Hippocampal-Hypothalamic Network Mechanisms of Maladaptive Contextual Eating

了解大脑如何支持日常行为是神经科学的核心目标，设计与生物相关的干预措施，重新平衡异常的神经元活动，取消不适应的行为模式，可能会产生深远的影响。值得注意的是，人类和动物的饮食往往超出了代谢和动态平衡的需要。在饥饿之前吃东西和不断探索新的食物是生存和适应的核心行为模式。然而，加剧的非动态平衡喂养现在是一个主要负担，代表着一种广泛传播的饮食失调，使个人暴露在肥胖之下，并影响他们的家庭、卫生部门和更广泛的英国经济。此外，进食障碍并不是孤立地发展起来的，通常与其他疾病一起发生，包括记忆障碍。从代谢和动态平衡的角度对食物摄入的神经生物学进行了广泛的研究，研究确定了下丘脑外侧区(LH)饥饿和饱腹感的神经底物。但记忆回路决定我们何时进食以及进食多少的认知过程仍未被探索。海马体(HPC)是记忆引导行为的核心大脑网络，最近被认为也处理与食物相关的信息。然而，支持这种助记控制摄食行为的神经元底物、编码方案和通路仍然难以捉摸。因此，在这里，我们寻求提供大脑网络级别的对记忆激活的非稳态喂养的机制理解。我们的方法将使用尖端的大脑记录技术，结合遗传方法来监测和操纵小鼠HPC和LH区细胞的活动，这些细胞以空间上下文相关的方式增加食物摄入量。该项目将涉及三个科学目标1。为了揭示过量进食对海马体记忆网络的影响，我们将调查进食美味食物的上下文升级与支持记忆的HPC活动动态之间的关系，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。我们将检验三个假设：(I)对食物摄取做出反应的HPC神经元的子集提供了最后一餐的内部表征；(Ii)可口食物的重复摄食体验使HPC网络活动倾向于异常的食物上下文细胞集合；以及(Iii)上下文进食的升级通过增强神经元在消耗行为中的同步性来诱导不必要的HPC网络可塑性。我们将(I)定义接受直接HPC神经输入的LH神经元的电生理学和分子图谱；以及(Ii)识别由高背景进食增加引起的HPC到LH活性的变化，包括跨网络HPC-LH细胞组合的计算。3.为了控制HPC到LH通路上的神经元活动并恢复正常的情境进食，我们将采用最先进的光遗传学干预措施，这些干预措施是(I)活动依赖的，(Ii)细胞类型选择性的，和(Iii)输入限定的，以探索控制HPC到1h通路上的活动和取消功能失调的摄食的策略。我们的第一个策略是将环境与可口食物配对的海马区表征“重新编程”为另一种中性表征。第二种策略是使用HPC网络动态的实时检测来“重新平衡”HPC连接的黄体生成素神经元的活动。总体而言，我们的实验将对全面理解大脑网络水平的机制做出重大贡献，这些机制潜在的不断升级的、上下文相关的摄食行为。我们的项目将进一步为进食障碍和记忆障碍之间高共患病率的神经元基础提供重要的新见解。

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.