Shedding light on the expression and function of Neuromedin U in the brain

When an organism is in a state of stress, the body will react to the stressor through allostatic processes to actively adapt to the changing environment. The brain plays a vital role in this physiological stress response by activation and regulation of the hypothalamus-pituitaryadrenal (HPA) axis. Activation of the HPA axis results into the release of glucocorticoids from the adrenal cortex to initiate behavioral, metabolic and cardiovascular coping mechanisms. Dysregulation of the HPA axis may lead to maladaptive physiological and behavioral responses. It is therefore not surprising that stress is linked to mental, metabolic and cardiovascular disorders. Understanding the role of key stress modulators in physiological and pathophysiological conditions could reveal important biological insights to drive the search for new and effective treatments for stress-induced (pyscho)pathologies.
Neuromedin U (NMU) is an endogenous and conserved peptide produced in neuronal and nonneuronal tissues throughout the body. NMU stimulates NMUR1 and NMUR2 to exert pleiotropic physiological roles, including regulation of the stress response. This modulatory role makes NMU an appealing target to investigate in the stress response in health and disease. The overall goal of my research was to understand where NMU is distributed in the brain and how it modulates the physiological stress response. The experiments in this work were focused on two aims:
1. Investigate the role of NMU in the regulation of the HPA axis at cellular and
behavioral level, by administration of exogenous NMU in the brain of C57BL/6J mice.
2. Develop in-depth insights into the neuroanatomical distribution of NMU in the
brain, using a newly developed Nmu-Cre knock-in mouse as genetic tool.
This doctoral work resulted into two manuscripts, described in chapter III and chapter V of this thesis. In the first manuscript we studied how exogenous NMU-8, the shortest bioactive isoform of NMU, modulates the activation of the HPA axis. We found that NMU-8 increased activity of hypothalamic stress regions and stress-related behavior, measured as swim stress. Interestingly, these effects were less pronounced after previous exposure to swim stress. Surprisingly, when analyzing the downstream effects we found that NMU lowered corticosterone levels. These findings show that NMU plays a key modulatory role in the xi regulation of the HPA axis and depends on previous stress exposure. This suggests that severe stress exposure may potentially affect the interaction between NMU and its receptors. We call for further investigation to elucidate the exact mechanism-of-action.
In the second manuscript we characterized the brain of a newly developed Nmu-Cre knock-in mouse at neuroanatomical level to develop in-depth insights into where NMU-expressing neurons are distributed in the brain. With this study we provided an in-depth whole-brain characterization of NMU-expressing neurons, using an Nmu-Cre knock-in mouse that can be used as a genetic tool to target NMU-expressing neurons and modulate their function. In addition, we unveiled a midline NMU modulatory circuit with the ventromedial hypothalamus as a key node.
Altogether, this doctoral work contributes significantly to the field of NMU as it provides new fundamental insights into the neuroanatomical and functional aspects of the NMU system in the brain. Additional investigation is recommended to further characterize the NMU neuronal populations and explore their cell-circuitry. This will lead to a better understanding of the role of NMU in key physiological processes. By developing and characterizing the Nmu-Cre knockin mouse, this study has also provided a new genetic state-of-the-art tool that can be used by researchers working on NMU in various fields to unravel the role of NMU in health and disease. In conclusion, NMU could be an interesting target in the search for new, promising therapies for stress-induced diseases such as depression, anxiety and eating disorders.