Biology subjects

O'Byrne, K. T.

Publications and source records attributed to O'Byrne, K. T..

4 recordsLinked to original sources

bioRxiv2025

Amygdala GABA Neurons: Gatekeepers of Stress and Reproduction

Stress can disrupt menstrual cycles, cause infertility, and lead to other reproductive disorders. The posterodorsal medial amygdala (MePD) processes stress signals and regulates the gonadotropin-releasing hormone (GnRH) pulse generator through GABAergic inhibitory projections to the hypothalamus. However, how stress is processed in the MePD - especially involving its dense GABA and Urocortin-3 (UCN3) neurons - remains poorly understood. In this study, we combine in vivo GRadient-INdex (GRIN) lens mini-endoscopic calcium imaging (to track neuronal activity), optogenetics, clustering analysis, and computational modeling to investigate the MePD circuitry. Our findings reveal two anti-correlated GABA subpopulations in the MePD that dictate responses to both UCN3 neuron stimulation and restraint stress. Our computational modeling suggests that mutual inhibition between these GABA groups drives the anti-correlated activity and predicts how these interactions shape downstream responses to stimulation of GABA and UCN3 neurons. We test these predictions using optogenetics and confirm that GABA neurons are critical for the transmission of UCN3 signals to regulate luteinizing hormone (LH) pulse frequency. Our study is the first to show how GABA neurons in the amygdala mediate stress effects on reproductive health, uncovering key neural mechanisms linking emotional and reproductive functions.

physiology↗

bioRxiv2024

Neuronal Network Dynamics in the Posterodorsal Amygdala: Shaping Reproductive Hormone Pulsatility

Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region which is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ in-silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections outputs on the GnRH pulse generators activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity, and offers insights into stress-related dysregulation.

neuroscience↗

bioRxiv2021

Modulation of pulsatile GnRH dynamics across the ovarian cycle: the role of excitability within the arcuate kisspeptin network

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

neuroscience↗

bioRxiv2018

A mathematical model of the hypothalamic network controlling the ultradian secretion of reproductive hormones.

Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons co-expressing kisspeptin, neurokoinin-B and dynorphin that drives the pulsatile release of GnRH. How this neural network generates and controls the appropriate ultradian frequency essential for gametogenesis and ovulation is unknown. Here, we present a mathematical model of the GnRH pulse generator with theoretical evidence and in vivo experimental data showing that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low frequency optogenetic stimulation of the neural construct. Further increases in basal activity markedly increase pulse frequency. Model predictions that such behaviors are concomitant of non-linear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our mathematical model sheds light on the long-elusive GnRH pulse generator offering new horizons for fertility regulation.

physiology↗