From identity to function: unveiling the cellular complexity of hypothalamic feeding circuits

The hypothalamus is arguably the most complex part of the brain, with the greatest heterogeneity of cellular populations. It is an integration center for peripheral signals and external stimuli and plays a key role in coordinating a myriad of fundamental biological functions, including energy homeostasis. To fully understand how the hypothalamus functions, we first need to unravel cellular heterogeneity of this brain region. In hypothalamic research, the vast majority of 'ground truths' have, until recently, emerged from low-throughput murine studies. However, the advent of high-throughput, single-cell approaches has dramatically altered the landscape and allow characterization of gene and protein expression, epigenomic features, cell morphology, and spatial organization. Recently, three-dimensional transcriptomic atlases of the macaque and human hypothalamus have been published and serve as growing resources for understanding hypothalamic cell types and organization in both healthy and disease states. Hypothalamic function is still primarily studied with the use of model systems, where cell culture methods are especially suitable for investigating molecular mechanisms, while animal models provide the opportunity to disentangle complex neural circuits as well as measure behavior and physiological changes. Here, we review what the latest technological advancements and functional discoveries have revealed to us about the hypothalamus, with a focus on feeding behavior.