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Investigating Kiss1 neuron regulation of the mammalian reproductive axis using optogenetic and chemogenetic approaches (William Colledge, Susan Jones)

Supervisors: William Colledge, Susan Jones

Kisspeptin neuropeptides, encoded by the Kiss1 gene, are key regulators of the mammalian reproductive axis by potently stimulating GnRH release. A fundamental step in understanding how the reproductive axis is co-ordinated with other physiological processes is an accurate description of the neuronal circuitry communicating with Kiss1 neurons. We have used conditional viral tracing to define neuronal populations with synaptic inputs onto Kiss1 neurons. Several of these neuronal populations are probably physiologically relevant in controlling the reproductive axis. These include the suprachiasmatic nucleus, which communicates information about day length; the subfornical organ, which provides information about peripheral metabolic status; the amygdala, which responds to pheromone signals, the paraventricular nucleus which controls stress responses and POMC and NPY neurons in the ARC, which regulate feeding behaviour.

The student will investigate the functional significance of these inputs into Kiss1 neurons using optogenetic and chemogenetic methods. The student will learn:

1. Stereotaxic delivery of viral vectors to appropriate brain areas.

2. How to measure electrophysiological responses in Kiss1 neurons.

3. ELISA assays to measure LH release after CNO injection to show in vivo activation of Kiss1 neurons.

AAV vectors encoding light activated ChR2 or CNO-activated DREADD proteins will be delivered by stereotaxic injection into the relevant brain areas and electrophysiological responses from fluorescently labelled Kiss1 neurons measured after optogentic or chemogentic stimulation.

Manipulation of neuronal control of the reproductive axis using opto- or chemogenetic approaches will be explored as a potential mechanism of influencing fertility and breeding in the mouse model, for example by increasing or decreasing kisspeptin and  thereby GnRH release. The outcome of these experiments could have applications in human and animal fertility.

Relevant references

Seminara, S.B., Messager, S., Chatzidaki, E.E., Thresher, R.R., Acierno, J.S., Shagoury, J.K., Bo-Abbas, Y., Kuohung, W., Schwinof, K.M., Hendrick, A.G., Zahn, D., Dixon, J., Kaiser, U.B., Slaugenhaupt, S.A., Gusella, J.F., O’Rahilly, S., Carlton, M.B., Crowley, W.F., Aparicio, S.A. and Colledge, W.H. (2003). The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349:1614-1627.

Xavier d'Anglemont de Tassigny, Lisa A. Fagg, John P. C. Dixon, Kate Day, Harry G. Leitch, Alan G. Hendrick, Dirk Zahn, Isabelle Franceschini, Alain Caraty, Mark B. L. Carlton, Samuel A. J. R. Aparicio, and William H. Colledge. (2007). Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci 104: 10714-10719.

Gary Aston-Jones and Karl Deisseroth (2013), Recent advances in optogenetics and pharmacogenetics. Brain Res. 1511: 1–5.


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