Project ID NS-MH2024_48


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Life Course & Population Sciences, Department of Women & Children’s HealthWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Wolfson Centre for Age-Related DiseasesWebsite

The amygdala, a key upstream regulator of the hypothalamic GnRH pulse generator

(i) Scientific basis of project:
The amygdala, a key limbic brain structure commonly known for its role in higher-order emotional processing, is implicated in stress-induced suppression of gonadotrophin-releasing hormone (GnRH) pulse generator frequency, to cause infertility. Our pioneering discovery that kisspeptin signalling in the medial amygdala robustly regulates hypothalamic GnRH pulse generator frequency, provides new insight into how the amygdala controls reproduction. The medial amygdala comprises primarily GABAergic neurones with a predominantly (60%) inhibitory GABA output to the hypothalamus. The medial amygdala is also rich in the stress neuropeptide urocortin-3, which is activated by psychological stress.

(ii) Aims:
We hypothesise that the urocortin system regulates kisspeptin-GABAergic signalling intrinsic to the medial amygdala to mediate the effects of psychological stress on fertility.

(iii) Techniques and skills:
O’Byrne and Cox have worked together for many years and have a vast experience in complex in-vivo experimentation. This project will use the latest cutting-edge technologies of combined targeted optogenetic manipulations with in-vivo gradient-index (GRIN) lens microendoscopic systems to monitor in real time neurone calcium dynamics, a proxy for neuronal activity, of selective GCaMP-expressing neurones.

(iv) Objectives:
1. To establish the functional dynamic relationship between the kisspeptin and GABA neurocircuitry in the medial amygdala that underlie the upstream regulation of the hypothalamic GnRH pulse generator frequency using in-vivo optogenetics and deep-brain GCaMP6 GRIN lens microendoscopic calcium imaging.
2. To determine how the GABAergic projections from the medial amygdala modulate the frequency of the hypothalamic GnRH pulse generator.
3. To determine how stress activated urocortin-3 neurones regulate kisspeptin-GABA neurocircuitry in the medial amygdala to suppress GnRH pulse generator frequency.

Representative Publications

McIntyre C, Li XF, Ivanova D, Wang J, O’Byrne KT. Hypothalamic PVN CRH neurons signal through PVN GABA neurons to suppress GnRH pulse generator frequency in female mice. Endocrinology. 2023 May 29;164(6):bqad075. doi: 10.1210/endocr/bqad075.

Voliotis M, Li XF, De Burgh R, Lass G, Lightman SL, O’Byrne KT, Tsaneva-Atanasova K. Mathematical modelling elucidates core mechanisms underpinning GnRH pulse generation. J Neuroscience. 2019; pii: 0828-19. doi: 10.1523/JNEUROSCI.0828-19.2019.

McIntyre C, Li XF, de Burgh R, Ivanova D, Lass G, O’Byrne KT. GABA Signaling in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice. Endocrinology. 2022 Nov 14;164(1):bqac197. doi: 10.1210/endocr/bqac197.

M Ghamari-Langroudi, GJ Digby, JA Sebag, GL Millhauser, R Palomino, R Matthews, T Gillyard, IR Tough, HM Cox, JS Denton & RD Cone. G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 2015, 520:94-98 doi: 10.1038/nature14051.

Alamshah A, McGavigan AK, Spreckley E, Kinsey-Jones JS, Amin A, Tough IR, O’Hara HC, Moolla A, Banks K, France R, Hyberg G, Norton M, Cheong W, Lehmann A, Bloom SR, Cox HM, Murphy KG. L-arginine promotes gut hormone release and reduces food intake in rodents. Diabetes Obes Metab. 2016 May;18(5):508-18. doi: 10.1111/dom.12644.

Tough IR, Lund ML, Patel BA, Schwartz TW, Cox HM. Paracrine relationship between incretin hormones and endogenous 5-hydroxytryptamine in the small and large intestine. Neurogastroenterol Motil. 2023 Apr 3:e14589. doi: 10.1111/nmo.14589.