Analysis of the effects of aversive experience on non-defensive behaviors and und

描述(由申请人提供)：在动物和人类身上发生的令人厌恶的事件会在大脑中产生深刻而弥漫的变化。例如，在健康的大脑中，暴露在厌恶事件中需要平衡防御性和非防御性行为的表达。这种平衡的形成、维持和灵活性方面的缺陷可能会导致精神健康问题，如焦虑症和创伤后应激障碍。因此，确定经验调节多种行为表达的机制是理解影响数百万美国人的医疗状况的关键一步。在海洋软体动物海兔中，暴露在厌恶刺激下，诱导防御和非防御行为的同时调节。具体地说，厌恶刺激导致两种相反的行为变化：习得的防御反应(即敏感化)的增强和摄食行为的抑制。对进食的敏化和抑制具有相似的时间进程，这取决于厌恶刺激的数量。虽然海兔致敏的细胞和分子机制已经被广泛地描述，但那些抑制取食的潜在机制仍然很大程度上是未知的。PI的实验室最近开始分析由厌恶刺激引起的取食抑制的细胞和生化基础。在细胞水平上，摄食的抑制伴随着对摄食表达至关重要的决策神经元(B51)兴奋性的降低。最近的证据表明，对摄食的抑制和B51兴奋性的降低，至少部分是由循环GMP信号级联介导的。此外，在海兔中介导敏化的5-羟色胺不改变摄食或B51的兴奋性，这表明由厌恶刺激产生的防御和摄食神经回路的变化可能是由不同的和/或多种神经调节剂介导的(S)。该项目将采用体内和体外相结合的方法：1)通过研究cGMP信号级联反应的作用，表征细胞内与摄食抑制和B51兴奋性降低有关的信号；2)通过研究一氧化氮依赖途径的贡献，确定哪种神经调节剂介导了摄食抑制和B51兴奋性降低；3)探索敏化和摄食抑制之间的关系，试图通过操纵动物的动机状态和延长暴露于厌恶刺激的时间来“分离”这两种行为变化。这个项目中概述的实验提出了对通过经验调节多个行为相关神经回路的机制的详细分析。海兔的这一系列研究将有助于理解在包括人类在内的更复杂的动物中，非防御性神经回路如何改变它们的活动，以及它们与防御回路的关系，以应对厌恶的刺激。

DESCRIPTION (provided by applicant): The experience of an aversive event produces in animals and in humans profound and diffuse changes within the brain. For example, in the healthy brain, exposure to an aversive event requires balancing the expression of defensive and non-defensive behaviors. Deficits in the formation, maintenance and flexibility of this balance can lead to mental-health problems, such as anxiety disorders and post-traumatic stress disorder. Therefore, characterizing the mechanisms by which experience regulates the expression of multiple behaviors represents a critical step to understand medical conditions affecting millions of Americans. In the marine mollusk Aplysia californica, exposure to aversive stimuli induces the concurrent modulation of defensive and non-defensive behaviors. Specifically, aversive stimuli induce two opposite behavioral changes: a learned enhancement of defensive responses (i.e., sensitization) and a suppression of feeding behavior. Sensitization and suppression of feeding share analogous time courses that depend on the amount of aversive stimulation. Whereas the cellular and molecular mechanisms underlying sensitization in Aplysia have been extensively characterized, those underlying the suppression of feeding remain largely unknown. The PI's lab has recently begun to analyze the cellular and biochemical underpinning of the suppression of feeding induced by aversive stimuli. At the cellular level, the suppression of feeding is accompanied by a decreased excitability of a decision-making neuron (B51) critical for the expression of feeding. Recent evidence indicates that suppression of feeding and decreased B51 excitability are, at least in part, mediated by the cyclic GMP signaling cascade. In addition, serotonin, which mediates sensitization in Aplysia, does not alter either feeding or B51 excitability, suggesting that changes in the defensive and feeding neural circuits produced by aversive stimuli may be mediated by distinct and/or multiple neuromodulator(s). Using a combination of in vivo and in vitro procedures, this project will: 1) characterize the intracellular signals responsible for feeding suppression of and B51 decreased excitability by examining the role of the cGMP signaling cascade; 2) identify which neuromodulator mediates the suppression of feeding and decreased B51 excitability by investigating the contribution of a nitric oxide dependent pathway and 3) explore the relationship between sensitization and feeding suppression, by attempting to "uncouple" these two behavioral changes by manipulating the animal's motivational state and extending the exposure to aversive stimuli. The experiments outlined in this project propose a detailed analysis of the mechanisms responsible for the modulation of multiple behaviorally-relevant neural circuits by experience. This line of research in Aplysia will contribute to the understanding of how non-defensive neural circuits change their activity and their relations with defensive circuits in response to aversive stimuli in more complex animals, including humans.