Functional Diversity In Hypothalamus

The hypothalamus is a critical regulator of many physiological processes and behaviors that are essential for life. Each anatomically-defined hypothalamic nucleus consists of functionally heterogeneous neuronal subpopulations that dictate distinct innate behaviors such as feeding, mating, and parental care.

We are interested in studying how the developing hypothalamus generates diverse neuronal identities that ultimately give rise to distinct survival behaviors. We focus our initial studies on two intermingled neuronal subpopulations in the arcuate nucleus of the hypothalamus that play an essential role in feeding regulation. Neurons that produce the orexigenic neuropeptide Y (NPY) and agouti-related protein (AgRP) directly stimulate food intake, whereas those synthesizing the anorexigenic peptide pro-opiomelanocortin (POMC) suppress feeding.

To understand how common hypothalamic progenitors generate two neuronal populations that have the opposite effects on food intake, we took advantage of transgenic mouse lines in which POMC or NPY/AgRP neurons are genetically labeled by green fluorescent proteins. We isolated these neurons from the developing hypothalamus and purified them via fluorescence activated cell sorting. Through cell type-specific transcriptomics analysis, we identified several transcription regulators that show differential expression patterns in one population but not the other. Meanwhile, we have developed genetic tools (e.g. POMC::CreERT2 and AgRP::CreERT2 mice) to target these factors specifically in POMC or AgRP neurons in a spatiotemporally controlled manner across different stages of life.

We are currently investigating the potential roles of these differentially-expressed transcription factors in specifying the orexigenic vs. the anorexigenic cell fates during development as well as in maintaining energy homeostasis throughout adulthood. With these studies, we hope to establish a framework that would help us to understand how diverse neuronal identities are established and maintained in the hypothalamus, and how intrinsic genetic programs interact with environmental cues to shape adult behaviors that are essential for survival.