Lateral Habenula and Memory Guided Response Flexibility

项目摘要 由于海马（HPC）神经活动不能可靠准确地预测未来的选择， 依赖任务、依赖经验和有意行为必须在HPC下游启用， 也许在关于一个人的内部状态的信息（例如动机，压力和情绪的水平）具有 大脑皮层对未来行为的指令产生偏差的机会。事实上，一个人往往可以“知道”在给定的情况下该做什么。 然而，一个人的内部状态的条件往往阻止甚至期望的反应发生。的 本申请检验了外侧缰（LHb）对于 确定HPC/mPFC相关内存和决策的表达式，因为它集成了 具有HPC/mPFC输出的当前内部状态信息以启用（或不启用）响应（60）。这 更普遍但更狭隘的观点认为，LHb指导选择行为，因为它 表示负任务条件（11，23 -26）。AIM 1将测试HPC-mPFC- LHb电路是必要的，以准确地执行HPC和mPFC依赖的空间延迟 需要灵活决策的交替任务。Exp. 1：由于没有已知的直接 HPC和LHb之间的连接，将使用已建立的（蝇蕈醇诱导的） 分离范式初步数据表明，HPC-LHb相互作用是准确的， 延迟交替任务的表现。Exp. 2：mPFC和LHb之间的直接联系已被证实。 描述（4）。因此，LHb中mPFC末端的光学抑制将测试mPFC-LHb的必要性。 交互以实现准确的任务性能。目的2将表征HPC-LHb θ相干性的性质 在空间延迟交替任务的执行。然后我们将确定相对贡献 记忆（通过mPFC输入）和内部状态信息（通过外侧下丘脑或LH输入）， HPC-LHb相干性。将研究结构间的协调θ相位和功率关系， 更好地理解信息流的方向，以及在θ波发作期间共享的信息的性质 连贯性使用相同的动物，我们将确定记忆系统输入的相对影响（通过 PFC）和内部状态输入（通过LH）对HPC-LHb θ相干性的影响。 总之，这个R21应用程序为一个新的假设寻求“概念证明”证据，该假设可能导致 改善外侧缰核介导的行为控制障碍的新治疗方法。

PROJECT SUMMARY Since hippocampal (HPC) neural activity does not reliably and accurately predict future choices in context- dependent tasks, experience-dependent and intentional behaviors must be enabled downstream of HPC, perhaps where information about one’s internal state (e.g. level of motivation, stress, and emotion) has an opportunity to bias cortical instructions for future behaviors. Indeed often one may ‘know’ what to do in a given situation, yet the condition of one’s internal state often prevent even desired responses from occurring. The present application tests the novel hypothesis that the lateral habenula (LHb) is pivotally important for determining the expression of HPC/mPFC-dependent memory and decisions because it integrates current internal state information with HPC/mPFC output to enable (or not) responses (60). This hypothesis is not predicted by the more common but narrower view that LHb directs choice behavior because it signals negative task conditions (11,23-26). AIM 1 will test whether interactions across the HPC-mPFC- LHb circuit are necessary to perform accurately on a HPC and mPFC-dependent spatial delayed alternation task that requires flexible decision making. Exp. 1: Since there are no known direct connections between HPC and LHb, their interactions will be studied using an established (muscimol-induced) disconnection paradigm. Preliminary data show that HPC-LHb interactions are necessary for accurate performance on the delayed alternation task. Exp. 2: Direct connections between mPFC and LHb have been described (4). Thus, optical inhibition of mPFC terminals in LHb will test the necessity of mPFC-LHb interactions for accurate task performance. Aim 2 will characterize the nature of HPC-LHb theta coherence during spatial delayed alternation task performance. Then we will determine the relative contributions of memory (via mPFC input) and internal state information (via lateral hypothalamus, or LH, input) to HPC-LHb coherence. Coordinated theta phase and power relationships across structures will be studied to better understand the direction of information flow, and the nature of information shared during bouts of theta coherence. Using the same animals, we will then determine the relative influence of memory system input (via PFC) and internal state input (via LH) on HPC-LHb theta coherence using retroviral and optogenetic methods. In summary, this R21 application seeks ‘proof of concept’ evidence for a novel hypothesis that could lead to new therapeutic approaches to improve lateral habenula-mediated disorders of behavioral control.