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的预测信号，和/或当增援意外情况发生变化时发出信号。本文认为，通过更动态和更广泛的系统地看待DA对认知的贡献，我们可以更好地理解DA功能的重要性；我们不仅需要考虑DA如何调节传出结构的可塑性，而且还需要考虑DA神经元本身是如何受到经验的调节的。上一次赠款期间的研究提供了令人信服的证据，表明发展议程的作用是依赖于背景的。目前的建议包括四个具体的目标，使我们能够检验这样的假设，即DA神经元奖赏信息信号的背景调控来自现有记忆和前额叶皮质(PFC)决策系统的输入和海马区(HPC)的背景评估(HPC)。PFC和HPC被认为通过经验依赖的方式将感觉信息通过被盖传递到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)高密度单单位记录，以便我们可以了解(相对于DA信号)PFC，HPC和两个被盖区，脚桥核(PPTg)和被盖外侧背核(LDTg)内的神经密码，2)可逆性失活的脑结构，以测试感兴趣区域之间的功能连接，以及3)行为遗传学分析，以确定NMDA系统在DA调节中的作用。目标1将确定调节DA活性的结构中神经代表的性质：PPTg、LDTg、HPC和PFC。目的2确定腹侧被盖区(VTA)和黑质(SNC)DA神经元的上下文敏感性是否源于PPTG、LDT、HPC或PFC输入。目标3将确定PPTg、LDTg和PFC神经表征的上下文敏感性最终是来自HPC还是PFC。目的4将通过在行为自由的小鼠身上测试这些细胞特性来测试是否是传入输入的谷氨酸(NMDA)成分调节DA细胞的猝发放电，这些小鼠选择性地缺失DA细胞上的NR1受体。广泛的意义：了解上下文信息如何调节DA神经元的信号传递对于药物复发、帕金森病和正常年龄相关的学习下降的治疗发展至关重要。与公共卫生相关：多巴胺系统的故障与许多疾病(如帕金森氏病)和适应不良状况(如吸毒和青少年犯罪)有关。这项工作建议描绘大脑的记忆系统如何修改多巴胺神经元的神经代码，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.