Biology subjects

Lightman, S. L.

Publications and source records attributed to Lightman, S. L..

7 recordsLinked to original sources

bioRxiv2025

Perirhinal cortex structure and function is dysregulated by corticosteroid treatment

Glucocorticoids play a crucial role in the stress response and in the regulation of circadian function, as well as cognitive, cardiovascular, metabolic and immunological processes. While synthetic glucocorticoids (sGC) are widely used in treating inflammatory disorders, their impact on cognitive functions, which include memory deficits and dysregulation of mood, remains less understood. Here, we demonstrate that chronic treatment with the sGC methylprednisolone (MPL) dysregulates the synaptic proteome and impairs cognitive function in the perirhinal cortex, a region critical for recognition memory and visual perception. Further, we show that synaptic structure and plasticity are altered by MPL treatment, highlighting the mechanisms through which sGCs disrupt mnemonic processing. These results may have broad implications for understanding the cognitive side effects of widely used sGC treatments.

neuroscience↗

bioRxiv2024

Characterisation of behaviours relevant to apathy syndrome in the aged male rat

Apathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy. Using the effort for reward and progressive ratio tasks we found that aged rats (21-27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task. While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.

animal behavior and cognition↗

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↗

bioRxiv2022

Circadian regulation of hippocampal function is disrupted with chronic corticosteroid treatment

Neuropsychiatric disorders such as major depression and schizophrenia are highly prevalent and contribute substantially to disease burden worldwide. Despite this, progress understanding the pathophysiology has remained largely elusive, yet these disorders often exhibit a loss of regulation of biological rhythms, such as sleep/wake cycles and hormonal rhythms. Cushings disease, a condition characterized by chronic corticosteroid (cortisol) hypersecretion is associated with psychiatric and neurocognitive disorders and disruption to the circadian release of cortisol can result in depression and neurocognitive impairment. In rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity regulation via an intra-hippocampal circadian transcriptional clock. During the early active period, when corticosteroid availability is high, CA1 region excitatory and inhibitory post-synaptic currents were augmented along with long-term potentiation. In contrast, chronic corticosteroid exposure disturbed hippocampal function. The hippocampal transcriptome, as well as circadian regulation of synaptic plasticity were ablated, resulting in memory loss during hippocampal-dependent behavior. These findings identify how exposure to elevated levels of corticosteroid, that is often seen in neuropsychiatric illness, results in adverse critical hippocampal function. These data provide novel insights into the molecular mechanisms of neurocognitive disorders and provides evidence for corticosteroid-mediated intervention in disabling mental illnesses.

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↗

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↗

bioRxiv2020

Evidence for an apathy phenotype in aged mice

Apathy is widely reported in patients with neurological disorders or post viral infection but is also seen in otherwise-healthy aged individuals. This study investigated whether aged mice express behavioural and physiological changes indicative of an apathy phenotype. Using measures of motivation to work for reward, we found deficits in the progressive ratio task related to rate of responding. In an effort for reward task, aged mice were less willing to exert effort for high value reward. Aged mice exhibited reduced reward sensitivity and expressed lower measures of anxiety in the novelty supressed feeding test. In a test of cognition (novel object recognition) aged mice showed no impairments but activity was lower in a measure of exploration in a novel environment. Aged mice also showed an attenuated response to restraint stress with lower corticosterone and reduced paraventricular nucleus c-fos activation. Together, these data suggest aged mice show reduced goal-directed behaviour and reduced reward sensitivity and stress reactivity, reflective of emotional blunting and may be a suitable model for pre-clinical apathy research.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsBLAbasolateral amygdalaCeAcentral amygdalaCORTcorticosteroneEBDMeffort-based decision makingEfReffort for rewardESElectrosprayHLPChigh performance liquid chromatographyMSmass spectrometryNORTnovel object recognition testNSFTnovelty supressed feeding testPRprogressive ratioPVNparaventricular nucleus of the hypothalamusSPTsucrose preference testView Full Text

animal behavior and cognition↗