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

从恐惧反应到工具性行动：大脑区域和β受体阻滞剂

• 批准号: 8444798
• 负责人: Christopher Kenneth Cain
• 金额: $ 24.18万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-07 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444798
• 关键词: Adrenergic Agents; Adrenergic Receptor; Adrenergic beta-Antagonists; Affect; Agonist; Amygdaloid structure; Anxiety; Aversive Stimulus; Behavior; Behavior Control; Behavior Therapy; Brain; Brain region; Cells; Data; Emotional; Emotions; Exposure to; FOS gene; Feeling; Freezing; Fright; Goals; Human; Image; Infusion procedures; Isoproterenol; Lateral; Learning; Lesion; Mediating; Memory; Modeling; Neuromodulator; Neurons; Norepinephrine; Pathology; Patients; Performance; Phenotype; Physiological Processes; Population; Prefrontal Cortex; Process; Propranolol; Proteins; Publishing; Rattus; Reaction; Receptor Activation; Receptor Signaling; Recovery; Rodent; Role; Short-Term Memory; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Training; Work; adrenergic; avoidance behavior; base; brain cell; conditioned fear; coping; innovation; neural circuit; neuromechanism; novel; prevent; receptor; response; success

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. PUBLIC HEALTH RELEVANCE: Instrumental active avoidance (AA) depends on the suppression of Pavlovian fear reactions, yet, the brain mechanisms mediating this response competition are unknown. In rats, we will identify critical brain regions and evaluate whether ?-adrenergic receptor signaling impedes AA by promoting competing Pavlovian fear reactions. Given that AA processes likely contribute to both the pathology (e.g. avoidance) and treatment (e.g. active coping) of anxiety, the findings may have therapeutic importance.

描述（由申请人提供）：在治疗病理性焦虑期间，可以促进“积极应对”策略，因为它们：1）使患者能够控制对厌恶刺激的暴露，2）防止恐惧反应和感觉，3）可能产生更持久的恢复。这是很好地模拟了主动回避（AA）训练，其中受试者学会取代最初的恐惧反应与工具的行动，防止暴露于厌恶 刺激。然而，一些过度恐惧的受试者从未掌握AA任务。有趣的是，这种较差的AA表型反映了表现上的缺陷，而不是学习上的缺陷，因为破坏巴甫洛夫反应的大脑损伤无需进一步训练即可挽救AA（Choi等人，2010; Lazaro.Munoz等人，2010年）。因此，AA训练后的防御反应似乎取决于巴甫洛夫记忆和工具记忆之间的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，如果反应不可用，则会重新出现（Cain和LeDoux，2007; Lovibond等人，2008;所罗门和韦恩，1954）。巴甫洛夫恐惧反应的神经回路和机制是众所周知的，但对AA的了解甚少，特别是在人类中。关于调节主动防御反应与被动防御反应的竞争性选择的神经回路和递质系统，我们所知更少。 我们的长期目标是阐明大脑系统，细胞，分子和生理过程所必需的抑制巴甫洛夫恐惧和建立永久的积极应对反应。我们将开始对大鼠AA相关脑活动（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，我们也将测试特定的假设杏仁核和前额叶皮质（PFC）去甲肾上腺素在AA表达的作用，考虑到这些地区的重要性，这种神经调节情绪和防御行为。我们的目标是：1）鉴定其中活动与良好与不良AA表现相关的脑区域和细胞群，以及2）确定肾上腺素能信号传导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传导通过促进竞争性巴甫洛夫恐惧反应来对抗工具性行为的表达。我们将通过向CE注射普萘洛尔或异丙肾上腺素并评估大鼠的条件性恐惧和AA来测试这一点。我们希望普萘洛尔能抑制恐惧反应，并选择性地增强不良回避者的AA，异丙肾上腺素能将良好的回避者转化为高度冻结的不良回避者。将对其他候选区域进行类似评估，但预期无影响。如果成功的话，这些研究将确定特定的大脑区域和积极应对的关键信号通路。他们还可能提出一种创新的方法，将联合收割机阻断剂与行为疗法结合起来，在焦虑的人群中建立永久的积极应对策略。此外，由于回避可能是适应不良的，这些研究可能会确定一个机制，是错误的病理性焦虑。 公共卫生相关性：工具性主动回避（AA）依赖于对巴甫洛夫恐惧反应的抑制，然而，介导这种反应竞争的脑机制尚不清楚。在大鼠中，我们将确定关键的大脑区域，并评估是否？肾上腺素能受体信号传导通过促进竞争性巴甫洛夫恐惧反应来阻碍AA。考虑到AA过程可能有助于焦虑的病理学（例如回避）和治疗（例如积极应对），这些发现可能具有治疗意义。