Dopamine Regulation During Context Processing

一种著名的理论认为，DA细胞为即将到来的奖励产生预测性信号 和/或它们在增援应急情况发生变化时发出信号。这里有人争辩说， 以更动态、更宽广的系统视角看待S对认识的贡献，我们可以 更好地理解DA功能的意义；我们不仅需要考虑DA如何 调节传出结构的可塑性，但也调节DA神经元本身的可塑性 由经验决定的。上一次资助期间的研究提供了令人信服的证据 该DA功能依赖于上下文。本提案包括四个具体目标 这将使我们能够检验这样一个假设，即DA神经元信号的上下文调节 奖励信息是从来自现有记忆的输入和 前额叶皮质(PFC)的决策系统和语境评估 海马(HPC)。PFC和HPC被认为影响了DA奖励的时机 通过经验依赖的感觉信息向DA选通相对于显著提示的信号 通过被盖的神经元。这幅作品结合了1)高密度单 单元记录，以便我们能够理解(相对于DA信号)内部的神经编码 PFC、HPC和两个被盖区，桥脚核(PPTg)和 被盖背外侧核(LDTg)，2)可逆性脑结构失活测试 用于感兴趣区域之间的功能连接，以及3)行为遗传分析 确定NMDA系统在DA调节中的作用。目标1将决定 调节DA活性的结构中的神经代表：PPTg、LDTg、HPC和PFC。 目标2将确定腹侧被盖区DA神经元的上下文敏感性 区域(VTA)和黑质(SNC)是由PPTG、LDT、HPC或PFC输入引起的。目标3 将决定PPTg、LDTg和PFC神经表征的上下文敏感性是否 最终源自HPC或PFC。目标4将测试它是否是谷氨酸(NMDA) 传入输入的组成部分，通过测试以下各项来调节DA细胞的突发放电 选择性缺失DA上NR1受体的自由行为小鼠的细胞特性 细胞。广泛的意义：了解上下文信息如何通过DA调节信令 神经元对于药物治疗的发展是至关重要的 复发、帕金森病、S病，与正常年龄相关的学习能力下降。

A prominent theory argues that DA cells generate predictive signals for impending reward and/or they signal when reinforcement contingencies change. It is argued here that by taking a more dynamic and broad systems view of DA¿s contribution to cognition, we can better understand the significance of DA function; we need to consider not only how DA regulates plasticity in efferent structures, but also how DA neurons themselves are regulated by experience. Studies from the last grant period provide compelling evidence that DA function is context-dependent. The present proposal includes four Specific Aims that will allow us to test the hypothesis that context regulation of DA neuronal signaling of reward information is derived from a combination of inputs from existing memory and decision making systems of the prefrontal cortex (PFC) and context evaluation by hippocampus (HPC). PFC and HPC are thought to impact the timing of the DA reward signal relative to salient cues by experience-dependent gating of sensory information to DA neurons via the tegmentum. This work incorporates a combination of 1) high density single unit recording so that we can understand (relative to DA signals) the neural codes within the PFC, HPC, and two tegmental areas, the pedunculopontine nucleus (PPTg) and the lateral dorsal tegmental nucleus (LDTg), 2) reversible inactivation of brain structures to test for functional connectivity between regions of interest, and 3) behavioral genetic analysis to identify the role of the NMDA system in DA regulation. Aim 1 will determine the nature of neural representation in structures that regulate DA activity: PPTg, LDTg, HPC and PFC. Aim 2 will determine whether the context-sensitivity of DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SNc) is due to PPTg, LDT, HPC, or PFC input. Aim 3 will determine whether context-sensitivity of PPTg, LDTg and PFC neural representations is ultimately derived from HPC or PFC. Aim 4 will test whether it is the glutamate (NMDA) component of the afferent input that regulates burst firing by DA cells by testing these cellular properties in freely behaving mice that are selectively missing NR1 receptors on DA cells. Broad Significance: Understanding how context information regulates signaling by DA neurons is of fundamental importance for therapeutic development in cases of drug relapse, Parkinson¿s disease, and normal age associated decline in learning.