HEBBIAN LONG-TERM POTENTIATION AND LEARNING IN APLYSIA

该项目的长期目标是阐明简单生物体--加州海兔--学习和记忆的神经机制。这种无脊椎动物的防御性撤退系统构成了这一目的的重要模式系统。反射表现出几种简单的学习形式，包括经典的条件反射。此外，反射背后的神经回路也相对较好地被理解。这个回路的一个中心组成部分是调节反射的感觉神经元和运动神经元之间的突触连接。在这种动物的平行学习中，感觉运动型突触的强度发生了变化。因此，感觉运动型突触是对海兔学习进行细胞分析的有利起点。该项目将专注于一种突触可塑性的形式，神经科学家长期以来一直认为这种形式可以调节脊椎动物大脑的学习和记忆-赫比安增强。然而，由于大脑的巨大复杂性，以及脊椎动物表现出的学习形式的复杂性，事实证明很难令人信服地将赫比安增强与记忆联系起来。最近的研究表明，海兔的感觉运动性突触具有Hebbian增强效应。这一事实允许使用海兔对Hebbian增强在简单形式的联想学习中的作用进行简约主义分析-经典的撤退反射条件反射。该项目的目标将是：(1)试图通过使用N-甲基-D-天冬氨酸受体的药物拮抗剂在经典条件反射中发挥作用的证据，N-甲基-D-天冬氨酸受体是已知介导Hebbian可塑性的受体类型；(2)确定经典条件作用是否涉及Hebbian可塑性和突触竞争之间的相互作用；(3)确定经典条件作用是否涉及Hebbian可塑性和由单胺类递质激活的细胞通路之间的相互作用；以及(4)试图发现维持Hebbian增强的长期细胞变化。预计这项拟议研究的结果将有助于理解强调学习和记忆的过程。这样的理解将成为改善阿尔茨海默氏症等记忆疾病的治疗基础。

The long-term objective of this project is to elucidate the neuronal mechanisms of learning and memory in a simple organism, Aplysia californica. The defensive withdrawal system of this invertebrate constitutes an important model system for this purpose. The reflex exhibits several simple forms of learning, including classical conditioning. Furthermore, the neuronal circuitry that underlies the reflex is relatively well understood. A central component of this circuitry is the synaptic connection between the sensory and motor neurons that mediate the reflex. Changes in the strength of the sensorimotor synapse have been shown to parallel learning by this animal. The sensorimotor synapse is therefore an advantageous starting point for a cellular analysis of learning in Aplysia. The project will focus on a form of synaptic plasticity that has long been thought by neuroscientists to mediate learning and memory in the vertebrate brain-Hebbian potentiation. Due to the brain's tremendous complexity, however, as well as to the sophistication of the forms of learning exhibited by vertebrates, it has proved difficult to convincingly link Hebbian potentiation and memory. Recently, it has been shown that sensorimotor synapses of Aplysia exhibit Hebbian potentiation. This fact permits the use of Aplysia for a reductionist analysis of the role of Hebbian potentiation in a simple form of associative learning-classical conditioning of the withdrawal reflex. The goal of the project will be: (1) to attempt to provide evidence that Hebbian plasticity plays a role in classical conditioning through the use of pharmacological antagonists of N-methyl-D-aspartate receptors, the receptor type known to mediate Hebbian plasticity; (2) to determine whether classical conditioning involves an interaction between Hebbian plasticity and synaptic competition; (3) to determine whether classical conditioning involves an interaction between Hebbian plasticity and cellular pathways activated by monoaminergic transmitters; and (4) to attempt to discover the long-term cellular changes that maintain Hebbian potentiation. It is expected that the findings from the proposed research will contribute to an understanding of the processes that underline learning and memory. Such an understanding will serve as a basis for treatments to ameliorate diseases of memory, such as Alzheimer's.