Hippocampal network mechanisms for memory-guided behavior

记忆引导行为的海马网络机制

• 批准号: 10442695
• 负责人: Jill K Leutgeb
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442695
• 关键词: Aging; Alzheimer' s Disease; Anatomy; Animals; Behavior; Behavioral; Brain; Brain Diseases; Cells; Code; Complex; Computer Models; Consumption; Data; Decision Making; Deterioration; Disease; Epilepsy; Episodic memory; Event; Frequencies; Future; Gender; Generations; Goals; High Frequency Oscillation; Hippocampus (Brain); Impairment; Learning; Lesion; Location; Medial; Memory; Memory Loss; Mental Depression; Modeling; Neurons; Neurosciences Research; Patients; Pattern; Performance; Phase; Physiology; Play; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Radial; Rattus; Reporting; Research Project Grants; Retrieval; Rewards; Role; Running; Schizophrenia; Services; Sex Differences; Short-Term Memory; Site; Source; Stress; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Therapeutic Intervention; Traumatic Brain Injury; Update; Work; arm; awake; comorbidity; dentate gyrus; granule cell; hippocampal subregions; insight; memory process; neural circuit; neural network; novel; preservation; prospective; relating to nervous system; response; spatial memory; support network

PROJECT DESCRIPTION While the significance of brain oscillations as an indication of synchronized neuronal activity has been widely acknowledged, our understanding of how coordinated neuronal firing patterns support behavior and memory processing is only beginning to emerge. In particular, oscillations in complex memory tasks are highly dynamic with frequent transitions between predominant frequency ranges. Different brain states that are associated with behavior are characterized by a wide range of oscillatory frequencies that likely reflect distinct underlying network mechanisms to support different phases of memory. Yet, memory-guided behavior requires the uninterrupted retention and updating of task-relevant information across numerous transitions between brain states. One of the remaining key outstanding questions is thus how information is not only retained but also organized to become task-relevant throughout these transitions. To study this question, we will focus on the hippocampal dentate-CA3 network where we have recently shown that the dentate gyrus is critical for the generation of prospective coding of future correct choices by CA3 cells during sharp-wave ripples (SWRs) in a dentate-dependent working memory task. SWRs are high-frequency oscillations that are accompanied by brief increases in firing rates during which behaviorally relevant events are replayed. While our previous work determined that the prospective coding occurred during SWRs at reward locations, we propose to next determine whether the dentate inputs to CA3 are also critical for prospective coding during theta oscillations along the path to future reward locations. Given that our previous and preliminary data support the possibility that the dentate is necessary for prospective coding in CA3 during SWRs and theta states, we propose to next identify how prospective coding is coordinated across the transition between these brain states in order to support the planning of future decisions and trajectories. We predict that the neuronal representations of all available choices are played out during SWRs, while a selection of the next choice occurs during the subsequent theta state. Finally, we will establish a causal relationship between predictive neuronal firing sequences generated during high-frequency oscillations and predictive sequences in theta states by disrupting CA3 SWRs and examining subsequent behavioral choices and subsequent spike sequences in theta cycles. Taken together, these studies will allow us to describe network mechanisms in the hippocampus that dynamically interleave across brain states to support hippocampus-dependent memory. Our work will potentially also have significant implications for therapeutic intervention in diseases with gender-dependent memory comorbidities, as we will investigate potential sex differences for dentate-CA3 network computations critical for memory formation. This fills a gap in our understanding as no studies on functional network differences have been reported for this circuit despite clear evidence for sex differences in dentate-CA3 anatomy, plasticity, and response to aging, stress and diseases such as depression and epilepsy.

项目说明 虽然脑振荡作为同步神经元活动的指示的意义已经被广泛地 公认，我们对协调的神经元放电模式如何支持行为和记忆的理解 处理才刚刚开始出现。特别是，复杂内存任务中的振荡是高度动态的 主要频率范围之间的频繁转换。与行为相关的不同大脑状态 以广泛的振荡频率为特征，这些振荡频率可能反映了不同的潜在网络机制 支持不同阶段的内存。然而，记忆引导的行为需要不间断的保持和更新 在大脑状态之间的多次转换中获取与任务相关的信息。剩余的未解决的关键问题之一 因此，问题是如何不仅保留信息，而且组织信息，使其在整个过程中与任务相关 过渡。为了研究这个问题，我们将重点研究我们最近发现的海马齿状-CA3网络 结果表明，齿状回对于CA3细胞对未来正确选择的预期编码是至关重要的 在齿状依赖工作记忆任务中的尖锐波纹(SWR)期间。SWR是高频振荡 这伴随着发射率的短暂增加，在此期间，与行为相关的事件会重播。而我们的 以前的工作确定了预期编码发生在奖励位置的SWR期间，我们建议下一步 确定CA3的齿状输入是否也对沿 通向未来奖励地点的路径。鉴于我们之前和初步的数据支持齿状突起 在SWR和theta状态期间，CA3中的预期编码是必要的，我们建议接下来确定预期如何 在这些大脑状态之间的转换中协调编码，以支持对未来的规划 决定和轨迹。我们预测，所有可用选择的神经元表征在 SWRS，而下一个选项的选择发生在随后的theta状态中。最后，我们将建立一个因果关系 高频振荡时产生的预测性神经元放电序列与预测性神经元放电序列的关系 通过扰乱CA3 SWR并检查随后的行为选择和随后的尖峰来实现theta状态的序列 Theta循环中的序列。总而言之，这些研究将使我们能够在 海马体在大脑状态之间动态交错，以支持海马体依赖的记忆。我们的工作将 对性别依赖记忆疾病的治疗干预也有潜在的重要意义 合并症，因为我们将调查对Dentate-CA3网络计算至关重要的潜在性别差异 记忆的形成。这填补了我们理解上的一个空白，因为还没有关于功能网络差异的研究 尽管有明确的证据表明齿状-CA3解剖、可塑性和对 衰老、压力以及抑郁症和癫痫等疾病。