Dopamine Regulation During Context Processing

描述（由申请人提供）：一个著名的理论认为，DA细胞对即将到来的奖励和/或强化偶然性变化产生预测信号。本文认为，从更动态和更广泛的系统角度来看待数据分析对认知的贡献，我们可以更好地理解数据分析功能的意义；我们不仅需要考虑DA如何调节传出结构的可塑性，还需要考虑DA神经元本身是如何受经验调节的。上一个资助期的研究提供了令人信服的证据，表明DA功能与环境有关。目前的建议包括四个具体目标，这将使我们能够验证这样的假设，即奖励信息的DA神经元信号的环境调节来自于来自前额皮质（PFC）现有记忆和决策系统以及海马体（HPC）的环境评估的组合输入。PFC和HPC被认为通过经验依赖的门控将感觉信息通过被盖传递给DA神经元，从而影响相对于显著线索的DA奖励信号的时间。这项工作结合了1)高密度单单元记录，以便我们能够理解（相对于DA信号）PFC， HPC和两个被盖区，桥脚核（PPTg）和侧背被盖核（LDTg）内的神经编码；2)可逆的脑结构失活以测试感兴趣区域之间的功能连接；3)行为遗传分析以确定NMDA系统在DA调节中的作用。目的1将确定调节DA活动的结构中的神经表征的性质：PPTg、LDTg、HPC和PFC。目的2将确定腹侧被皮层（VTA）和黑质（SNc）中的DA神经元的上下文敏感性是否归因于PPTg、LDT、HPC或PFC输入。目的3将确定PPTg、LDTg和PFC神经表征的上下文敏感性最终是否来自HPC或PFC。目的4将通过在DA细胞上选择性缺失NR1受体的自由行为小鼠中测试这些细胞特性，来测试传入输入的谷氨酸（NMDA）成分是否调节DA细胞的突发放电。广泛意义：了解上下文信息如何调节DA神经元的信号传导，对于药物复发、帕金森病和正常年龄相关的学习能力下降的治疗发展具有重要意义。公共卫生相关性：多巴胺系统的功能障碍与许多疾病（如帕金森病）和适应不良状况（如吸毒成瘾和青少年犯罪）有关。这项工作提出描述大脑的记忆系统如何修改多巴胺神经元的神经密码，从而允许开发新的治疗干预措施。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Malfunction of the dopamine system has been implicated in many disorders (e.g. Parkinson's disease) and maladaptive conditions (e.g. drug addiction and juvenile delinquency). This work proposes to delineate how memory systems of the brain modify the neural codes of dopamine neurons, allowing for new therapeutic interventions to be developed.