Dopamine Regulation During Context Processing

描述（由申请人提供）：一个著名的理论认为，DA细胞产生即将到来的奖励和/或信号时，强化偶然性变化的预测信号。有人认为，通过采取更动态和广泛的系统观DA的认知的贡献，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，而且DA神经元本身是如何调节的经验。研究从最后一个赠款期间提供了令人信服的证据表明，DA功能是依赖于上下文的。本建议包括四个具体目标，这将使我们能够测试的假设，即背景调节DA神经元信号的奖励信息是来自现有的记忆和决策系统的前额叶皮层（PFC）和海马（HPC）的上下文评估的输入的组合。PFC和HPC被认为是影响的DA奖励信号的时间相对于显着的线索经验依赖性门控的感觉信息，DA神经元通过被盖。这项工作结合了1）高密度的单一单位记录，使我们能够了解（相对于DA信号）PFC、HPC和两个被盖区（脚桥核（PPTg）和外侧背侧被盖核（LDTg））内的神经代码，2）脑结构的可逆失活以测试感兴趣区域之间的功能连接，3）行为遗传学分析以确定NMDA系统在DA调节中的作用。目的1将确定调节DA活性的结构中的神经表征的性质：PPTg，LDTg，HPC和PFC。目的2将确定腹侧被盖区（VTA）和黑质（SNc）中DA神经元的上下文敏感性是否是由于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是否最终来自HPC或PFC。目的4将测试是否是谷氨酸（NMDA）成分的传入输入，调节DA细胞通过测试这些细胞特性在自由行为的小鼠选择性缺失DA细胞上的NR 1受体的突发放电。广泛意义：了解背景信息如何调节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学习能力下降的治疗开发至关重要。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（如药物成瘾和青少年犯罪）有关。这项工作旨在描述大脑的记忆系统如何修改多巴胺神经元的神经代码，从而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.