Top-down control of Olfactory Processing and Behavior by Melanocortin System
1 Institute of Zoologyu2013Developmental Biology, University of Cologne, Germany
2 Department of Neuroscience-University of Copenhagen
Background: Animals rely on their senses for finding food resources. In mammals, energy homeostasis and food uptake is orchestrated by the AgRP and POMC neurons located in the arcuate nucleus of the hypothalamus. They are under the control of hormones mediating the metabolic state of the animal and in turn project to and control so-called second-order neurons of the melanocortin system located in multiple areas of the brain. POMC neurons mediate “satiety” via the release of αMSH, which binds and activates Melanocortin 4 receptors (Mc4Rs) on second-order neurons. AgRP neurons mediate “hunger” and initiate foraging activity via the release of AgRP (an Mc4R inverse agonist), NPY and GABA. In the past few years, it was shown that the melanocortin system is also largely conserved in zebrafish (Löhr et al. 2018; Reinoss et al. 2020). Several former studies in mammals have addressed the interplay of olfaction, the sense of smell, and energy homeostasis. Food odor sensing and mitral cell activity in the olfactory bulb (OB) is influenced by the nutritional state of the animals. Thus, upon food odor presentation, mitral cells in fasted rats are activated in higher proportions compared to the fed controls (Pager, J. et. al, 1972). Furthermore, Orexin-positive fibers, other mediators of hunger, have been shown to project to the OBs (Hardy, A. B., et. al. 2005).
Objectives: In this project, we aim to elucidate the anatomical and functional interplay between the olfactory and the melanocortin systems, by taking advantage of the zebrafish model.
Materials and Methods: In Situ hybridization, immunohistochemistry, transgenic approach, pharmacology approach, odor preference behavioral assays, ex vivo calcium imaging.
Results and Conclusions: We show that in adult zebrafish, both AgRP and POMC neurons project to the OBs as well as to higher-order areas corresponding to the mammalian olfactory cortex, while OB neurons display expression of mc4r. Furthermore, pERK staining indicates that upon food odor presentation, OB cells are activated more strongly in fasted than in fed fish, and that OB cells of fasted fish are also activated upon treatment with the Mc4R agonist MTII. Counter stainings of OB neurons with specific markers (e.g identifying glutamatergic mitral cells, and GABAergic interneurons) are ongoing to determine the neurochemical identity of such odor and aMSH/AgRP-responsive OB neurons. Ongoing experiments will determine the effect of pharmacological manipulation of Mc4R in odor preference assays, and in ex vivo calcium imaging of neural activity in the olfactory system as well as in hunger and satiety.
References:
Löhr et al., (2018). Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit, Cell Reports 23, 1728-1741
Reinoss et al, (2020). Hypothalamic Pomc Neurons Innervate the Spinal Cord and Modulate the Excitability of Premotor Circuits, Current Biology 30, 4579–4593,
Pager, J., Giachetti, I., Holley, A., behavior, J. L. M.-P. &, & 1972, undefined. (n.d.). A selective control of olfactory bulb electrical activity in relation to food deprivation and satiety in rats. Elsevier. Retrieved April 26, 2023, from https://www.sciencedirect.com/science/article/pii/0031938472900145
Hardy, A. B., Aïoun, J., Baly, C., Julliard, K. A., Caillol, M., Salesse, R., & Duchamp-Viret, P. (2005). Orexin A Modulates Mitral Cell Activity in the Rat Olfactory Bulb: Patch-Clamp Study on Slices and Immunocytochemical Localization of Orexin Receptors. Endocrinology, 146(9), 4042–4053. https://doi.org/10.1210/EN.2005-0020