Biology subjects

Walker, J. J.

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

7 recordsLinked to original sources

bioRxiv2026

Differential control of corticotroph Ca2+ signalling by corticotrophin-releasing hormone and arginine vasopressin

Corticotroph cells convert hypothalamic inputs into adrenocorticotrophic hormone secretion via intracellular calcium (Ca2+) signalling, but how they integrate corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) across physiological concentration ranges remains unclear. Here, we quantified intracellular Ca2+ responses in isolated rat corticotrophs to CRH and AVP, applied alone and in combination, to characterise response magnitude, temporal dynamics, and cell recruitment. Both secretagogues increased Ca2+ signalling in a concentration-dependent manner, but with distinct effects: AVP generally evoked larger responses, faster response onset, and greater cell recruitment than CRH when applied alone. Under co-stimulation, increasing CRH concentration increased the proportion of cells classified as synergistic without altering positive synergy values, suggesting CRH-dependent control of interaction likelihood rather than interaction strength. Marked cell-to-cell heterogeneity was observed across all conditions, consistent with corticotroph subpopulations differing in activation thresholds. Together, these findings show that AVP drives broad corticotroph recruitment, whereas CRH modulates how corticotrophs integrate convergent inputs, defining complementary roles in shaping pituitary output.

neuroscience↗

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↗

bioRxiv2023

State-dependent alteration of respiration in a rat model of Parkinson disease

Parkinson disease (PD) is the second most frequent neurodegenerative disorder. Besides major deficits in motor coordination, patients may also display sensory and cognitive impairments, which are often overlooked despite being inherently part of the PD symptomatology. Amongst those symptoms, respiration, a key mechanism involved in the regulation of multiple physiological and neuronal processes, appears to be altered. Importantly, breathing patterns are highly correlated with the animals behavioral states, and although respiration has been investigated in different models of PD, no study has yet taken into consideration the potential impact of behavioral state on respiration deficits in these models. To explore this variable, we first characterized the respiratory parameters in a neurotoxin-induced rat model of PD (6-OHDA) across different vigilance states: sleep, quiet waking and exploration. We noted a significantly higher respiratory frequency in 6-OHDA rats during quiet waking compared to Sham rats. A higher respiratory amplitude was also observed in 6-OHDA rats during both quiet waking and exploration. No effect of the treatment was noted during sleep. Given the relation between respiration and olfaction and the presence of olfactory deficits in PD patients, we then investigated the odor-evoked sniffing response in PD rats, using an odor habituation/cross-habituation paradigm. No substantial differences were observed in olfactory abilities between the two groups, as assessed through sniffing frequency. These results corroborate the hypothesis that respiratory impairments in 6-OHDA rats are vigilance-dependent. Our results also shed light on the importance of considering the behavioral state as an impacting factor when analyzing respiration. HighlightsO_LISpecific respiratory patterns associated to different vigilance states C_LIO_LISpecific alteration of respiration during quiet waking in a rodent model of PD C_LIO_LIPreserved olfactory abilities as assessed through sniffing in a rodent model of PD C_LI

neuroscience↗

bioRxiv2022

Circadian distribution of epileptiform discharges in epilepsy: candidate mechanisms of variability

Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy - so-called interictal epileptiform activity - with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy. Author summary65 million people have epilepsy worldwide. Many of these people report specific triggers that make their seizures (the primary symptom of epilepsy) more likely. Here, we use a mathematical model to understand the relationship between possible triggers and rhythms in epileptiform activity observed across the day. The mathematical model describes the activity of connected brain regions, and how the excitability of these regions can change in response to different stimuli. Based on data collected from people with idiopathic generalized epilepsy, we identify transitions between sleep stages and variation in concentration of the stress-hormone cortisol as candidate factors that influence how likely it is for epileptiform activity to occur. By including those factors into the model, we show they can explain most of the daily variability. More broadly, our approach provides a framework for better understanding what factors drive the occurrence of epileptiform activity and offers the potential to suggest experiments that can validate model predictions.

neuroscience↗

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↗