Hippocampal-Hypothalamic Network Mechanisms of Maladaptive Contextual Eating

适应不良的情境饮食的海马-下丘脑网络机制

• 批准号: MR/W004860/1
• 负责人: David Dupret
• 金额: $ 116.51万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW004860%2F1
• 关键词: Hippocampal; Hypothalamic; Network; Mechanisms; Maladaptive

Understanding how the brain supports everyday behaviour is a central goal of neuroscience, with potential far-reaching consequences for designing biologically relevant interventions that rebalance aberrant neuronal activity and cancel maladaptive behavioural patterns.Notably, humans and animals are prone to eat beyond metabolic, homeostatic needs. Eating before being hungry and continually exploring new food items are behavioural patterns central to survival and adaptation. However, exacerbated non-homeostatic feeding is now a major burden, representing a wide spread eating disorder that expose individuals to obesity and affect their families, the health sector and the wider UK economy. Moreover, eating disorders do not develop in isolation and typically occur along with other conditions including dysfunctional memory.The neurobiology of food-intake has been widely investigated from a metabolic and homeostatic perspective, with studies identifying neural substrates of hunger and satiety in the lateral hypothalamus (LH). But the cognitive processes where memory circuits shape when and how much we eat remain unexplored. The hippocampus (HPC) is a brain network central to memory-guided behaviour that has been recently suggested to also process food-related information. However, the neuronal substrates, coding schemes and pathways underpinning such a mnemonic control of feeding behaviour remain elusive. Accordingly, here we seek to deliver a brain network-level mechanistic understanding of memory-invigorated, non-homeostatic feeding.Our approach will use cutting-edge technologies for brain recordings combined with genetic approaches to monitor and manipulate the activity of cells in the HPC and LH regions of mice that escalate their food intake in a spatial context dependent manner. This project will address three scientific objectives.1. To reveal the effect of excessive eating on the hippocampal memory network.We will investigate the relationships between escalated contextual eating of highly palatable food and HPC activity dynamics known to support memory, associating changes in neuronal firing activity with individual's propensity to consume food resources. We will test three hypotheses: (i) a subset of food-intake-responding HPC neurons provides an internal representation of the last meal; (ii) repeated feeding experience of palatable food biases HPC network activity towards aberrant food-context cell assemblies; and (iii) escalated contextual eating induces unwanted HPC network plasticity by enhancing neuronal synchronisation during consummatory behaviour.2. To uncover cross-network HPC-to-LH activity motifs in escalated contextual feeding.We will (i) define the electrophysiological and molecular profiles of LH neurons that receive direct HPC neural inputs; and (ii) identify HPC-to-LH activity changes caused by heightened contextual eating, including the computation of cross-network HPC-LH cell assemblies. 3. To manipulate neuronal activity along the HPC-to-LH pathway and restore normal contextual eating.We will deploy state of the art optogenetic interventions that are (i) activity-dependent, (ii) cell-type-selective, and (iii) input-defined, in order to probe strategies that control activity along the HPC-to-LH pathway and cancel dysfunctional feeding. Our first strategy consists in "reprograming" hippocampal representations of environments paired with palatable food into alternative, neutral representations. The second strategy consists in "rebalancing" the activity of HPC-connected LH neurons using real-time detection of HPC network dynamics.Collectively, our experiments will make a major contribution to a comprehensive understanding of the brain network-level mechanism underlying escalated, context-dependent feeding behaviour. Our project will further provide important new insights into the neuronal foundation of the high co-morbidity between eating disorders and dysfunctional memory.

了解大脑如何支持日常行为是神经科学的一个核心目标，对于设计生物相关干预措施，重新平衡异常的神经元活动并消除适应不良的行为模式，可能会产生深远的影响。在饥饿之前进食和不断探索新的食物是生存和适应的核心行为模式。然而，加剧的非稳态喂养现在是一个主要的负担，代表了广泛传播的饮食失调，使个人肥胖，影响他们的家庭，卫生部门和更广泛的英国经济。此外，进食障碍并不是孤立发展的，通常沿着其他情况，包括记忆障碍。食物摄入的神经生物学已经从代谢和稳态的角度进行了广泛的研究，研究确定了外侧下丘脑（LH）中饥饿和饱腹感的神经底物。但是，记忆回路塑造我们何时吃、吃多少的认知过程仍然没有被探索。海马体（HPC）是一个大脑网络，对记忆引导的行为至关重要，最近有人提出它也处理与食物相关的信息。然而，神经基板，编码方案和路径支撑这样的记忆控制的进食行为仍然难以捉摸。因此，在这里，我们试图提供一个大脑网络水平的机械理解的记忆，非稳态feeding. We的方法将使用尖端技术的大脑记录结合遗传学的方法来监测和操纵细胞的活动，在HPC和LH区域的小鼠，逐步增加他们的食物摄入量在一个空间环境依赖的方式。该项目将涉及三个科学目标。为了揭示过度进食对海马记忆网络的影响，我们将研究高度可口的食物和HPC活动动力学之间的关系，将神经元放电活动的变化与个体消耗食物资源的倾向联系起来。我们将测试三个假设：（i）食物摄取响应HPC神经元的子集提供最后一餐的内部表示;（ii）可口食物的重复喂养经验使HPC网络活动偏向异常的食物背景细胞组装;以及（iii）逐步增加的背景进食通过增强消费行为期间的神经元同步来诱导不需要的HPC网络可塑性。为了揭示在不断升级的情境进食中跨网络HPC-LH活性基序，我们将（i）定义接受直接HPC神经输入的LH神经元的电生理和分子特征;（ii）识别由增强的情境进食引起的HPC-LH活性变化，包括跨网络HPC-LH细胞组装的计算。3.为了操纵沿着HPC到LH通路的神经元活动并恢复正常的背景进食，我们将部署最先进的光遗传学干预措施，这些干预措施是（i）活动依赖性的，（ii）细胞类型选择性的，和（iii）输入定义的，以探索控制沿着沿着HPC到LH通路的活动并取消功能失调的进食的策略。我们的第一个策略是将海马体对环境的表征与可口的食物配对，“重新编程”成另一种中性的表征。第二个策略包括在“重新平衡”的HPC连接LH神经元的活动，使用实时检测HPC网络dynamics.Collectively，我们的实验将作出重大贡献，以全面了解脑网络水平的机制升级，上下文相关的喂养行为。我们的项目将进一步提供重要的新的见解，神经元基础的高共患病率之间的饮食失调和记忆功能障碍。

项目成果

Disk-Drive-Like Operations in the Hippocampus

海马体中类似磁盘驱动器的操作

• DOI: 10.1101/2022.10.05.511000
• 发表时间: 2022
• 作者: Nicola W

Over and above frequency: Gamma oscillations as units of neural circuit operations.

• DOI: 10.1016/j.neuron.2023.02.026
• 发表时间: 2023-04-05
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Fernandez-Ruiz A;Sirota A;Lopes-Dos-Santos V;Dupret D
• 通讯作者: Dupret D