Hippocampal network mechanisms for memory-guided behavior

记忆引导行为的海马网络机制

• 批准号: 10022333
• 负责人: Jill K Leutgeb
• 金额: $ 36.85万
• 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/10022333
• 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; Structure; 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.

项目描述 虽然脑振荡作为同步神经元活动的指示的重要性已被广泛地 我们承认，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 加工才刚刚开始出现。特别是，复杂记忆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 其特征在于宽范围的振荡频率，这可能反映了不同的潜在网络机制， 支持不同的记忆阶段。然而，记忆引导的行为需要不间断的保留和更新 任务相关的信息在大脑状态之间的大量转换。剩下的一个关键问题 因此，问题是如何不仅保留信息，而且还组织信息，使其在整个过程中与任务相关 过渡。为了研究这个问题，我们将集中在海马齿状回-CA 3网络，我们最近已经 表明齿状回对于CA 3细胞产生未来正确选择的前瞻性编码至关重要 在一个依赖于牙齿的工作记忆任务中，驻波是高频振荡 伴随着短暂的放电率增加，在此期间行为相关的事件被重放。虽然我们的 先前的工作确定，预期编码发生在奖励地点的SWR期间，我们建议下一步 确定CA 3的齿状输入是否也对沿沿着 通往未来奖励地点的道路。鉴于我们先前和初步的数据支持齿状突起是 在SWRs和theta状态期间，CA 3中的前瞻性编码是必要的，我们建议下一步确定前瞻性编码是如何进行的。 编码在这些大脑状态之间的过渡中协调，以支持未来的规划。 决策和轨迹。我们预测，所有可用选择的神经元表征都是在 而在随后的theta状态期间发生下一个选择的选择。最后，我们将建立一个因果关系 在高频振荡期间产生的预测性神经元放电序列与预测性神经元放电序列之间的关系 通过破坏CA 3 SWR并检查随后的行为选择和随后的尖峰， theta循环中的序列总之，这些研究将使我们能够描述网络中的机制， 海马体动态地在大脑状态之间交错，以支持海马体依赖的记忆。我们的工作将 也可能对性别依赖性记忆疾病的治疗干预具有重要意义 共病，因为我们将研究齿状CA 3网络计算的潜在性别差异， 记忆形成这填补了我们理解的空白，因为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回-CA 3解剖结构、可塑性和对 衰老、压力和抑郁症、癫痫等疾病。