MOLECULAR AND CELLULAR MECHANISMS OF A NEURONAL NETWORK FOR OLFACTORY LEARNING

描述（由申请人提供）：学习是神经系统的一项基本功能，使动物能够根据适应值调节行为。虽然对学习的分子基础知识的不断增加提供了对学习机制的见解，但我们的理解无法解释大多数学习范式中的行为变化。该领域的一个主要挑战是将底层神经网络的功能与行为联系起来，并解决神经回路的特性如何编码学习。我们使用遗传模式生物秀丽隐杆线虫来解决这个问题。在过去的资助期内，我们已经建立了一种厌恶嗅觉学习的形式，通过这种方式，线虫学会了避免致病细菌的气味。这种形式的学习类似于加西亚效应，在加西亚效应中，动物学会避免与胃部不适有关的食物的气味或味道。利用这种学习范式，我们描述了底层神经网络的结构和功能。特别是，我们发现由5 -羟色胺能神经元ADF和下游中间神经元RIA以及运动神经元组成的5 -羟色胺能神经回路特异性地调节习得性嗅觉偏好。ADF中的血清素信号调节致病菌的厌恶学习。ADF通过增加细胞内钙信号响应细菌气味，而秀丽隐杆线虫CaMKII的同源物UNC-43在ADF中起调节学习的作用。突触后神经元RIA是厌恶学习的关键。RIA显示与头部运动相关的区隔轴突活动。同时，RIA轴突室也表现出由嗅觉刺激引起的同步活动。有趣的是，我们发现厌恶训练调节了活动模式

DESCRIPTION (provided by applicant): Learning is an essential function of the nervous system that allows animals to modulate behavior with adaptive values. While increasing amount of knowledge on the molecular underpinnings of learning provide insights into the mechanisms underlying learning, our understanding cannot explain behavioral changes in most learning paradigms. One major challenge of the field is to link the function of the underlying neuronal network with behavior and to address how the property of neural circuitry encodes learning. We use the genetic model organism C. elegans to address this question. In the past funding period, we have established a form of aversive olfactory learning whereby the nematode learns to avoid the smell of pathogenic bacteria that make it ill. This form of learning is analogous to Garcia effect, in which animals learn to avoid the smell or taste of a food that is associated with stomach distress. Using this learning paradigm, we have characterized the structure and function of the underlying neuronal network. Particularly, we show that a serotonergic neural circuit composed of the serotonergic neuron ADF and the downstream interneuron RIA, as well as motor neurons specifically regulate learned olfactory preference. The serotonin signal in ADF regulates the aversive learning on pathogenic bacteria. ADF responds to bacterial odors with increased intracellular calcium signals and the C. elegans homolog of CaMKII, UNC-43, acts in ADF to regulate learning. The postsynaptic neuron RIA is critically required for the aversive learning. RIA displays compartmentalized axonal activity that is correlated with head movement. Meanwhile, RIA axonal compartments also display synchronous activity that is evoked by olfactory stimuli. Interestingly, we show that the aversive training modulates the activity pattern of ADF and RIA in a way that is consistent with training-induced behavioral changes in olfactory preference. Thus, we hypothesize that these learning-correlated changes in the functional attributes of ADF and RIA neurons encode learning. We propose to test this hypothesis by characterizing the regulatory mechanisms and function of the learning correlates in ADF and RIA. We will first define the interaction between these two learning correlates by testing the possibility that the learning correlate in ADF regulates the learning correlate in RIA. We will als characterize the regulation of these learning correlates by examining the effect of several genetic factors that we have identified to mediate learning. We will also define the neurotransmission of ADF that regulates RIA activity. Second, we will characterize the function of the learning correlates in ADF and RIA. We will use molecular and optogenetics to manipulate the property of these neurons to (1) eliminate the training-induced changes in their activity patterns; and (2) "build" the learning correlates with genetic methods in the key neurons of the circuit, and then test the resulting effects on olfactory learning. These studies will revea how experience modulates the function of a neural network and leads to experience-dependent behavioral changes.