Subfornical organ

Subfornical organ
Mesial aspect of a brain sectioned in the median sagittal plane. (Subfornical organ not labeled, but fornix and foramen of Monro are both labeled near the center.)
Details
Identifiers
Latin	organum subfornicale
MeSH	A08.713.840
NeuroNames	hier-437
NeuroLex ID	Subfornical organ
Dorlands /Elsevier	o_06/12596286
TA	A14.1.08.412 A14.1.09.449
FMA	75260
Anatomical terms of neuroanatomy [edit on Wikidata]

The subfornical organ (SFO), situated on the ventral surface of the fornix (the reasoning behind the organ's name), at the interventricular foramina (foramina of Monro), is one of the circumventricular organs of the brain, meaning that it is highly vascularized and does not have a blood-brain barrier, unlike the vast majority of regions in the brain. The SFO is a sensory circumventricular organ responsive to a wide variety of hormones and neurotransmitters, as opposed to a secretory circumventricular organ.

Anatomy

Similar to the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ is a sensory circumventricular organ situated in the lamina terminalis and lacking the blood-brain barrier, 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.^[1] 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.^[1] Functionally, however, the SFO may be viewed in two portions, the dorsolateral peripheral (pSFO) division and the ventromedial core segment.^[2]

Study of subfornical organ anatomy is still ongoing but recent evidence has demonstrated the presence of endothelin (a potent vasoconstrictor) receptors.^[1] This seems logical as SFO neurons have been shown to be intrinsically osmosensitive.^[1] Finally, it has been established that SFO neurons maintain resting membrane potential in the range of -57 to -65 mV.^[1]

General function

The subfornical organ is a circumventricular organ active in many bodily processes including, but not limited to, osmoregulation,^[2] cardiovascular regulation,^[2][3] and energy homeostasis.^[3] In a study by Ferguson, both hyper- and hypotonic stimuli facilitated an osmotic response.^[1] Most of these processes involve fluid balance through the control of the release of some kind of hormone: for example angiotensin or vasopressin.

Cardiovascular regulation

The subfornical organ's impact on the cardiovascular system is again mostly seen through fluid balance. The SFO plays a role in vasopressin regulation. Vasopressin (ADH) is a hormone that, when bonded to receptors in the kidneys, increases water retention in the cardiovascular system by decreasing the amount of fluid transferred out of the blood to the urine by the kidneys. This regulation of blood volume has effects on other aspects of the cardiovascular system. Increased or decreased blood volume has an effect on blood pressure, which is regulated by baroreceptors, and can in turn affect the strength of ventricular contraction in the heart, although heart rate is generally not affected by blood volume. Additional research has demonstrated that the subfornical organs 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.^[3]

SFO neurons have also 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.^[1]

Appetite and energy homeostasis

The subfornical organ has also been shown to have a significant impact on appetite. These mechanisms are not as clear as the neural mechanisms by which the SFO regulates fluid balance; however the most prevalent theory links the SFO's role in appetite control to its influence on energy, particularly glucose consumption. Recent study has focused on the SFO 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.^[4] Additionally, it is assumed that the SFO is the lone forebrain structure capable of constant monitoring of circulating concentrations of glucose, due to its lack of a blood-brain barrier.^[4] This responsiveness to glucose again serves to solidify the SFO’s integral role as a regulator of energy homeostasis.^[4]

Relationship with other circumventricular organs

Other circumventricular organs are the area postrema in the brainstem and the organum vasculosum of the lamina terminalis (OVLT).

The OVLT and the SFO are both strongly interconnected with the nucleus medianus, and together these three structures comprise the so-called "AV3V" region - the region anterior and ventral to the third ventricle. The AV3V region is very important in the regulation of fluid and electrolyte balance, by controlling thirst, sodium excretion, blood volume regulation, and vasopressin secretion.

The SFO is outside the blood–brain barrier, and so neurons in this region can respond to factors that are present in the systemic circulation. The circumventricular organs express high density of Glucagon-like peptide 1 (GLP-1)receptors and participate in the central regulation of energy intake.

Hormones and receptors

Neurons in the subfornical organ have receptors for many hormones that circulate in the blood but which do not cross the blood–brain barrier, including angiotensin, atrial natriuretic peptide, endothelin and relaxin. The role of the SFO in angiotensin regulation is particularly important, as it is involved in communication with the nucleus medianus (also called the median preoptic nucleus). Some neurons in the SFO are osmoreceptors, being sensitive to the osmotic pressure of the blood. These neurons project to the supraoptic nucleus and paraventricular nucleus to regulate the activity of vasopressin-secreting neurons. These neurons also project to the nucleus medianus which is involved in controlling thirst. Thus, the subfornical organ is involved in fluid balance.

Other important hormones have been shown to excite the SFO, specifically serotonin, carbamylcholine (carbachol), and atropine. These neurotransmitters however seem to have an effect on deeper areas of the SFO than angiotensin, and antagonists of these hormones have been shown to also primarily effect the non-superficial regions of the SFO (other than atropine antagonists, which showed little effects). In this context, the superficial region is considered to be 15-55μm deep into the SFO, and the "deep" region anything below that.

From these reactions to certain hormones and other molecules, a model of the neuronal organization of the SFO is suggested in which angiotensin-sensitive neurons lying superficially are excited by substances borne by blood or cerebrospinal fluid, and synapse with deeper carbachol-sensitive neurons. The axons of these deep neurons pass out of the SFO in the columns and body of the fornix. Afferent fibers from the body and columns of the fornix polysynaptically excite both superficial and deep neurons. A recurrent inhibitory circuit is suggested on the output path.^[5]

Genetics

The expression of various genes in the subfornical organ have been studied. For example, it was seen that water deprivation in rats led to an upregulation of the mRNA that codes for angiotensin II receptors, allowing for a lower angiotensin concentration in the blood that produce the "thirst" response. It also has been observed to be a site of thyroid transcription factor 1 (TTF1) production, a protein generally produced in the hypothalamus.^[6]

Pathology

Hypertension

Hypertension, or high blood pressure, is highly affected by the concentration of angiotensin. Injection of angiontensin has actually been long used to induce hypertension in animal test models to study the effects of various therapies and medications. In such experiments, it has been observed that an intact and functioning subfornical organ limits the increase in mean arterial pressure due to the increased angiotensin.^[7]

Dehydration

As stated above, angiotensin receptors (AT1) have been shown to be upregulated due to water deprivation. These AT1 receptors have also shown an increased bonding with circulating angiotensin after water deprivation. These findings could indicate some sort of morphological change in the AT1 receptor, likely due to some signal protein modification of the AT1 receptor at a non-bonding site, leading to an increased affinity of the AT1 receptor for angiotensin bonding.^[8]

Relevant experiments

Feeding

Although generally viewed primarily as having roles in homeostasis and cardiovascular regulation, the subfornical organ has been thought to control feeding patterns through taking inputs from the bloodstream (various peptides indicating satiety) and then stimulating hunger. It has been shown to induce drinking in rats as well as eating.

One study looks at different stimulation current values, to determine if this has an effect on the amount of feeding that occurs. The rats studied were separated into three groups: rats with electrodes in their subfornical organ with no current passing through (sham), rats with stimulated subfornical organs, and rats with areas other than the subfornical organ stimulated. The group with stimulated subfornical organs was separated into groups with 100mA and 200mA stimulations. All rats were satiated (food and drink) before observations/stimulations were done, and were also monitored for general activity. The group with subfornical stimulation at 100mA drank an increased amount, but did not consume any additional food, and the group with 200mA consumed both more water and more food. All groups without subfornical organ stimulation did not eat or drink at all.^[9]

Other studies look specifically at drinking, as the SFO is known to have an important role in fluid balance. One such study looked into the connection between the SFO and the median preoptic nucleus. Rats with both partially or fully severed connections to the median preoptic nucleus showed a significantly decreased tendency to drink water when compared to the control group. Then when angiotensin was injected subcutaneously, drinking incidence went back to original levels. These findings are consistent with a model that postulates that osmoreceptors and angiotensin receptors in the SFO send excitatory neural information to the median preoptic nucleus for the mobilization of thirst.^[10]

Future research and treatment possibilities

One of the reasons the subfornical organ, along with all circumventricular organs, is increasingly being studied is its potential for novel pharmaceutical due to the lack of a blood-brain barrier. The blood-brain barrier has long been an obstacle in drug delivery to the brain, as only certain molecules are transported across the endothelial cells that form tight junctions along the vasculature in the brain.

Current research in this area has focused on a less naturally occurring component of the brain that lacks a blood-brain barrier: certain types of high grade gliomas. The rapidly dividing tumorous glial cells require rapidly formed blood vessels, and as a result, the endothelial cell tight junctions do not form, and the vessels are "leaky". Treatment targeted towards these tumors are trending towards medication internalized in some sort of vesicle, with the size of the vesicle determining where in the body they collect. The vesicles are then coated with various ligands/receptors (for gliomas, most commonly used is the folate receptor mechanism as it is highly expressed by glioma cells) to bind to their target cells and release the contained medication. This approach to drug delivery in the brain could easily be replicated in the SFO, and reduce abnormalities seen in the SFO as well as the physiological mechanisms it plays a role in.^[11]

References

1. 1 2 3 4 5 6 7 Ferguson, A. V., & Bains, J. S. (1996). Electrophysiology of the circumventricular organs. Frontiers in Neuroendocrinology, 17(4), 440-475. doi: 10.1006/frne.1996.0012.
2. 1 2 3 Kawano, H., and Masuko, S. (2010). Region-specific projections from the subfornical organ to the paraventricular hypothalamic nucleus in the rat. Neuroscience 169, 1227-1234.
3. 1 2 3 Smith, P. M. and Ferguson, A. V. (2012), Cardiovascular Actions of Leptin in the Subfornical Organ are Abolished by Diet-Induced Obesity. Journal of Neuroendocrinology, 24: 504–510. doi: 10.1111/j.1365-2826.2011.02257.x.
4. 1 2 3 Medeiros, N., Dai, L., and Ferguson, A.V. (2012). Glucose-responsive neurons in the subfornical organ of the rat—a novel site for direct CNS monitoring of circulating glucose. Neuroscience 201, 157-165.
5. ↑ Buranarugsa P, Hubbard J I (1978). "The neuronal Organization of the rat subfornical organ in vitro and a test of the osme- and morphine receptor hypotheses". J. Physiol. 291 (4): 101–16. 
6. ↑ Son Y J, Hur M K, Ryu B J, Park S K (2003). "TTF-1, a homeodomain-containing transcription factor, participates in the control of body fluid homeostasis by regulating angiotensinogen gene transcription in the rat subfornical organ.". The Journal of Biology and Chemistry. 
7. ↑ Bruner C A, Mangiopane M L, Fink, G D, (1985). "Subfornical organ. Does it protect against angiotensin II-induced hypertension in the rat?". Circ. Res. doi:10.1161/01.res.56.3.462. 
8. ↑ Sanvitto G L, Johren 0, Hauser W, Saavedra J M, (1997). "Water deprivation upregulates ANG II AT1 binding and mRNA in rat subfornical organ and anterior pituitary". Journal of Physiology. 
9. ↑ Smith P, (2010). "Acute electrical stimulation of the subfornical organ induces feeding in satiated rats". Physiology and Behavior 99 (4): 534–37. doi:10.1016/j.physbeh.2010.01.013. 
10. ↑ Lind R. Wallace, (1982). "Subfornical organ-median preoptic connections and drinking and pressor responses to angiotensin II". The Journal of Neuroscience 2 (3): 1043–51. 
11. ↑ McNeeley K, (2007). "Decreased circulation time offsets increased efficacy of PEGylated nanocarriers targeting folate receptors of glioma". The Journal of Neuroscience 18 (38). 

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