Central control of cardiovascular and thermoregulatory functions

The maintenance of body temperature in homeothermic organisms requires a concerted response to the always changing environmental conditions. This includes for instance the regulation of brown fat thermogenesis, but also the control of heat dissipation through peripheral blood vessels. We have recently identified a novel population of thyroid hormone dependent neurons in the anterior hypothalamic area (Mittag et al. 2013), which adjusts blood pressure and heart rate in a temperature dependent manner. Since we have recently shown that alterations in cardiovascular functions, i.e. peripheral vasoconstriction, play an important role for heat dissipation (Warner et al. 2013), it can be speculated that these neurons are an integral part of the central circuitry that mediates the whole body adaptation to cold or heat. However, little is known about the exact properties of the novel neurons, to which stimuli they respond, and under which (patho)physiological conditions they might operate.

We have started to manipulate the novel hypothalamic neurons using the stereotaxic injection of AAV, to obtain a cell specific gene expression. This technique will be expanded in the proposed project to express genes that can be used to visualize the projections of these neurons (mCherry) or monitor their response to different stimuli (Ca2+ sensor) including hormones or neurotransmitters.

The aim of the project is to characterize the novel hypothalamic neurons in greater detail with regard to their neuroanatomy and responsiveness to understand their role in the body’s adaptation to cold.

References

Gay, L., M. R. Miller, P. B. Ventura, V. Devasthali, Z. Vue, H. L. Thompson, S. Temple, H. Zong, M. D. Cleary, K. Stankunas and C. Q. Doe (2013). "Mouse TU tagging: a chemical/genetic intersectional method for purifying cell typespecific nascent RNA." Genes Dev 27(1): 98-115.

Mittag, J., D. J. Lyons, J. Sallstrom, M. Vujovic, S. Dudazy-Gralla, A. Warner, K. Wallis, A. Alkemade, K. Nordstrom, H. Monyer, C. Broberger, A. Arner and B. Vennstrom (2013). "Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions." J Clin Invest 123(1): 509-516.

Warner, A., A. Rahman, P. Solsjö, K. Gottschling, B. Davis, B. Vennstrom, A. Arner and J. Mittag (2013). "Inappropriate heat dissipation ignites brown fat thermogenesis in mice with a mutant thyroid hormone receptor alpha 1." Proc Natl Acad Sci U S A.

Publications

Harder, L., Dudazy-Gralla, S., Müller-Fielitz, H., Leffler, J. H., Vennström, B., Heuer, H., and Mittag, J.: Maternal Thyroid Hormone is Required for Parvalbumin Neuron Development in the Anterior Hypothalamic Area. J Neuroendocrinol, vol. 30, e12573, 2018, doi: 10.1111/jne.12573. 
Podcast: https://onlinelibrary.wiley.com/doi/10.1111/jne.12573

Harder, L., Schanze, N., Sarsenbayeva, A., Kugel, F., Köhrle, J., Schomburg, L., Mittag, J., and Hoefig, C. S.: In vivo Effects of Repeated Thyronamine Administration in Male C57BL/6J Mice. Eur Thyroid J, vol. 7, pp3-12, 2017, DOI: 10.1159/000481856. 

Oelkrug, R., Herrmann, B., Geissler, C., Harder, L., Koch, C., Lehnert, H., Oster, H., Kirchner, H., and Mittag, J.: Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy. Mol Metab, vol. PII: S2212-8778(17), pp. 30367-8, 2017, doi.org/10.1016/j.molmet.2017.06.016

Renko, K., Hoefig, C. S., Dupuy, C., Harder, L., Schwiebert, C., Köhrle, J., and Schomburg, L.: A non-radioactive DEHAL assay for testing substrates, inhibitors and monitoring endogenous activity.Endocrinology, vol. 157(12), pp. 4516-4525, 2016, doi: 10.1210/en.2016-1549 

Hoefig, C. S., Harder, L., Oelkrug, R., Meusel, M., Vennström, B., Brabant, G., and Mittag, J.: Thermoregulatory and Cardiovascular Consequences of a Transient Thyrotoxicosis and Recovery in Male Mice. Endocrinology, vol. 157(7), pp. 2957-67, 2016, doi: 10.1210/en.2016-1095 

Hoefig, C. S., Jacobi, S. F., Warner, A., Harder, L., Schanze, N., Vennström, B., and Mittag, J.: 3-Iodothyroacetic acid lacks thermoregulatory and cardiovascular effects in vivo. Br J Pharmacol., vol. 172(13), pp. 3426-33, 2015, doi: 10.1111/bph.13131