Research Area: Cellular and Molecular Mechanisms of Neuromodulation
Website: https://www.cecad.uni-koeln.de/research/principal-investigators/prof-dr-peter-kloppenburg/ or https://www.zoologie.uni-koeln.de/kloppenburg.html
1. Research Background:
A significant part of the control system that regulates body weight and energy balance is formed by small neuronal networks located in the hypothalamus. These control circuits adjust food intake and energy expenditure according to the needs of the organism and the availability of fuel sources in the periphery of the body. Mismatch between energy intake and expenditure can cause metabolic disorders including obesity and type 2 diabetes mellitus, whose prevalence is increasing in western societies. To better understand and counteract obesity and associated metabolic disorders, increasing efforts are being made to define the control mechanisms that regulate body weight and energy homeostasis.
2. Research questions addresses by the group:
Our research focuses on neuromodulation and the question of how plasticity of the neurocircuits in control of energy homeostasis is regulated on the cellular and molecular level on short time scales and during the lifespan. In this context, we are especially interested in the biophysical mechanisms that determine neuronal excitability and synaptic plasticity. The aim of our studies is to understand how the modulation of intrinsic and synaptic properties of single neurons (or groups of neurons) regulate the function of complex neuronal systems and ultimately control the (feeding) behavior of an organism.
3. Possible projects:
Differential aminergic modulation of identified neurons in the paraventricular nucleus of the hypothalamus
The paraventricular nucleus of the hypothalamus (PVH) is an important autonomic control center, which integrates signals from neuroendocrine and autonomous pathways to regulate autonomic renal and cardiovascular functions, stress responses, and is crucial for controlling the energy balance (Ferguson et. Al. 2008). Lesioning the PVN causes hyperphagic obesity in rats (Leibowitz et al. 1981) and injection of the melanocortin-4 receptor agonist melanotan-2 into the PVN reduces food intake, while the functional antagonist agouti-related-protein (and neuropeptide Y) increases food intake (Cowley et al. 1999). Studies in rats, and more recently also in mice, revealed that the PVH is a complex hypothalamic nucleus that compromises many subdivisions with various neuron types, which can be differentiated by their morphological, immunocytochemical or physiological characteristics (Biag et al. 2012; Luther et al. 2002; Simmons and Swanson, 2009; Tasker and Dudek 1991).
In agreement with previous work in rats (Luther et al. 2002; Tasker and Dudek 1991) we have established cell type-specific electrophysiological parameters that allow the identification of three main neuron types in the PVH. In brief: Magnocellular neuroendocrine neurons show delayed action potential firing after hyperpolarization, parvocellular preautonomic neurons generate low threshold action potentials, and parvocellular neurosecretory neurons showed moderate spike frequency adaptation.
Currently, we combine electrophysiological characterization and peptide immunocytochemistry to achieve a more complete characterization of PVH neurons and thereby improving the definition of neuron (sub-)types in the PVH. Furthermore, since there are mice lines available that express Cre recombinase under the control of the respective peptide promoters, are establishing these mice lines to aid targeted electrophysiological recordings and FACS for cell type specific transcriptomics.
In addition to humoral signaling there is also modulation by synaptic input from other brain regions that can directly modify the activity of the hypothalamic circuits. One brain structure that has been associated with the modulation of hypothalamic microcircuits is the dopaminergic system. Previous work suggests that the PVH receives direct dopaminergic input (Ogundele et al. 2017; Liposits et al. 1989).
Here, we ask whether the catecholamine dopamine is a direct modulator of energy homeostasis-regulating neurons in the PVH. This question is of particular relevance, since the brain’s dopaminergic system integrates information about the state of the organism and, depending on that information, provides modulatory output in anticipation of behavioral action (Arias-Carrión et al. 2010).
The proposed experiments, will define in detail the biophysical and cellular mechanisms that mediate modulation of the different PVH neuron types by dopamine. We expect that these results will foster our understanding of how state dependent and metabolic signals are processed at the single-cell and circuit level in this prominent autonomic control center.
4. Applied Methods and model organisms:
State of the art electro- and optophysiological recordings in mouse models (Hess et al. 2013; Joucla et al., 2010, 2013; Klöckener et al., 2011; Könner et al., 2011; Paeger et al. 2017a,b; Steculorum et al. 2015, 2016).
5. Desirable skills and qualifications:
High interest in single cell physiology and membrane biophysics.
- Arias-Carrión, O., Stamelou, M., Murillo-Rodríguez, E., Menéndez-González, M., Pöppel, E. (2010) Dopa-minergic reward system: a short integrative review. Int Arch Med 3:24. doi: 10.1186/1755-7682-3-24.
- Biag, J., Huang, Y., Gou, L., Hintiryan H., Askarinam, A., Hahn, J.D., Toga, A.W., Dong, H.W., 2012. Cyto- and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6J male mouse: a study of immunostaining and multiple fluorescent tract tracing. J Comp Neurol 520(1), 6-33. doi: 10.1002/cne.22698.
- Cowley, M. A., Pronchuk, N., Fan, W., Dinulescu, D.M., Colmers, W.F., Cone, R.D, 1999. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24(1),155-63.
- Ferguson, A.V., Latchford, K.J., Samson, W.K. 2008. The paraventricular nucleus of the hypothalamus - a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets 12(6):717-27. doi: 10.1517/1472818.104.22.1687.
- Hess M.E., Hess S., Meyer K.D., Verhagen L.A., Koch L., Brönneke H.S., Dietrich M.O., Jordan S.D., Saletore Y., Elemento O., Belgardt B.F., Franz T., Horvath T.L., Rüther U., Jaffrey S.R., Kloppenburg P., Brüning J.C. (2013) The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 16, 1042-8.
- Joucla, S., Franconville, R., Pippow, A., Kloppenburg, P., Pouzat, C., 2013. Estimating background-subtracted fluorescence transients in calcium imaging experiments: a quantitative approach. Cell Calcium 54(2):71-85. doi: 10.1016/j.ceca.2013.04.005.
- Joucla, S., Pippow, A., Kloppenburg, P., Pouzat, C., 2010. Quantitative estimation of calcium dynamics from ratiometric measurements: a direct, nonratioing method. J Neurophysiol 103(2):1130-44. doi: 10.1152/jn.00414.2009.
- Klöckener T., Hess S., Belgardt B.F., Paeger L., Verhagen L.A., Husch A., Sohn J.-W., Hampel B., Dhillon H., Zigman J.M., Lowell B.B., Williams K.W., Elmquist J.K., Horvath T.L., Kloppenburg P., Brüning J.C. (2011) High-fat Feeding Promotes Obesity via Insulin Receptor/PI3k-Dependent Inhibition of SF-1 VMH Neurons. Nat Neurosci 14:911-918
- Könner A.C., Hess S., Tovar S., Mesaros A., Sánchez-Lasheras C., Evers N., Verhagen L.A.W., Brönneke H.S., Kleinridders A., Hampel B., Kloppenburg P., Brüning J.C. (2011) Role for Insulin Signaling in Catecholaminergic Neurons in Control of Energy Homeostasis. Cell Metab 13:720-728
- Leibowitz, S., 1978. Paraventricular nucleus - primary site mediating adrenergic-stimulation of feeding and drinking. Pharmacol Biochem Be 8, 163–175.
- Liposits, Z., Paull, W.K. (1989) Association of dopaminergic fibers with corticotropin releasing hormone (CRH)-synthesizing neurons in the paraventricular nucleus of the rat hypothalamus. Histochemistry 93:119–127.
- Luther, J., Daftary, S., Boudaba, C., Gould, G., Halmos, K., Tasker, J. (2002) Neurosecretory and non-neurosecretory parvocellular neurones of the hypothalamic paraventricular nucleus express distinct electrophysiological properties. J Neuroendocrinology 14, 929–961.
- Simmons, D.M., Swanson, L.W. (2009) Comparison of the spatial distribution of seven types of neuroendocrine neurons in the rat paraventricular nucleus: toward a global 3D model. J Comp Neurol 516(5), 423-41. doi: 10.1002/cne.22126.
- Paeger L., Pippow A., Hess S., Paehler M., Klein A.C., Husch A., Pouzat C., Brüning J.C., Kloppenburg P. (2017b) Energy imbalance alterd Ca2+ handling and excitability of POMC neurons. eLlife 6. pii: e25641. doi: 10.7554/eLife.25641.
- Paeger, L., Karakasilioti, I., Altmüller, J., Frommolt, P., Brüning, J.C., Kloppenburg, P. (2017a). Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenaline. eLife 6. pii: e25770. doi: 10.7554/eLife.25770.
- Steculorum, S.M., Ruud, J., Karakasilioti, I., Backes, H., Engström Ruud, L., Timper, K., Hess, M.E., Tsaousidou, E., Mauer, J., Vogt, M.C., Paeger, L., Bremser, S., Klein, A.C., Morgan, D.A., Frommolt, P., Brinkkötter, P.T., Hammerschmidt, P., Benzing, T., Rahmouni, K., Wunderlich, F.T., Kloppenburg, P., Brüning J.C. (2016) AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue. Cell 165, 125–138.
- Steculorum, S.M., Paeger, L., Bremser, S., Evers, N., Hinze, Y., Idzko, M., Kloppenburg, P., Brüning, J.C. (2015) Hypothalamic UDP Increases in Obesity and Promotes Feeding via P2Y6-Dependent Activation of AgRP Neurons. Cell 162, 1404–1417.
- Tasker, J.G., Dudek, F.E. (1991) Electrophysiological properties of neurones in the region of the paraventricular nucleus in slices of rat hypothalamus. J Physiol 434, 271-93.
- Ogundele, O.M., Lee, C.C., Francis, J. (2017) Thalamic dopaminergic neurons projects to the paraventricular nucleus-rostral ventrolateral medulla/C1 neural circuit. Anat Rec (Hoboken) 300(7):1307-1314. doi: 10.1002/ar.23528.