Role of intercalated amygdala neurons in the extinction of conditioned fear

嵌入杏仁核神经元在条件性恐惧消除中的作用

• 批准号: 8019052
• 负责人: DENIS PARE
• 金额: $ 38.24万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-19 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019052
• 关键词: Adverse effects; Affect; Amygdaloid structure; Animals; Anxiety Disorders; Area; Axon; Behavioral; Brain Stem; Cell Nucleus; Cells; Chemosensitization; Clinical; Conditioned Stimulus; Dependence; Extinction (Psychology); Freezing; Fright; Glutamates; Health; Human; Hypothalamic structure; In Vitro; Intercalated Cell; Interneurons; Learning; Lesion; Mediating; Memory; Methods; Modeling; N-Methylaspartate; Nature; Neurons; Pharmacological Treatment; Phase; Phobic anxiety disorder; Play; Population; Process; Rattus; Research; Role; Slice; Stimulus; Structure of terminal stria nuclei of preoptic region; Synapses; Testing; Training; base; conditioned fear; conditioning; design; extracellular; feeding; improved; learning extinction; neurobiotin; postsynaptic; presynaptic; prevent; response; sensory stimulus; treatment strategy

DESCRIPTION (provided by applicant): Research on the circuits mediating the acquisition of conditioned fear responses constitutes our best hope of understanding human anxiety disorders. The model typically used to study this process is classical fear conditioning where a neutral sensory stimulus (CS) acquires the ability to elicit fear responses after pairing to a noxious stimulus. However, perhaps more important from a clinical perspective is to understand how fear responses subside. Experimentally, this extinction process is modeled with repetitive presentations of the CS alone, resulting in the decline of conditioned fear to control levels. This approach is similar to that used to treat human phobias where subjects are presented with the feared object in the absence of danger. Extinction is known to result from a new learning, which takes place in the amygdala, and competes with the original fear memory to prevent the expression of conditioned fear. However, the mechanisms underlying this new extinction learning remain unclear. This proposal tests the hypothesis that the intercalated (ITC) neurons of the amygdala mediate extinction. The acquisition of conditioned fear is known to involve a potentiation of CS inputs to the basolateral amygdala (BLA). In turn, BLA cells excite more neurons in the central amygdala (CE), which, via their projections to the brainstem and hypothalamus, evoke fear responses. We focus on ITC neurons because they can control the impact of BLA inputs on CE neurons and hence the expression of conditioned fear. Indeed, ITC cells are GABAergic, they receive glutamatergic inputs from BLA, and they generate feed-forward inhibition in CE. Moreover, BLA inputs to ITC neurons can undergo NMDA-dependent LTP. Last, ITC neurons receive a heavy projection from the infralimbic cortex, a cortical area thought to play a critical role in extinction. This leads us to hypothesize that extinction results from an NMDA-dependent potentiation of BLA synapses conveying CS information to ITC neurons, leading to a decreased responsiveness of CE cells to BL inputs about the CS. To test the hypothesis, we will first examine whether extinction is associated with a potentiation of BLA inputs to ITC cells by comparing the amplitude of BLA-evoked responses in ITC neurons recorded with the patch method in slices obtained from rats that underwent fear conditioning only vs. rats that underwent fear conditioning and extinction. Next, we will perform extracellular recordings of ITC cells during fear conditioning, extinction training, and extinction recall, and ask do ITC neurons become more responsive to the CS as a result of extinction training, as predicted by our model. Finally, to test whether ITC cells mediate the influence of the infralimbic cortex on extinction, we will study the responses of extracellularly recorded ITC neurons to infralimbic stimuli and test whether the nature, latency, and duration of evoked responses are compatible with the idea that ITC neurons generate the inhibition of CE neurons by IL stimuli. PUBLIC HEALTH RELEVANCE: Although anxiety disorders affect close to 13% of the population, most available pharmacological treatments have a limited efficacy and entail important side effects. It is thus imperative that we improve our understanding of the mechanisms underlying anxiety disorders to design better treatment strategies. If supported, the hypothesis tested here would open new strategies for the treatment of anxiety disorders.

描述（由申请人提供）：对调节条件恐惧反应获得的回路的研究构成了我们理解人类焦虑症的最大希望。研究这一过程的典型模型是经典的恐惧条件反射，其中中性感觉刺激（CS）在与有害刺激配对后获得了引发恐惧反应的能力。然而，从临床角度来看，也许更重要的是了解恐惧反应是如何消退的。在实验中，这种消失过程是通过单独重复呈现CS来模拟的，导致条件性恐惧下降到控制水平。这种方法类似于用于治疗人类恐惧症的方法，即在没有危险的情况下向受试者展示恐惧的物体。已知的灭绝是由新的学习产生的，它发生在杏仁核中，与原始的恐惧记忆竞争，以防止条件恐惧的表达。然而，这种新灭绝学习的机制尚不清楚。这一提议验证了杏仁核的插层神经元介导灭绝的假设。条件恐惧的习得与基底外侧杏仁核（BLA）的CS输入增强有关。接着，BLA细胞刺激中央杏仁核（CE）的更多神经元，这些神经元通过投射到脑干和下丘脑，引起恐惧反应。我们之所以关注ITC神经元，是因为它们可以控制BLA输入对CE神经元的影响，从而控制条件恐惧的表达。确实，ITC细胞是gaba能细胞，它们接受BLA的谷氨酸能输入，并在CE中产生前馈抑制。此外，BLA输入到ITC神经元可以经历nmda依赖的LTP。最后，ITC神经元接收到来自边缘下皮层的大量投射，这个皮层区域被认为在灭绝中起着关键作用。这使我们假设，这种消失是由向ITC神经元传递CS信息的BLA突触的nmda依赖性增强引起的，从而导致CE细胞对CS的BL输入的反应性降低。为了验证这一假设，我们将首先通过比较仅接受恐惧条件反射的大鼠与接受恐惧条件反射和消退的大鼠的切片上用贴片法记录的ITC神经元中BLA诱发反应的振幅，来研究消退是否与BLA输入ITC细胞的增强有关。接下来，我们将在恐惧条件反射、消退训练和消退回忆期间对ITC细胞进行细胞外记录，并询问ITC神经元是否像我们的模型预测的那样，在消退训练后对CS的反应更敏感。最后，为了验证ITC细胞是否介导了边缘下皮层对消退的影响，我们将研究细胞外记录的ITC神经元对边缘下刺激的反应，并测试诱发反应的性质、潜伏期和持续时间是否与ITC神经元通过IL刺激对CE神经元产生抑制的观点相一致。公共卫生相关性：虽然焦虑症影响了近13%的人口，但大多数现有的药物治疗效果有限，而且会产生严重的副作用。因此，我们必须提高对焦虑症潜在机制的理解，以设计更好的治疗策略。如果得到支持，这一假设将为治疗焦虑症开辟新的策略。