The endocrine gland responsible for the bodys circadian rhythm is the

Photoperiod and Melatonin Synthesis

The mammalian pineal gland is unique in that its biosynthetic activity is controlled by an environmental variable, namely, the prevailing photoperiod. Pineal melatonin production occurs exclusively during the dark phase of the daily photoperiodic cycle. In modern societies, daily periods of environmental light and darkness have been markedly subverted by the introduction of artificial light sources. If of sufficient intensity and proper wavelength, high nighttime melatonin levels are quickly suppressed by perception of artificial light by the eyes at night. Likewise, during transmeridian travel, the normal 24 h circadian melatonin rhythm is disturbed due to changes in the light/dark cycle.

The SCN are a critical relay in the neural connections between the eyes and the pineal gland. A variety of clock genes in the SCN ensure that these neurons are inherently active during the dark portion of every 24 h period. The active/inactive period of the SCN neurons has a duration of approximately 25 h; thus, it is not normally in synchrony with the prevailing 24 h light/dark cycle. The natural light/dark cycle acting via the retina entrains the circadian SCN rhythm to precisely 24 h.

The ability of light to regulate melatonin synthesis is readily apparent when individuals are exposed to artificial light at night; this exposure is followed by a rapid drop in circulating melatonin levels. The influence of light on the pineal gland is also seen in individuals living at the extremes of latitude. During the winter months, the daily period of light can be very short, in which case the pineal produces more melatonin for a longer duration than during the summer months when day lengths are exceptionally long. The duration of elevated melatonin production is typically proportional to the duration of dark exposure. The circadian melatonin cycle with high levels at night and low values during the day may be disrupted in some individuals, e.g., in blind individuals incapable of light perception and in Smith-Magenis syndrome, where the melatonin cycle free-runs.

Abstract

The pineal gland is a small neuroendocrine organ whose main and most conserved function is the nighttime secretion of melatonin. In lower vertebrates, the pineal gland is directly photosensitive. In contrast, in higher vertebrates, the direct photosensitivity of the pineal gland had been lost. Rather, the action of this gland as a relay between environmental light conditions and body functions involves reception of light information by the retina. In parallel to this sensory regression, the pineal gland (and its accessory organs) appears to have lost several functions in relation to light and temperature, which are important in lower vertebrate species. In humans, the functions of the pineal gland overlap with the functions of melatonin. They are extremely widespread and include general effects both on cell protection and on more precise functions, such as sleep and immunity. Recently, the role of melatonin has received a considerable amount of attention due to increased cancer risk in shift workers and the discovery that patients suffering from neurodegenerative diseases, autism, or depression exhibit abnormal melatonin rhythms.

IV.C The Pineal Gland

The PG, common to all mammalian species, is a relatively simple circumventricular organ with respect to its histological organization. It is routinely found at the dorsal–caudal region of the third cerebral ventricle just above the posterior commissure and medial to both habenular nuclei. The PG possesses essentially one predominant cell type, the so-called pinealocyte. The basic function of the normal intact, PG is antigonadotrophic and it actively synthesizes and releases the indole, melatonin. The neural regulation of the normal intact PG has been well investigated. Primary control of the PG is exerted by the prevailing light–dark environmental photoperiod acting through the suprachiasmatic nuclei (SCN). Environmental information perceived by the eyes is transferred to the PG over a complex series of neuronal pathways, which include the SCN and the PVN of the hypothalamus, pregangionic sympathetic neurons in the upper thoracic spinal cord, and postgangionic sympathetic neurons in the superior sympathetic ganglion. Direct innervation of the PG is from the superior cervical sympathetic ganglion. Production of the pineal hormone melatonin is cyclic, with high levels of synthesis occuring at night (dark environment) and low levels occuring during the day (light environment). This cyclic synthesis is controlled by the neural pathways mentioned previously coupled with direct retinohypothalamic pathways. The synthesis of melatonin at night is a consequence of norepinephrine (NE) released from postganglionic sympathetic nerve endings that terminate in the vicinity of the pinealocyte processes. The PG possesses a pineal recess, which is continuous with the lumen of the third cerebral ventricle. This recess is lined by ependymal cells and occasional small axonal varicosities can be seen on their surfaces. These varicosities have been interpreted to be monoaminergic.

The pineal gland was identified as a distinct structural component of the vertebrate brain for several centuries prior to its description in the human by Galen of Pergamon (c. 130–200). It is now understood that the main function of the pineal is to receive information about the current state of the light–dark cycle from the environment and convey this information through the secretion of the hormone melatonin to the internal physiological systems of the body. Relative to other endocrine and neuroendocrine systems, the pineal gland has undergone a great deal of change during its evolutionary development. In cold-blooded vertebrates, the cells of the pineal gland include photoreceptors that contact neurons to communicate with other organs in the body. The avian pineal gland is also a directly photosensory organ and secretes melatonin in response to this signal. In mammals, pinealocytes producing melatonin have replaced photoreceptors and the gland receives its information about light and darkness from the retina through multiple neuronal connections. Melatonin is secreted during the dark period of the day and, through its elevated blood levels, informs, through specific cell receptors, the peripheral organs and tissues regarding the light/dark cycle. In addition to its function of sending information to the periphery regarding light and dark, melatonin from the pineal gland also contributes to the entrainment of the central SCN oscillator to the light–dark cycle. This chapter covers the anatomical features of the pineal gland, the synthesis and secretion of melatonin, the biological actions of melatonin, and various clinical aspects related to the pineal gland.

Melatonin

The pineal gland secretes a hormone called melatonin during the dark cycle.4–11 In the absence of light, certain dorsal parvocellular neurons in the autonomic subdivision of the paraventricular hypothalamic nucleus (PVH) provide tonic stimulation to the pineal gland via a circuitous pathway4–7 (Fig. 26–2). These PVH glutaminergic neurons project to sympathetic preganglionic neurons in the intermediolateral cell column (IML) of the upper thoracic spinal cord. The preganglionic sympathetic neurons provide a cholinergic projection to postganglionic neurons located in the superior cervical ganglion. The postganglionic neurons are noradrenergic and project to the pineal gland. The release of norepinephrine stimulates the pineal gland via alpha and beta receptors (mainly beta 1). Noradrenergic stimulation on the pineal gland results in increased cyclic adenosine monophosphate (AMP) in the pinealocytes and this induces expression of serotonin N-acetyltransferase (also known as arylalkylamine N-acetyltransferase [AA-NAT]). This enzyme catalyzes the rate-limiting step in the synthesis of melatonin. Therefore, the amount of this enzyme controls the production of melatonin.

In the presence of light, some neurons of the SCN directly inhibit those neurons in the PVH that are responsible for stimulating the pineal gland to secrete melatonin. Thus, light inhibits melatonin secretion and the absence of inhibition (absence of light) allows secretion of melatonin. Melatonin is sometimes called the dark hormone. The melatonin secreted by the pineal gland provides inhibitory feedback information to SCN neurons. Therefore, the SCN and pineal gland are mutually inhibitory. Important facts about human circadian rhythms are summarized in Box 26–1.

Melatonin is not essential for circadian rhythms in humans because removal of the pineal gland has minimal effects. In other species such as birds, the pineal gland is essential. The SCN has a high density of two types of melatonin receptors (MT1 and MT2). The MT1 receptor is a G protein–coupled receptor that activates protein kinase C. When melatonin binds the MT1 receptor on SCN neurons, this decreases SCN-alerting signal. The MT2 receptor is a G protein–coupled receptor that inhibits the guanine cyclase pathway and results in a shift in circadian phase. A third type of melatonin receptor (MT3) does not affect the pineal gland. Exogenous melatonin by oral administration can also affect the SCN. The half-life of exogenous melatonin is short (30–45 min) unless sustained-release melatonin preparations are used. As might be expected, the effects of exogenous melatonin are largest when no endogenous melatonin is being secreted.8 Exogenous melatonin can decrease the SCN-alerting signal (hypnotic effects) and cause a phase shift of circadian rhythms (discussed in a later section). Melatonin acting on blood vessels in the skin causes vasodilatation and increased blood flow results in heat loss and lowering of the body temperature.

Suprachiasmatic nucleus output via the human pineal gland

The pineal gland, or epiphysis cerebri, is a key structure of the circadian system. It contains pinealocytes, which produce melatonin (for references see Swaab, 2003). The pineal gland is innervated by a multisynaptic pathway from the SCN via the PVN, the intermediolateral column of the upper thoracic spinal cord and the superior cervical ganglion, which sends noradrenergic fibers to the pineal gland. The human pineal gland has a dense noradrenergic plexus. During darkness, due to stimulation arising from the SCN, noradrenaline is released from the sympathetic nerve endings in the pineal gland to activate N-acetyltransferase, the enzyme which catalyses the rate-limiting step of the synthesis of melatonin from serotonin. Serum and cerebrospinal fluid (CSF) melatonin levels in human are high at night and low during the day. Apart from the stimulatory input from the SCN, the main environmental stimulus that modifies the rhythmic melatonin fluctuations is light intensity. It is generally thought that melatonin reaches its targets in the brain via the peripheral circulation, although melatonin may also diffuse into the brain from the CSF. The SCN thus imposes circadian fluctuations indirectly on many more brain structures and functions by means of melatonin from the pineal gland – provided that melatonin receptors are present in those areas. In its turn, depending on the time of exposure, two distinct, separable, effects on the SCN, melatonin may elicit acute neuronal inhibition and phase shifting. We propose that this direct action of melatonin on the SCN is not only the neuroendocrine mediator of the circadian rhythm of sleep, but also influences arterial blood flow, decreases blood pressure, and blunts noradrenergic activation (Scheer et al., 2004). Melatonin is therefore clinically used in an increasing number of disorders (see below).

Introduction

The pineal gland, also called the epiphysis cerebri, was thought to be essentially non-functional until several important findings in the early 1960s revealed that the pineal gland is highly metabolically active (Axelrod et al., 1965) and that it exerts considerable control over reproductive physiology (Hoffman and Reiter, 1965). Since these early observations, knowledge of the cell biology of the pineal (Reiter, 1991) and of its physiological interactions (Bartness et al., 1994) has accumulated at a rapid pace. It is now clear that this endocrine gland, which for so many years labored in obscurity, may be the most widely acting gland in the body. There is little doubt that the major endocrine product of the pineal gland, melatonin, besides readily entering cells and subcellular compartments, easily passes through all morphophysiological barriers, e.g., the blood–brain barrier, and exerts actions that modify primary intracellular events.

This chapter reviews the anatomy of the pineal gland which is pertinent to understanding its endocrine status, it summarizes the cell biology of the metabolic events in the organ which culminate in production of the pineal hormone melatonin, and it describes the endocrine and metabolic consequences of melatonin after its release from the pineal gland. While length constraints on the chapter made it impossible to comprehensively cover each issue, the references cited, as well as the list of recommended reading material, will lead the interested reader to more detailed accounts of each of the subjects.

Anatomy, Function, and Normal Imaging

The pineal gland is a midline, ovoid structure located at the anterior aspect of the quadrigeminal plate cistern, between the two superior colliculi of the tectum (Figure 1(A) and (B)). The gland arises from the posterior wall of the third ventricle, to which it is attached by the pineal stalk.1 The pineal stalk is composed of a superior lamina, which merges with the habenular commissure (attached to the thalami), and an inferior lamina, which is attached to the posterior commissure bridging the upper midbrain. The two laminae are separated by the suprapineal recess of the third ventricle. The cistern of the velum interpositum is located between the two layers of the tela choroidea, lies superior to the pineal gland and inferior to the splenium, and contains the internal cerebral veins. Owing to these anatomic relationships, intrinsic lesions of the pineal gland have a predictable pattern of regional mass effect: they encroach on the posterior aspect of the third ventricle, elevate the internal cerebral veins, deform the tectum of the midbrain, and occasionally cause aqueductal compression.

The pineal gland is predominantly made up of pineocytes, which are specialized neuronal cells with features of photoreceptors. A small portion (5%) of the pineal gland consists of astrocytes.2 This cellular composition explains the signal intensity of the gland on magnetic resonance imaging (MRI), which is similar in appearance to gray matter. Following injection of contrast, the gland enhances avidly owing to a fenestrated capillary bed.3 While it may appear bright on diffusion-weighted imaging (DWI) trace maps like other gray matter structures (Figure 1(C)), the normal pineal gland will have apparent diffusion coefficient (ADC) values similar to the remainder of the brain parenchyma. This feature may help distinguish it from some pathologic conditions.4 According to cross-sectional studies of gland size, the pineal gland is relatively small in infancy, with a mean volume reported to be 27 mm;3 enlarges by the age of 2 to approximately 56–100 mm3; and stabilizes in size thereafter.5,6 The gland plays a role in regulating circadian rhythms and responses to seasonal changes, body temperature, and levels of circulating hormones such as melatonin.7,8

Melatonin and ‘Biological Clock’ System

The pineal gland (epiphysis cerebri), the eyes, and the suprachiasmatic nuclei (SCN) of the hypothalamus develop from the roof of the diencephalon. These are the major structures of the biological clock system in vertebrates. They are involved in the perception and/or translation of photic information, and thereby facilitate an organism's adaptive adjustment to rhythmic changes in environmental illumination due to the Earth's daily rotation around the sun. In phylogenetically primitive vertebrates, whose pineal glands have direct access to light, a light stimulus elicits an acute physiological response via photoreceptor cells in the pineal gland and can inhibit melatonin production or entrain a circadian rhythm of the intrinsic pineal oscillator. However, in mammals, including humans, the pineal gland is shielded from direct light input and lacks photoreceptors or an active endogenous oscillator. A near-24-h (circadian) rhythm of activity in the human pineal gland depends on the periodic signal from the SCN. The neurons of this small hypothalamic structure are capable of sustaining a circadian pattern of activity, even in the absence of a rhythmic environmental input, and are normally active during the day and slow down at night. The activation of SCN neurons has an inhibitory effect on the pineal gland, defining a nocturnal pattern of melatonin secretion. However, the amplitude and the phase of the periodic signal from SCN can be modified by endogenous and exogenous factors. If SCN neurons are activated at night (e.g., by environmental light perceived by the retina), melatonin production declines. Melatonin, in turn, can attenuate the activity of SCN. This melatonin action supports a normal decline in the activity of the major circadian pacemaker at night, further promotes melatonin secretion, and contributes to an overall increase in the amplitude of circadian body rhythms. Melatonin can also produce a shift in the circadian phase of SCN activity, advancing or delaying it. The magnitude and the direction of the phase-shifting effect largely depend on the time of melatonin administration.

Anatomy

The pineal gland (epiphysis cerebri) of mammals is a pine-like structure of the dorsal thalamus (epithalamus) placed over a recess of the third ventricle.

The pineal gland in mammals is a neuroendocrine structure and the main source of circulating melatonin, the hormone that regulates the circadian and seasonal rhythms. Melatonin is generally secreted with a nadir during daytime and a peak during night time, in response to an internal rhythm generated by the suprachiasmatic nucleus of the hypothalamus. The presence of a pineal gland in cetaceans is somewhat controversial and there is still no consensus about it (see Table 7.2). Some species have been reported to lack one, like the Amazon river dolphin (Inia geoffrensis) (Gruenberger, 1970), the Pacific white-sided dolphin (Lagenorhynchus obliquidens) (Arvy, 1971), the spinner dolphin (Stenella longirostris) (Arvy, 1971), the narwhal (Monodon monoceros) (fetal) (Holzmann, 1991), the short-beaked common dolphin (D. delphis) (Oelschläger et al., 2008), and the dwarf sperm whale (Kogia sima) (Oelschläger et al., 2010).h On the other hand, while Fuse (1936) described the pineal gland as “rudimentary” in the finless porpoise (N. phocaenoides), some authors reported the presence of an actual epiphysis in fetuses and adults of larger species (see Panin et al., 2012, for details).

Table 7.2. List of Dolphin Species with References Reporting Absence/Presence of a Pineal Gland

The presence of a pineal gland apparently is not constant among all the individuals of a determinate cetacean species.i The common bottlenose dolphin, T. truncatus, represents an emblematic case. Neither McFarland et al. (1969) nor Ridgway (1990) were able to detect a pineal body in several brains of this species they dissected. On the contrary, Morgane and Jacobs (1972) observed a pineal gland “present up to the adult stage,” and recently Lyamin et al. (2008) reported an unmistakable image of a large pineal gland in a pregnant female bottlenose dolphin. The authors attributed the large size of the gland to pregnancy.j However, the gland does not appear or disappear completely in a given species. Our group examined a series of bottlenose dolphin brains by gross dissection to evaluate the presence of a pineal gland, but failed to detect one in 29 brains (Panin et al., 2012). We also did not find the gland in a series of Risso’s dolphins, striped dolphins, and in a single common dolphin. In one instance, we saw what macroscopically looked like a gland in the correct epithalamic position (Fig. 7.7). However, the structure was later found under the microscope to be composed of pial vessels without pinealocytes.