Circumventricular organs

Circumventricular organs (CVOs) are structures in the brain that are characterized by their extensive vasculature and lack of a normal blood brain barrier (BBB).^[1] The CVOs allow for the linkage between the central nervous system and peripheral blood flow; additionally they are an integral part of neuroendocrine function.^[2] The lack of a blood brain barrier allows the CVOs to act as an alternative route for peptides and hormones in the neural tissue to the peripheral blood stream, while still protecting it from toxic substances.^[3][4] CVOs can be classified in two ways, the sensory and the secretory organs. The sensory organs include the area postrema (AP), the subfornical organ (SFO) and the organum vasculosum of lamina terminalis (OVLT). They have the ability to sense plasma molecules and then pass that information into other regions of the brain. Through this, they provide direct information to the autonomic nervous system from systemic circulation.^[1][5] The secretory organs include the subcommissural organ (SCO), the posterior pituitary (also known as the neurohypophysis), the pineal gland, the median eminence and the intermediate lobe of the pituitary.^[2] These organs are responsible for secreting hormones and glycoproteins into the peripheral vascular system using feedback from both the brain environment and external stimuli.

All of the circumventricular organs, besides the SCO, contain extensive vasculature and fenestrated capillaries which leads to a ‘leaky’ BBB at the site of the organs. Furthermore, all CVOs contain neural tissue, allowing them to play a role in the neuroendocrine system. It is highly debated if the choroid plexus can be included as a CVO. It has a high concentration of fenestrated capillaries, but its lack of neural tissue and its primary role of producing cerebrospinal fluid (CSF) usually excludes the choroid plexus from the CVO classification.^[2]

Research has also linked CVOs to body fluid regulation, cardiovascular functions, immune responses, thirst, feeding behavior and reproductive behavior.^[2]

Sensory organs

Area postrema

Its bilateral structure makes it lie on either side of the medullary midline, at the junction between the medulla and the spinal cord.^[6]

Function

There is little information known about this structure in humans. However, it is known that the area postrema is the locus, or site, of the chemoreceptor trigger zone for vomiting.^[7] It functions as the fundamental physiological mechanism of the CNS for this reaction, which is triggered in the presence of noxious stimulation.^[6] The area postrema also has integrative capacities that enable it to send major and minor efferents to sections of the brain involved in the autonomic control of cardiovascular and respiratory activities.^[6]

Organum vasculosum of the lamina terminalis (OVLT)

Anatomy

Classified as a sensory circumventricular organ (along with the SFO and AP),^[4] the OVLT is situated in the anterior wall of the third cerebral ventricle.^[8] It lacks the tight endothelial blood brain barrier characteristic of the CVOs.^[8][9] The OVLT is further characterized by the afferent inputs from the subfornical organ (SFO), the median pre-optic nucleus (MnPO) region, the brain stem, and even the hypothalamus. Conversely, the organum vasculosum maintains efferent projections to the stria medullaris and basal ganglia.^[5]

As a major player in the maintenance of the mammalian body fluid homeostasis, the OVLT features the primary neurons responsible for osmosensory balance.^[9][10] These neurons, in turn, feature angiotensin type I receptors which are used by circulating angiotensin II to initiate water intake and sodium consumption.^[4] In addition to the angiotensin receptors, the neurons of the OVLT are also characterized by the presence of a nonselective cation channel deemed the transient receptor potential vanilloid 1, or TRPV1.^[9][10] Though there are other receptors within the TRPV family, a study by Ciura, Liedtke, and Bourque demonstrated that hypertonicity sensing operated via a mechanical mechanism of TRPV1 but not TRPV4.^[9] Despite a significant amount of data, the anatomy of the OVLT is not yet fully comprehended.

Function

As previously mentioned, the organum vasculosum of the lamina terminalis features neurons responsible for the homeostatic conservation of osmolarity.^[10] In addition, the fenestrated vasculature of the OVLT allows the glial astrocytes and neurons of the OVLT to perceive a wide variety of plasma molecules whose signals may be transduced into other regions of the brain, and therefore elicit autonomic and inflammatory reactions.^[4]

In experiments, mammalian OVLT neurons were shown to transduce hypertonicity by the activation of the TRPV1 nonselective cation channels. These channels are highly permeable to calcium and are responsible for membrane depolarization and increased action potential discharge.^[9] Stated simply, an increase in osmolarity results in a reversible depolarization of the OVLT neurons.^[5] This can be seen through the predominantly excitatory effects of ANG on the OVLT through the TRPV1 receptor. In this context, it is worthy to note the OVLT neurons typically feature a resting membrane potential in the range of -50 to -67 mV with input resistances ranging from 65 to 360 MΩ.^[5]

Despite a solid understanding of the OVLT’s role in the maintenance of body fluid homeostasis, other functions are less understood. For example, it is thought that the OVLT may also play a role in the regulation of LH secretion via a negative feedback mechanism.^[5] It is also hypothesized that the OVLT may be the mechanism through which pyrogens function to initiate a febrile response in the CNS.^[5] Finally, OVLT neurons have been observed to respond to temperature changes indicating that the organum vasculosum of the lamina terminalis is subject to different climates.^[5]

Subfornical organ (SFO)

Anatomy

The subfornical organ is a sensory CVO situated in the lamina terminalis and lacking the BBB, the absence of which characterizes the circumventricular organs. Protruding into the third ventricle of the brain, the highly vascularized SFO can be divided into three anatomical zones.^[5] The central zone is composed exclusively of the glial cells and neuronal cell bodies. Conversely, the rostral and caudal areas are mostly made of nerve fibers while very few neurons and glial cells can be seen in this area.^[5] Functionally, however, the SFO may be viewed in two portions, the dorsolateral peripheral (pSFO) division and the ventromedial core segment.^[11]

As an important mechanism of both energy and osmotic homeostasis, the SFO has many efferent projections. In fact, SFO neurons have been experimentally shown to broadcast efferent projections to regions involved in cardiovascular regulation including the lateral hypothalamus with fibers terminating in the supraoptic (SON) and paraventricular (PVN) nuclei, and the anteroventral 3rd ventricle (AV3V) with fibers terminating in the OVLT and the median preoptic area.^[5][12][13] It seems that the most essential of all these connections is the SFO’s projections to the paraventricular hypothalamic nucleus.^[11] Based on their functional relevance, the SFO neurons can be branded as either GE, featuring nonselective cation channels, or GI, featuring potassium channels.^[12] While the afferent projections of the SFO are considered less important than the various efferent connections, it is still notable that the subfornical organ receives synaptic input from the zona incerta and arcuate nucleus.^[14]

Study of subfornical organ anatomy is still ongoing but recent evidence has demonstrated the presence of endothelin (a potent vasoconstrictor) receptors.^[5] This observation coincides with the fact that SFO neurons have been shown to be intrinsically osmosensitive.^[5] Finally, it has been established that SFO neurons maintain resting membrane potential in the range of -57 to -65 mV.^[5]

Function

The subfornical organ is a circumventricular organ active in many bodily processes including, but not limited to, osmoregulation,^[11][14] cardiovascular regulation,^[11][13] and energy homeostasis.^[13] In a study by Ferguson, both hyper- and hypotonic stimuli facilitated an osmotic response.^[5] This observation demonstrated the fact that the SFO is involved in the maintenance of blood pressure. Featuring an AT1 receptor for ANG, the SFO neurons demonstrate an excitatory response when activated by ANG, therefore increasing blood pressure.^[5] The induction of the drinking response via the SFO can be antagonized, however, by the peptide, ANP.^[5] Additional research has demonstrated that the subfornical organ may be an important intermediary though which leptin acts to maintain blood pressure within normal physiological limits via descending autonomic pathways associated with cardiovascular control.^[13]

Recent study has focused on the subfornical organ as an area particularly important in the regulation of energy. The observation that subfornical neurons are perceptive of a wide range of circulating energy balance signals, and that electrical stimulation of the SFO in rats resulted in food intake supports the SFO’s importance in energy homeostasis.^[12] Additionally, it is assumed that the SFO is the lone forebrain structure capable of constant monitoring of circulating concentrations of glucose.^[12] This responsiveness to glucose again serves to solidify the SFO’s integral role as a regulator of energy homeostasis.^[12]

Secretory organs

Subcommissural organ

Anatomy

The subcommissural organ (SCO) is a small secretory organ located near the anterior entrance of the sylvian aqueduct and at the midline roof of the third ventricle.^[15] The SCO also covers and penetrates the posterior commissure. It is aberrant from other CVOs in that lacks a high concentration of fenestrated capillaries, making its BBB less permeable. On the other hand, its large role in the neuroendocrine system awards it the CVO classification.^[2] Related to its secretory function, the SCO is partially composed of ependymal cells. These ependymocytes are characterized by an elongated cell body covered in cilia, which contains secretory materials. The most prominent of these is the glycoprotein SCO-spondin.^[15][16]

Function

The main function of the SCO is the secretion of the glycoprotein SCO-spondin. When SCO-spondin is released, it travels into the third ventricle, where it aggregates to create Reissner’s fibers (RF).^[17] Reissner's fibers are long fibrous projections that travel caudally through the sylvian aqueduct and can terminate as far as the spinal cord. These fibers contribute to the maintenance of the patency of the sylvian aqueduct. If the SCO were to malfunction, causing a loss of the Reissner's fibers, a medical condition known as Congenital Hydrocephalus (CH) can develop. CH is an ailment characterized by a large and abnormal accumulation of cerbrospinal fluid (CSF) in the brain and is usually caused by genetic mutations.^[15]

While the function of the subcommissural organ is still under investigation, it has been hypothesized that it is also part of the mechanism of aldosterone secretion and CSF detoxification, along with osmoregulation.^[17] The SCO is innervated by many systems, the most common of which is associated with the serotonergic system. The serotonergic system influences water and sodium intake. During water deprivation it will also reduce its innervation to the SCO. The reduction of input to the SCO causes a marked decrease in RF production. This finding implies that the subcommissural organ and its associated Reissner's fibers are an integral part of fluid electrolyte balance and water homeostasis.^[17]

Posterior pituitary

Anatomy

The pituitary is subdivided into two principal lobes, anterior and posterior, the latter of which is also known as the neurohypophysis.^[18] Each one functions as a separate endocrine organ. The posterior pituitary is made up by a stalk, the infundibulum, which consists of axonal projections that extend from the hypothalamus.^[18] It is located in the sella turcica of the sphenoid bone at the base of the skull.^[19]

Function

The posterior pituitary is sometimes referred to as the “master gland” because it has a crucial role in maintaining homeostasis and guiding the activity of other glands.^[19] The posterior lobe stores and releases oxytocin and vasopressin, also known as antidiuretic hormone (ADH), which are produced in the hypothalamus.^[18]

Median eminence

The median eminence (ME) is located in the inferior portion of the hypothalamus and is ventral to the third ventricle. While some publications do not list the ME as a CVO, when it is considered to be a circumventricular organ, it is classified as a secretory organ. The median eminence is rich in fenestrated capillaries, allowing for the passage of proteins and neurohormones. More specifically, the median eminence allows for the transport of neurohormones between the CSF and the peripheral blood supply.^[20] The major cell type that makes up the median eminence are specialized ependymal cells known as tanycytes. These contribute to the organ's ability to selectively allow macromolecules to pass from the central to the peripheral neuroendocrine systems.^[3][20]

Tanycytes line the floor of the third ventricle and can be characterized by a singular long projection that delves deep inside the hypothalamus. Tanycytes have been evolutionarily linked to radial glial cells of the central nervous system. The tanycytes of the median eminence are often found along the fenestrated peripheral capillaries. They are tightly packed on the capillaries, forming a seal between the third ventricle and the median eminence. This seal can be attributed to the tight junctions observed between tanycytes and functions to restrict the travel of molecules between the median eminence and the third ventricle.^[3] The median eminence is also closely linked to the transport of GnRH between the median eminence and the anterior pituitary. Neuronal projections of GnRH neurons actually end at the median eminence, allowing for its release into the portal blood system.^[21][22]

Pineal gland

Anatomy

Gross Anatomy

The morphology of the pineal gland varies greatly among mammals. The most commonly used classification for this gland takes into account its location relative to the diencephalon and the third ventricle of the brain, as well as its size and shape.^[23] Under these conditions, the human pineal gland is classified as type A.^[23] A type A pineal gland rests proximally to the posterior section of the diencephalon. It is located within 1-2mm of the midline of the brain.^[23] The pineal gland starts to develop during the second month of gestation. In the average adult, the dimensions are as follow: 5-9mm in length, 1-5mm in width and 3-5mm in thickness. Its average weight is 100–180 mg.^[23] The pineal gland consists of a central core made up of small lobes and a cortex that possesses a diffuse distribution of neurons. The principal cell type of the pineal is the pinealocyte sensu stricto. This type of cell has a prominent nucleus and a granular appearance.^[23]

Vascularization and Innervation

The level of vascularization in the pineal gland is high. It receives a large supply of blood from branches of the posterior choroidal arteries that derive from cerebral arteries in the posterior mesencephalon.^[23] The pineal gland is innervated by fibers from the peripheral parasympathetic and sympathetic systems, in addition to fibers from the central nervous system (CNS).^[24] However, the brain itself doesn’t supply it with much innervation. The most important set of fibers involved are the unmyelinated postganglionic sympathetic fibers from the superior cervical ganglia (SCG), which also form the bilateral nervi conarii.^[23] The second set of fibers enters the pineal gland anteriorly via the commissural peduncles.^[23] The third set of fibers is myelinated and forms the ventro-lateral pineal tract.^[23]

Function

The pineal gland is considered a secretory organ and its activity shows circadian oscillations.^[24] Its main function, secretion of the hormone melatonin, dies out when there is no input from the primary circadian pacemaker in the suprachiasmatic nuclei (SCN).^[23] Melatonin production is controlled by the previously mentioned circadian timing and is suppressed by light.^[23] It has also been hypothesized that the pineal gland has a role in reproduction.^[24] Pineal tumors can affect sexual development,^[23] but the effecting mechanism has yet to be established. In addition, melatonin has also been detected in preovulatory follicles, as well as fluids related to reproduction such as semen, amniotic fluid and breast milk.^[23]

Other pineal substances

Other peptides aside from melatonin have been detected in the pineal. They are most likely associated with a type of innervation deemed “pineal peptidergic innervation.”^[23] These include vasopressin, oxytocin, VIP, NPY, peptide histidine isoleucine, calcitonin gene-related peptide, substance P and somastotin.^[23] However, these probably accumulate in the pineal but are not produced by the gland itself.

References