Postnatal Development of the Circadian Rhythmicity of Human Pineal Melatonin Synthesis and Secretion (Systematic Review)

Abstract

Introduction: According to current knowledge, at birth, the pineal gland and melatonin receptors are already present and the suprachiasmatic nucleus is largely functional, and noradrenaline, the key pineal transmitter, can be detected in the early foetal period. It is still unclear why the pineal gland is not able to start its own pulsatile synthesis and secretion of melatonin in the first months of life, and as a result, infants during this time are dependent on an external supply of melatonin. Method: The causes and consequences of this physiological melatonin deficiency in human infancy are examined in a systematic review of the literature, in which 40 of 115 initially selected publications were evaluated in detail. The references of these studies were checked for relevant studies on this topic. References from previous reviews by the author were taken into account. Results: The development and differentiation of the pineal gland, the pinealocytes, as the site of melatonin synthesis, and the development and synaptic coupling of the associated predominantly noradrenergic neural pathways and vessels and the associated Lhx4 homebox only occurs during the first year of life. Discussion: The resulting physiological melatonin deficiency is associated with sleep disorders, infant colic, and increased crying in babies. Intervention studies indicate that this deficiency should be compensated for through breastfeeding, the administration of nonpooled donor milk, or through industrially produced chrononutrition made from nonpooled cow's milk with melatonin-poor day milk and melatonin-rich night milk.

Keywords: Lhx4-Homebox; chrononutrition; circadian rhythm; melatonin in infants; noradrenaline; pineal gland; pinealocytes.

Figure 4

Representation of the signal transduction chain for the activation of pulsatile pineal synthesis and secretion, with indication of the localisation of M1 and M2 melatonin receptors in the brain that are associated with sleep [204,205]. Light is converted into chemical impulses in the photosensitive ganglion cells of the retina, which stimulate the retinal formation of melanopsin. Melanopsin inhibits the synthesis of melatonin [206]. The central master clock SCN is activated via the retinohypothalamic tract. Via several sympathetic ganglia (paraventricular nucleus (PVN), upper thoracic medulla, cervical ganglion), melatonin synthesis in the pineal gland is inhibited by light or activated by darkness in the evening. The pineal gland secretes melatonin directly into the cerebrospinal fluid and via venous effluents into the jugular vein. Melatonin exerts its effects in particular via two receptor types (M1, M2), which stimulate the switch from wakefulness to sleep in the frontal pre-cortex (M1), after melatonin has induced the transition from wakefulness to NREM sleep via feedback mechanisms to the SCN (M1, M2). The thalamus, as the ‘gateway to consciousness’, is sent into NREM sleep via M2 receptors and is opened in this state for the transfer of verbal information from short-term memory to long-term memory in the hippocampus; the consolidation of memory content takes place to a large extent during undisturbed sleep. The transition from NREM to REM sleep is induced by M2 receptors in the ventrolateral periaqueductal grey matter. During REM sleep, REM muscle atonia is generated via several neural switching points, and motor information can now be stored (‘You learn to ride a bike in your sleep’). The basal forebrain is involved in these processes (M2). A highly simplified overview based on [79,204,207,208]. Slightly modified according to Paditz [209], with kind permission.

Figure 5

Expression of Lhx4 in the developing rat pineal gland. The arrow points to the pineal gland. Scale bar, 1 mm; E, embryonic day; P, postnatal day; ZT, zeitgeber time. Radiochemical in situ hybridisation for detection of Lhx4 mRNA in coronal sections of the brain from rats sacrificed at ZT6 (left) and ZT18 (middle) at the indicated developmental stages (one per row) ranging from E15 to P30. ZT18 sections were counterstained in cresyl violet for comparison (right). Reproduced from Hertz [198], with kind permission.

Figure 1

Flow chart with declaration of the selection procedure applied here. List of excluded items, see Supplement S1. Source of the flow chart: Page MJ, et al. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. This work is licensed under CC BY 4.0.

Figure 2

Melatonin concentrations in human breast milk with circadian rhythmicity in colostrum (daytime = blue) and in the first six months (daytime = grey) and at night in colostrum (orange) and in the first six months (yellow). Melatonin concentration in pg/mL. The data were taken from the review by Oliveira et al., 2024 and are presented graphically in aggregate form. The individual measured values for colostrum are taken from the studies by Qin (1), Aparici-Gonzalo (2), Pontes 2007 (3), Pontes 2006 (4), Honori-Franca (5), Silva (6), and Illnerova (7), as well as for mature milk from Kimata (1), Aparici-Gonzalo (2), Cohen Engler (3), Molad (4), and Silva (5) [20,37,38,39,142,143,144,145,147,178,179].

Figure 3

Analysis of relative optical density (O.D.) of inducible cAMP early repressor (ICER) hybridization signal in rat pineal gland (solid line) and superimposed pineal melatonin values (dashed line). ICER night-time values start to be significantly different from daytime values from P8 onward (P8: p < 0.05; P10, P15, P20, adult (Ad): p < 0.01). Night-time melatonin values start to be significantly different from daytime values at P8 (P8: p < 0.05; P15: p < 0.01) [189]. With kind permission.