On the innervation of the human fetal pineal gland

Descriptions of the pineal gland date back to antiquity, but its functions in humans are still poorly understood. In both diurnal and nocturnal vertebrates, its main product, the hormone melatonin, is synthesized and released in rhythmic fashion, during the dark portion of the day–night cycle. Melatonin production is controlled by an endogenous circadian timing system and is also suppressed by light. In lower vertebrates, the pineal gland is photosensitive, and is the site of a self-sustaining circadian clock. In mammals, including humans, the gland has lost direct photosensitivity, but responds to light via a multisynaptic pathway that includes a subset of retinal ganglion cells containing the newly discovered photopigment, melanopsin. The mammalian pineal also shows circadian oscillations, but these damp out within a few days in the absence of input from the primary circadian pacemaker in the suprachiasmatic nuclei (SCN). The duration of the nocturnal melatonin secretory episode increases with nighttime duration, thereby providing an internal calendar that regulates seasonal cycles in reproduction and other functions in photoperiodic species. Although humans are not considered photoperiodic, the occurrence of seasonal affective disorder (SAD) and its successful treatment with light suggest that they have retained some photoperiodic responsiveness. In humans, exogenous melatonin has a soporific effect, but only when administered during the day or early evening, when endogenous levels are low. Some types of primary insomnia have been attributed to diminished melatonin production, particularly in the elderly, but evidence of a causal link is still inconclusive. Melatonin administration also has mild hypothermic and hypotensive effects. A role for the pineal in human reproduction was initially hypothesized on the basis of clinical observations on the effects of pineal tumors on sexual development. More recent data showing an association between endogenous melatonin levels and the onset of puberty, as well as observations of elevated melatonin levels in both men and women with hypogonadism and/or infertility are consistent with such a hypothesis, but a regulatory role of melatonin has yet to be established conclusively. A rapidly expanding literature attests to the involvement of melatonin in immune function, with high levels promoting and low levels suppressing a number of immune system parameters. The detection of melatonin receptors in various lymphoid organs and in lymphocytes suggests multiple mechanisms of action. Melatonin has been shown to be a powerful antioxidant, and has oncostatic properties as well, both direct and indirect, the latter mediated by its effects on reproductive hormones. Finally, there are reports of abnormal daily melatonin profiles in a number of psychiatric and neurological disorders, but the significance of such abnormalities is far from clear.

The human pineal gland and it anterior attachments were investigated grossly in the fresh state and microscopically in the sagittal plane and 25° tangential to the coronal plane of sectioning. Fiber stains of tissue samples from the midline commissural attachments of the pineal gland indicated the presence of both myelinated and non-myelinated fibers connecting the pineal gland and the pre-tectal area. A previously unreported paired fiber tract was observed associated with the anterior inferio-ventro-lateral pineal gland. This paired tract appears to be physically separate and distinct from the posterior commissure. These tracts form a structural component of the wall of the pineal recess. The fibers coursing in this paired tract are myelinated, and are of two different sizes (1–3 μm diameter and 5–8 μm diameter) as determined by electron microscopy. Fibers from these tracts invade the pineal gland, and can be traced a short distance into the lateral pre-tectal area. The precise point of origin and termination for this paired tract is unknown.

This chapter discusses the literature published since 1965, the main problems of the innervation of the vertebrate pineal organ, and the nomenclature of the nervous connections of the epiphysis cerebri and of the accessory pineal organs with the epithalamus in submammalian vertebrates. The chapter presents the current state of knowledge about the innervation, with emphasis on the studies of the 13 years. In lower vertebrates, pineal nerve cells are distributed all over the pineal parenchyma sending their axons toward the brain. In adult mammals, these pineal nerve cells and, consequently, their central projections are absent; an efferent innervation is well developed. The difference in the nervous organization of the pineal in lower vertebrates and mammals raised different questions; therefore this chapter separately describes the results on the innervation of the pineal organ obtained in mammals and lower vertebrates.

The presence of a hitherto undiscovered nerve located in the subarachnoidal space just caudal to the pineal organ, connecting this organ and the posterior commissure, was demonstrated by light and electron microscopy in a series of 18 human fetuses. This nerve is believed to be ontogenetically equivalent to the pineal nerve observed in the anuran amphibians. The nerve was present in fetuses with a CRL of 56 mm and had not disappeared in fetuses with a CRL of 169 mm. The gestational age at which this human fetal nerve degenerates could not be determined in this study.

In addition to the bilateral conarian nerve a habenulopineal tract and an intrapineal ganglion were observed. The presence of the classical Pastori and Marburg ganglia was confirmed, and a new ganglion lying rostral to the pineal organ was seen too.

Average bipolar and monopolar evoked responses following photic, acoustic, olfactory bulb, amygdaloid complex, caudate nucleus, ventromedial hypothalamus (VMH), or pineal body stimulation were recorded simultaneously from pineal body and VMH of freely behaving rats. Permanent semimicroelectrodes (60 μm in diameter) were implanted 6 to 8 days before experiments were begun. Short-latency responses were observed in the pineal following amygdala, VMH, olfactory, acoustic, and photic stimulation, and in VMH following amygdala, olfactory, pineal, photic, and acoustic stimulation. Response latencies from VMH to pineal were shorter than from pineal to VMH. The data support the concept of neuronal connections between the pineal body and neural structure in the brain, at least in rats.