Circumventricular organs

The circumventricular organs are midline structures around the third and fourth ventricles that are in contact with blood and cerebrospinal fluid, and they facilitate special types of communication between the central nervous system and peripheral blood. Additionally, they are an integral part of neuroendocrine function. Highly permeable capillaries allow the CVOs to act as an alternative route for peptides and hormones in the neural tissue to sample from and secrete to circulating blood. CVOs also have roles in body fluid regulation, cardiovascular functions, immune responses, thirst, feeding behavior and reproductive behavior.

CVOs can be classified as either sensory or secretory organs serving homeostatic functions and body water balance. The sensory organs include the area postrema, the subfornical organ, and the vascular organ of lamina terminalis, all having the ability to sense signals in blood, then pass that information neurally to other brain regions. Through their neural circuitry, they provide direct information to the autonomic nervous system from the systemic circulation. The secretory organs include the subcommissural organ (SCO), the pituitary gland, the median eminence, and the pineal gland. These organs are responsible for secreting hormones and glycoproteins into the peripheral blood using feedback from both the brain environment and external stimuli.

Circumventricular organs contain capillary networks that vary between one another and within individual organs both in density and permeability, with most CVO capillaries having a permeable endothelial cell layer, except for those in the subcommissural organ. Furthermore, all CVOs contain neural tissue, enabling a neuroendocrine role.

Although the choroid plexus also has permeable capillaries, it does not contain neural tissue; rather, its primary role is to produce cerebrospinal fluid (CSF), and therefore is typically not classified as a CVO.

Sensory organs

The sensory organs are the area postrema, the vascular organ of the lamina terminalis, and the subfornical organ.

Area postrema

Anatomy

The area postrema is located in the caudal medulla oblongata near the junction of the brainstem and the spinal cord. In humans and in most other mammals that have been studied, it consists of swellings on either wall of the fourth ventricle. In rodents and lagomorphs, however, the area postrema forms a midline structure dorsal to the obex. When viewed histologically for its capillary distribution and morphology, the area postrema has numerous subregions separated according to capillary permeability, rates of blood flow, and duration of blood transit through respective capillary beds.

Function

Relatively little is known about the function of the area postrema in humans. However, there is strong evidence that the area postrema acts as the chemoreceptor trigger zone for vomiting, which is triggered by the presence of noxious stimulation from the blood. There is also evidence that the area postrema is the site at which angiotensin stimulates glucose metabolism, presumed efferent neural activity, blood pressure control, and thirst. 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.

Vascular organ of the lamina terminalis

Anatomy

Classified as a sensory circumventricular organ (along with the SFO and AP), the vascular organ of lamina terminalis (VOLT) is situated in the anterior wall of the third ventricle. Characteristically of the CVOs, it lacks the tight endothelial blood brain barrier. The vascular organ is further characterized by the afferent inputs from the subfornical organ (SFO), the median pre-optic nucleus (MnPO) region, the brainstem, and even the hypothalamus. Conversely, the vascular organ of the lamina terminalis maintains efferent projections to the stria medullaris and basal ganglia.

As a major player in the maintenance of the mammalian body fluid homeostasis, the VOLT features the primary neurons responsible for osmosensory balance. These neurons, in turn, feature angiotensin type I receptors, which are used by circulating angiotensin II to initiate water intake and sodium consumption. In addition to the angiotensin receptors, the neurons of the VOLT are also characterized by the presence of a nonselective cation channel deemed the transient receptor potential vanilloid 1, or TRPV1. 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. Despite a significant amount of data, the anatomy of the VOLT is not yet fully comprehended.

Function

As previously mentioned, the vascular organ of lamina terminalis features neurons responsible for the homeostatic conservation of osmolarity. In addition, the fenestrated vasculature of the VOLT allows the astrocytes and neurons of the VOLT to perceive a wide variety of plasma molecules whose signals may be transduced into other regions of the brain, thereby eliciting autonomic and inflammatory reactions.

In experiments, mammalian VOLT 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. Stated simply, an increase in osmolarity results in a reversible depolarization of the VOLT neurons. This can be seen through the predominantly excitatory effects of ANG on the VOLT through the TRPV1 receptor. In this context, it is worthy to note the VOLT neurons typically feature a resting membrane potential in the range of -50 to -67 mV with input resistances ranging from 65 to 360 MΩ.

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

Subfornical organ (SFO)

Anatomy

The subfornical organ is a sensory CVO situated on the underside of the fornix and lacking a 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 3–4 anatomical zones, especially by its capillary density and structure. 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 few neurons and glial cells can be seen in this area. Functionally, however, the SFO may be viewed in two portions – the dorsolateral peripheral division and the ventromedial core segment.

The SFO has many efferent projections, 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 VOLT and the median preoptic area. It seems that the most essential of all these connections is the SFO's projections to the paraventricular hypothalamic nucleus. Based on their functional relevance, the SFO neurons can be branded as either GE, featuring nonselective cation channels, or GI, featuring potassium channels. 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.

Study of subfornical organ anatomy is still ongoing but evidence has demonstrated slow blood transit time which may facilitate the sensory capability of SFO, enabling increased contact time for blood-borne signals to penetrate its permeable capillaries and influence regulation of blood pressure and body fluids. This observation coincides with the fact that SFO neurons have been shown to be intrinsically osmosensitive. Finally, it has been established that SFO neurons maintain resting membrane potential in the range of -57 to -65 mV.

Function

The subfornical organ is active in many bodily processes including, but not limited to, osmoregulation, cardiovascular regulation, Both hyper- and hypotonic stimuli facilitated an osmotic response. 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. The induction of the drinking response via the SFO can be antagonized, however, by the peptide, ANP. 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.

Recent research has focused on the subfornical organ as an area particularly important in the regulation of energy. The observation that subfornical neurons respond to 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. Additionally, it is assumed that the SFO is the lone forebrain structure capable of constant monitoring of circulating concentrations of glucose. This responsiveness to glucose again serves to solidify the SFO's integral role as a regulator of energy homeostasis.