(490a) Mathematical Modeling of Light-Mediated Cortisol Secretion and Evaluation of Downstream Effects On Cytokine Production

Circadian rhythmicity in mammals is regulated by a light sensitive central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. Multisynaptic neural pathways from the SCN communicate photic information to other brain regions such as the paraventricular nucleus of hypothalamus with its ultimate release of corticotrophin releasing hormone (CRH) (3). In addition to the SCN and the circadian clocks residing in brain region (central clocks), most peripheral tissues express circadian rhythmicity driven in cellular level by autoregulatory feedback loops of clock genes and proteins (peripheral clocks). Cortisol is an important entrainer of peripheral clocks since its production and secretion is regulated by the hypothalamic-pituitary-adrenal (HPA) axis through the release of CRH from the hypothalamus and adrenocorticotrophin hormone (ACTH) from the anterior pituitary gland (11) and therefore is assumed to retain the photic information. Cortisol, apart from entraining peripheral oscillators, feeds back to hypothalamus and anterior pituitary inhibiting the secretion of CRH and ACTH forming in such a way a negative feedback that leads to cortisol oscillating behavior (9). It turns out that maintaining synchrony between the environmental light cycles, centrally driven hormones, and peripheral oscillators, is important for normal physiological function since its loss, demonstrated by a loss of phase coherence between physiological parameters (i.e. cortisol), is correlated with several severe pathologies (6, 8). Interestingly, there are several works showing a direct link between loss of light entrainment and deteriorating inflammatory responses both at the systemic level (i.e. fever, anorexia) as well as at molecular level (i.e. secretion of pro-inflammatory cytokines) (2).

In this work, we discuss the development of a mathematical model which aims to evaluate the dynamic relations between light entrainment of the HPA axis and its downstream effects on peripheral clocks. In particular, we aim to investigate the changes of cortisol circadian secretion as a result of altered photoperiods as well as different light stimuli throughout the day cycle, that ultimately lead to different circadian characteristics of inflammatory mediators (pro-inflammatory cytokine) secreted by peripheral cells.

To study the effects of photoperiod on cortisol secretion and ultimately on inflammatory markers, we propose a unified model that incorporates two compartments; a central oscillator simulating the cortisol circadian production from HPA axis, and a peripheral oscillator simulating clock gene regulation of pro- and anti-inflammatory cytokine circadian secretion. Centrally, oscillations are maintained by the negative feedback between cortisol and CRH/ACTH hormones (10), and peripherally by the negative feedback of PER and CRY clock proteins on the translocation of CLOCK/BMAL heterocomplex to the nucleus of peripheral immune cells (1). In accordance with previous mathematical models (4), we represent light entrainment of CRH compartment by including an additive term in CRH equation, that represents the neural mediated regulation of the paraventricular nucleus of the hypothalamus. Entrainment at the central level, results in a phase shift of cortisol secretion in order to be orchestrated with light cycles, that further lead to a phase change of peripheral clocks since cortisol entrains clock genes by binding to a glucocorticoid responsive element (GRE) at the promoter region of Per1 and Per2 genes (7, 12).

Model predictions demonstrate that altered light periods, throughout a 24hr light/dark cycle, induce altered phases both in the central compartment as well as in peripheral clocks. Ultimately, these changes lead to modified homeostatic secretion of pro-inflammatory cytokines thus impacting the immune response of the host. Upon different light schedules, the organism seems to be exposed to different levels of inflammatory mediators in accordance with what has been observed experimentally in rodent experiments (2).

Our model highlights the implications of linking light mediated cortisol secretion and peripheral circadian regulation of inflammatory cytokines. Our aim is to provide further understanding of the chronobiological effects of loss of environmental entrainment ultimately leading in many circumstances to deteriorating clinical outcomes (5).

 References:

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