Hebbian Long-Term Potentiation and Learning in Aplysia

描述(申请人提供)：在美国，相当大比例的人患有行为障碍，包括创伤后应激障碍(PTSD)、焦虑症和药物成瘾，这些实际上是记忆功能障碍的疾病。因此，对学习和记忆的细胞生物学的了解应该有助于开发这些疾病的治疗方法。联想学习的基本形式之一是经典的条件反射。在经典的条件反射过程中，动物学会将中性刺激(条件性刺激)与强化刺激(无条件刺激)的传递联系起来。该项目将利用海洋软体动物加州海兔的显著实验优势，从机制上理解经典的条件反射。这种动物有一个简单的神经系统，非常适合电生理、药理学和分子实验技术。该项目将专注于海兔防御性撤退反射的经典条件反射。这种形式的学习是由同型突触的NMDA受体依赖的可塑性和异型突触的5-羟色胺能神经调节相结合的。PI假设突触后运动神经元是这两个过程之间联系相互作用的主要例证。该项目将研究Hebbian和神经调节过程之间潜在的突触后相互作用。为此，PI将对运动神经元中的钙进行成像，以确定突触后NMDA受体活性产生的细胞内钙与刺激5-羟色胺引起的突触后细胞内库释放的钙是否相互作用。此外，还将检测突触后钙-钙调蛋白激酶II和突触后代谢性谷氨酸受体的潜在作用。PI还将通过在海绵体运动神经元中表达阻断AMPA受体运输的结构，来研究突触后AMPA受体运输在经典条件反射中的调节作用。拟议的研究将同时使用感觉运动共培养和减少海兔的制剂。

DESCRIPTION (provided by applicant): A significant percentage of people in the US suffer from behavioral disorders, including posttraumatic stress disorder (PTSD), anxiety disorders, and drug addiction, that are effectively diseases of memory dysfunction. Therefore, an understanding of the cell biology of learning and memory should facilitate the development of treatments for these disorders. One of the fundamental forms of associative learning is classical conditioning. During classical conditioning an animal learns to associate a neutral stimulus (the conditioned stimulus) with the delivery of a reinforcing stimulus (unconditioned stimulus). This project will exploit the significant experimental advantages of the marine mollusk Aplysia californica to develop a mechanistic understanding of classical conditioning. This animal has a simple nervous system that is highly suited to electrophysiological, pharmacological, and molecular experimental techniques. The project will focus on a classical conditioning of the defensive withdrawal reflex in Aplysia. This form of learning is mediated by a combination of homosynaptic, NMDA receptor-dependent plasticity and heterosynaptic, serotonergic neuromodulation. The PI hypothesizes that the postsynaptic motor neuron is a major cite of associative interaction between these two processes. The project will investigate the potential postsynaptic interactions between Hebbian and neuromodulatory processes. Toward this end, the PI will perform imaging of calcium in the motor neuron to determine whether intracellular calcium resulting from postsynaptic NMDA receptor activity and calcium released from postsynaptic intracellular stores by serotonin stimulation interact. In addition, the potential rol of postsynaptic calcium- calmodulin kinase II and postsynaptic metabotropic glutamate receptors will be examined. The PI will also investigate the role of modulation of postsynaptic AMPA receptor trafficking in classical conditioning by expressing constructs in Aplysia motor neurons that block AMPA receptor trafficking. The proposed studies will use both sensorimotor cocultures and reduced preparations of Aplysia.