Blast Exposure Dysregulates Nighttime Melatonin Synthesis and Signaling in the Pineal Gland: A Potential Mechanism of Blast-Induced Sleep Disruptions

Abstract

Blast-induced traumatic brain injury (bTBI) frequently results in sleep-wake disturbances. However, limited studies have investigated the molecular signaling mechanisms underlying these sleep disturbances, and potentially efficacious therapies are lacking. We investigated the levels of melatonin and genes involved in melatonin synthesis pathway in the pineal glands of Sprague Dawley rats exposed to single and tightly coupled repeated blasts during the night and daytime. Rats were exposed to single and tightly coupled repeated blasts using an advanced blast simulator. The plasma, cerebrospinal fluid (CSF), and pineal gland were collected at 6 h, 24 h, or 1 month postblast at two different time points: one during the day (1000 h) and one at night (2200 h). Differential expressions of genes involved in pineal melatonin synthesis were quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Plasma and CSF melatonin levels were assessed using a commercial melatonin ELISA kit. The plasma and CSF melatonin levels showed statistically significant decreases at 6 h and 24 h in the blast-exposed rats euthanized in the night (in dim light), with no significant alterations noted in rats euthanized in the morning (daylight) at all three-time points. Blast-exposed rats showed statistically significant decreases in Tph1, Aanat, Asmt, and Mtnr1b mRNA levels, along with increased Tph2 mRNA, in the pineal gland samples collected at night at 6 h and 24 h. No significant changes in the mRNA levels of these genes were noted at 1 month. These findings imply that the melatonin circadian rhythm is disrupted following blast exposure, which may be a factor in the sleep disturbances that blast victims frequently experience.

RatDEGdb: a knowledge base of differentially expressed genes in the rat as a model object in biomedical research

“…Put together, these findings reflect the fact that ASMT gene encoding the melatonin synthesis enzyme acetylserotonin O-methyltransferase is one of the key hormones involved in the regulation of molecular and genetic processes in all hu man body in general including aggression (Melke et al, 2008; Trent et al, 2013;Gaitanis et al, 2023;Kang et al, 2023), depression (Talarowska et al, 2014), ontogenesis (Li W. et al, 2012;Zhang Z. et al, 2018), wound healing (Govindarajulu et al, 2022;Yang et al, 2023), ageing (Liu X. et al, 2022) oncoprotector (Lv et al, 2019), anti-inflammatory and im munomediatory mechanisms (Li G. et al, 2021).…”

Effect of Circadian Rhythm Disturbance on the Human Musculoskeletal System and the Importance of Nutritional Strategies

“…In the pathway, light plays a role as a signal molecule that is detected by the retina in the presence or absence of light. The light alters the pineal gland secretion, and the eyes are closed involuntarily to avoid any excessive exposure to light [ 35 , 36 , 37 ]. These mechanisms are regulated by the circadian rhythm, thus explaining their importance in daily life.…”

“…First, the pathways are activated by the signals detected by the photosensitive retinal ganglion cells, followed by the retinohypothalamic tract (RHT) pathway, which is then connected to the SCN, which then releases the output instruction via the paraventricular nucleus (PVN) and superior cervical ganglia (SCG). Then, the output is delivered to the targeted endocrine gland, such as the pineal gland, for melatonin inhibition and secretion [ 35 ]. Reduced blood pressure, lower levels of melatonin secretion, and an increase in cortisol are the factors that cause the body to naturally feel awake in the early morning, as the body has optimal cardiovascular efficiency, compromised muscle strength, and increased brain performance.…”

Circadian therapy interventions for glymphatic dysfunction in concussions injuries: A narrative review

“… 46 Cerebral melatonin levels are significantly decreased after acute concussion in animal models. 47 In humans, several studies document a decrease in salivary melatonin levels in acutely concussed patients. 48 , 49 Hence, reduced melatonin levels, increased sleep disturbances, and glymphatic dysfunction are all convergent and interconnected phenomena in the acute phase of concussion.…”