From Fear Reactions to Instrumental Action: Brain Regions and Beta Blockers

描述(由申请人提供)：在病理性焦虑的治疗过程中，可以推广“积极应对”策略，因为它们：1)使患者能够控制暴露在令人厌恶的刺激下；2)防止恐惧的反应和感觉；3)可能产生更持久的恢复。主动回避(AA)训练很好地模拟了这一点，在AA训练中，受试者学习用防止暴露在厌恶中的工具性动作来取代最初的恐惧反应 刺激物。然而，一些过于恐惧的受试者永远无法掌握AA任务。有趣的是，这种糟糕的AA表型反映的是表现上的缺陷，而不是学习上的缺陷，因为破坏巴甫洛夫反应的脑损伤在没有进一步培训的情况下拯救了AA(Choi等人，2010年；Lazaro.Munoz等人，2010)。因此，AA训练后的防御性反应似乎依赖于巴甫洛夫记忆和工具性记忆之间恐惧处理回路的竞争。这与观察结果一致，即一旦获得AA反应，恐惧反应就会消失，如果没有反应，恐惧反应就会重新出现(Cain和LeDoux，2007；Loviond等人，2008；所罗门和Wynne，1954)。巴甫洛夫式恐惧反应的神经回路和机制是众所周知的，但对再生障碍性贫血，特别是在人类中，人们知之甚少。对于调节主动防御反应与反应性防御反应的竞争性选择的神经回路和递质系统更是知之甚少。我们的长期目标是阐明抑制巴甫洛夫式恐惧和建立永久的积极应对反应所必需的大脑系统、细胞、分子和生理过程。我们将首先对大鼠与AA相关的大脑活动(c-fos表达)进行无偏成像，以确定恐惧回路中的关键反应选择点。然而，我们也将测试关于杏仁核和前额叶皮质(PFC)去甲肾上腺素在AA表达中的作用的特定假设，考虑到这些区域和这种神经调节剂对情绪和防御行为的重要性。我们的目标是：1)确定大脑区域和细胞群体，其中活动与良好的与不良的AA表现相关，以及2)确定肾上腺素能信号是否影响训练后的动作与反应选择。根据已发表的和初步的数据，我们的主要假设是，中央杏仁核(CE)中的肾上腺素能受体信号通过促进竞争的巴甫洛夫恐惧反应来反对工具性动作的表达。我们将通过向CE注射心得安或异丙肾上腺素来测试这一点，并评估大鼠的条件性恐惧和再生障碍性贫血。我们希望心得安能抑制恐惧反应，选择性地提高回避不良者的再生障碍性贫血，异丙肾上腺素能将良好的回避者转变为冷淡的回避者。其他候选地区将得到类似的评估，但预计将产生无效影响。如果成功，这些研究将确定对积极应对至关重要的特定大脑区域和信号通路。他们还可能提出一种创新的方法，将阻滞剂与行为疗法暂时结合起来，在焦虑的人中建立永久性的积极应对策略。此外，由于回避可能是不适应的，这些研究可能会发现病理性焦虑的一种错误机制。

DESCRIPTION (provided by applicant): "Active coping" strategies may be promoted during therapy for pathological anxiety because they: 1) give the patient control over exposure to aversive stimuli, 2) prevent fearful reactions and feelings, and 3) may produce a more permanent recovery. This is nicely modeled by active avoidance (AA) training where subjects learn to replace initial fear reactions with instrumental actions that prevent exposure to aversive stimuli. However, some excessively fearful subjects never master the AA task. Interestingly, this poor AA phenotype reflects a deficit in performance, rather than learning, since brain lesions that disrupt Pavlovian reactions rescue AA without further training (Choi et al., 2010; Lazaro.Munoz et al., 2010). Thus, defensive responding after AA training appears to depend on competition in fear processing circuits between Pavlovian and instrumental memories. This is consistent with observations that fearful reactions disappear once an AA response is acquired and reappear if the response is not available (Cain and LeDoux, 2007; Lovibond et al., 2008; Solomon and Wynne, 1954). The neural circuitry and mechanisms are well known for Pavlovian fear reactions but are poorly understood for AA, especially in humans. Even less is known about the neural circuits and transmitter systems mediating the competitive selection of active vs. reactive defensive responses. Our long term goal is to elucidate the brain systems, cells, molecules and physiological processes necessary for suppressing Pavlovian fear and establishing permanent active coping responses. We will begin with unbiased imaging of AA related brain activity in rats (c-fos expression) to identify critical response selection points inthe fear circuit. However, we will also test specific hypotheses about the role of amygdala and prefrontal cortex (PFC) norepinephrine in AA expression, given the importance of these regions and this neuromodulator to emotion and defensive behavior. Our objectives are to: 1) identify brain regions and cell populations where activity is associated with good vs. poor AA performance, and 2) determine whether adrenergic signaling influences action vs. reaction selection post training. Based on published and preliminary data, our main hypothesis is that ?-adrenergic receptor signaling in central amgydala (CE) opposes the expression of instrumental actions by promoting competing Pavlovian fear reactions. We will test this by injecting propranolol or isoproterenol into CE and assessing conditioned fear and AA in rats. We expect propranolol to suppress fear reactions and selectively enhance AA in poor avoiders, and isoproterenol to convert good avoiders to high freezing poor avoiders. Other candidate regions will be assessed similarly, but null effects are expected. If successful, these studies will identiy specific brain regions and signaling pathways critical for active coping. They may also suggest an innovative way to temporarily combine ¿.blockers with behavior therapy to establish permanent active coping strategies in anxious humans. Further, since avoidance can be maladaptive, these studies may identify a mechanism that is awry in pathological anxiety.