Hippocampal-Hypothalamic Network Mechanisms of Maladaptive Contextual Eating

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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.