Biology subjects

Walker, J. J.

Publications and source records attributed to Walker, J. J..

3 recordsLinked to original sources

bioRxiv2021

The dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after major surgery

Major surgery and critical illness produce a potentially life threatening systemic inflammatory response. The hypothalamic-pituitary-adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterise the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulses and multiple-pulses dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost - suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.

physiology↗

bioRxiv2021

The sodium leak channel NALCN encodes the major background sodium ion conductance in murine anterior pituitary cells

The pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shapes pituitary cell excitability by regulating ion channel properties of these cells. In addition, endocrine anterior pituitary cells fire action potentials spontaneously to regulate intracellular calcium ([Ca2+]i) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells have to critically regulate their resting membrane potential (RMP) close to firing threshold, but the molecular identity of the ionic mechanisms involved remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, acts to regulate excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na+ leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic interruption of NALCN channel activity drastically hyperpolarised the cells, suppressing firing and ([Ca2+]i) oscillations. Remarkably, we uncover that NALCN conductance formed a very small fraction of the total cell conductance, but yet had a profound impact on pituitary cell excitability. Our results also provide a possible mechanism through which hypothalamic and hormone feedback signals can powerfully affect pituitary activity to influence hormonal function.

physiology↗

bioRxiv2020

Dynamic hormone control of stress and fertility

Neuroendocrine axes display a remarkable diversity of dynamic signalling processes relaying information between the brain, endocrine glands, and peripheral target tissues. These dynamic processes include oscillations, elastic responses to perturbations, and plastic long term changes observed from the cellular to the systems level. While small transient dynamic changes can be considered physiological, larger and longer disruptions are common in pathological scenarios involving more than one neuroendocrine axes, suggesting that a robust control of hormone dynamics would require the coordination of multiple neuroendocrine clocks. The idea of apparently different axes being in fact exquisitely intertwined through neuroendocrine signals can be investigated in the regulation of stress and fertility. The stress response and the reproductive cycle are controlled by the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Hypothalamic-Pituitary-Gonadal (HPG) axis, respectively. Despite the evidence surrounding the effects of stress on fertility, as well as of the reproductive cycle on stress hormone dynamics, there is a limited understanding on how perturbations in one neuroendocrine axis propagate to the other. We hypothesize that the links between stress and fertility can be better understood by considering the HPA and HPG axes as coupled systems. In this manuscript, we investigate neuroendocrine rhythms associated to the stress response and reproduction by mathematically modelling the HPA and HPG axes as a network of interlocked oscillators. We postulate a network architecture based on physiological data and use the model to predict responses to stress perturbations under different hormonal contexts: normal physiological, gonadectomy, hormone replacement with estradiol or corticosterone (CORT), and high excess CORT (hiCORT) similar to hypercortisolism in humans. We validate our model predictions against experiments in rodents, and show how the dynamic responses of these endocrine axes are consistent with our postulated network architecture. Importantly, our model also predicts the conditions that ensure robustness of fertility to stress perturbations, and how chronodisruptions in glucocorticoid hormones can affect the reproductive axis ability to withstand stress. This insight is key to understand how chronodisruption leads to disease, and to design interventions to restore normal rhythmicity and health.

systems biology↗