Our work aims to build a strong understanding of the fundamental mechanisms of neuropeptide release and the underlying effects of peptides on neuronal networks and behaviours using in vivo and in vitro approaches.
Trustee of the Physiological Society
Trustee and treasurer of the British Society for Neuroendocrinology
The hypothalamus controls the secretion of all pituitary hormones and many homeostatic control systems; it controls appetite, thirst, body composition, metabolism, all aspects of reproduction, and physiological responses to stress. These neurones are mediators of many specific behaviours, including feeding, sexual and aggressive behaviours, social interaction, maternal care and bonding.
The brain uses more than 100 different peptides as chemical signals to communicate information, and these have a role in information processing that is quite unlike that of conventional neurotransmitters. Neuropeptides are released from all parts of a neuron, including the axon, soma and, especially, the dendrites, and so are not restricted spatially by synaptic wiring.
We are interested in understanding the basic mechanisms by which peptides affect the functional properties of neuronal networks, and exactly how they can have apparently specific behavioural effects. Of these, the vasopressin and oxytocin neurons have proved to be good model systems for revealing important aspects of many neuronal functions, including neuropeptide release, leading to the understanding of the importance of peptide release from neuronal dendrites.
The mechanisms for dendritic neuropeptide release can be very different from axon terminal release, and for vasopressin and oxytocin, differentially regulated release allows peptide effects in the body to be independent from peptide effects in the brain.
We are currently studying novel populations of vasopressin cells in the olfactory bulb and the retina. In the olfactory system, vasopressin is involved in social recognition and vasopressin signaling in this system underlies the ability of these neurons to filter out social odour cues. We recently found that the retina also contains many vasopressin-expressing cells, and that, strikingly, these communicate mainly with the suprachiasmatic nucleus, the body’s biological clock, regulating circadian rhythms.
Our studies address contemporary questions in neuroscience using whole animal physiological approaches including in vivo electrophysiology, microdialysis and behavioural analysis. The functions of the hypothalamus have been tightly conserved through mammalian evolution, making findings from rodents translatable to humans. The diversity of neuropeptides and the even greater diversity of receptors expressed at specific locations in the brain open many possibilities for precise molecular targeting of therapeutic interventions.
A) Coronal section through the rat hypothalamus at the level of the supraoptic (SON) and paraventricular nuclei (PVN); vasopressin cells are immunostained with fluorescent green and oxytocin cells with fluorescent red. B) Magnification of the SON. C) Large dense-cored vesicles in a section of a SON dendrite and D) an ‘omega’ fusion profile at the plasma membrane (arrow) showing an exocytotic event (arrow).
A) Coronal section through the rat olfactory bulb. Highlighted square shows glomerular region of the bulb. B) Confocal image shows a subpopulation of tufted cells in this region expressing the neuropeptide vasopressin (shown in green). Each glomerulus is surrounded by a heterogeneous population of other cells (their nuclei shown in blue), including periglomerular calretinin expressing cells (labeled in red).
Tsuji T, Tsuji C, Ludwig M, Leng G. The rat suprachiasmatic nucleus: the master clock ticks at 30Hz. J Physiol 2016;; 594(13): 3620-3650.
Pineda R, Plaisier F. Millar RP, Ludwig M. Amygdala kisspeptin neurons: putative mediators of olfactory control of the gonadotropic axis. Neuroendocrinology 2016 (Epub ahead of print)
Pineda R, Sabatier N, Ludwig M, Millar RP, Leng G. A direct neurokinin B projection from the arcuate nucleus regulates magnocellular vasopressin cells of the supraoptic nucleus. J Neuroendocrinol 2016;; 28(4): DOI:10.1111/jne.12342.
Yau JLW, Noble J, Kenyon CJ, Ludwig M, Seckl JR. Diurnal and stress-induced intrahippocampal corticosterone rise attenuated in 11β-HSD1 deficient mice: a microdialysis study in young and aged mice. Eur J Neurosci 2015;; 41(6): 787-792.
Yau JLW, Wheelan N, Noble J, Walker BR, Webster SP, Kenyon CJ, Ludwig M, Seckl JR. Intrahippocampal glucocorticoids generated by 11β-HSD1 affect memory in aged mice. Neurobiol Aging 2015;; 36(1): 334-343.
Leng G, Hashimoto H, Tsuji C, Sabatier N, Ludwig M. Discharge pattering of rat olfactory bulb mitral cells in vivo. Physiol Reports 2014;; 2(5): e12021.
Tobin VA, Arechaga G, Brunton PJ, Russell JA, Leng G, Ludwig M, Douglas AJ. Oxytocinase in the female rat hypothalamus: a novel mechanism controlling oxytocin neurons during lactation. J Neuroendocrinol 2014;; 26(4):205-216.
Son SJ, Filosa JA,Potapenko E, Biancardi VC, Zheng H, Patel KP, Tobin VA, Ludwig M, Stern JE.Dendritic peptide release mediates inter-population crosstalk between neurosecretory and preautonomic networks. Neuron 2013; 78(6): 1036-1049.
Tobin VA, Hirofumi H, Wacker DW, Takayanagi Y, Langnaese K, Caquineau C, Noack J, Landgraf R, Onaka T, Leng G, Meddle SL, Engelmann M, Ludwig M. An intrinsic vasopressin system in the olfactory bulb is involved in social recognition. Nature 2010; 464(7287): 413-417.
Leng G, Ludwig M. Neurotransmitters and peptides: whispered secrets and public announcements. J Physiol 2008; 586(23): 5625-5632.
Ludwig M, Leng G. Dendritic neuropeptide release and peptide dependent behaviours. Nat Rev Neurosci 2006; 7(2): 126-136.
Ludwig M, Pittman QJ. Talking back: dendritic neurotransmitter release. Trends Neurosci 2003; 26(5): 255-261.
Ludwig M, Sabatier N, Bull PM, Landgraf R, Dayanithi G, Leng G. Intracellular calcium stores regulate activity-dependent release from dendrites. Nature 2002; 418(6893): 85-89.
“Model Animals in neuroendocrinology: From worm to mouse to man”. Masterclass in Neuroendocrinology Series (2017), Eds: Ludwig M & Levkowitz G
“Oxytocin and vasopressin: from molecules to function”. Special Edition of Experimental Physiology- (2000) Eds: Douglas AJ, Leng G, Ludwig M & Russell JA. 85S. Proceedings of WCNH conference.
“Dendritic neurotransmitter release”. Ed: Ludwig, M, Springer, New York, 2005.
Journal of Neuroendocrinology Special Issue, Perinatal Physiology: from Uterus to Brain. Guest Editors M Ludwig, AJ Douglas. Vol. 20(4), 2008.