐惧条件反射测量的声音惊吓反射。例如，AX+可能意味着两个线索，例如一起呈现的安静风扇产生的光和气流，随后是电击。如果是这样的话，那么BX-意味着第二个提示，如音调和扇子，当一起出现时，不会出现电击。在这个过程中，一种极度的恐惧， 而B是安全信号，因为它预测不会发生电击。在这样的训练之后，人们可以测试安全提示B是否会通过同时呈现A和B来减少对A的恐惧。我们在老鼠和人类身上都发现，经过这种训练后，B开始抑制恐惧，这种效果不是由于外部抑制。在人类中，我们将评估早期生活压力的影响，在这个范例中使用有或没有重度抑郁症（MDD）的患者，有或没有早期生活压力，以及有或没有早期生活压力的社交恐惧症患者。在雄性和雌性恒河猴中，我们将建立相同的程序，然后使用正常饲养条件或 反复的母亲分离，我们早期生活压力的模型。此外，我们将使用另一个测试，我们认为这是一个更焦虑的措施，而不是刺激特定的恐惧。人类和猴子在黑暗中比在光明中更容易受惊。在老鼠这种夜行动物身上，我们发现它们在光照下比在黑暗中更容易受惊，这种效应取决于终纹的床核，而不是杏仁核的中央核。在大鼠脑室内灌注CRF后，当惊吓增强时，发现了类似的效果。基于这样一个事实，即黑暗或光线增强的惊吓，以及CRF增强的惊吓大鼠，涉及不可预测的 威胁，我们认为这些影响可能更类似于焦虑与刺激特定的恐惧。因此，我们将评估黑暗增强惊吓在这些相同的患者组，以及在男性和女性恒河猴，正常饲养或饲养与早期生活压力。

The major hypothesis that guides studies in this project is that early life stress leads to a reduction in the ability to respond to safety signals. Despite substantial anecdotal evidence in support of this hypothesis, direct tests in humans or animals, using well-controlled behavioral paradigms, have been limited. In both rodents and humans, we have developed a discrimination procedure, referred to as AX+, BX-, that allows for the independent evaluation of excitation and inhibition of fear conditioning measured with the acoustic startle reflex. For example, AX+ could mean that two cues, such as a light and air flow created by a quiet fan presented together, are followed by shock. If so, then BX- would mean that a second cue, such as a tone and the fan, when presented together, would not be followed by shock. In this procedure, A elicits fear, whereas B is a safety signal, because it predicts that no shock will occur. Following such training, one can test whether B, the safety cue, will reduce fear to A by presenting A and B together. We have found in both rats and humans that B comes to inhibit fear following such training and this effect is not due to external inhibition. In humans, we will evaluate effects of early life stress in this paradigm using patients with or without major depressive disorders (MDD), with or without early life stress, as well as patients with social phobia with or without early life stress. In male and female rhesus monkeys we will set up this same procedure and then evaluate effects of early life stress using normal rearing conditions or rearing with repeated maternal separation, our model of early life stress. In addition, we will use another test we believe is a more a measure of anxiety than stimulus specific fear. Both humans and monkeys startle more in the dark than in the light. In rats, a nocturnal animal, we find they startle more in the light than in the dark, and this effect depends on the bed nucleus of the stria terminalis and not the central nucleus of the amygdala. A similar effect is found in rats when startle is enhanced after intraventricular infusion of CRF. Based on the fact that dark or light-enhanced startle, as well as CRF-enhanced startle in rats, involves unpredictable threat, we have suggested these effects may be more akin to anxiety vs. stimulus specific fear. Hence, we will evaluate dark-enhanced startle in these same patient groups, as well as in male and female rhesus monkeys, following normal rearing or rearing with early life stress.