Vomeronasal organ

Overview
The vomeronasal organ (VNO), or Jacobson's organ, is an auxiliary olfactory sense organ that is found in many animals and some adult humans that was discovered by Ludvig Jacobson in 1813.

It develops from the nasal (olfactory) placode, at the anterior edge of the neural plate (cranial nerve zero). It is a chemoreceptor organ which is completely separated from the nasal cavity the majority of the time, being enclosed in a separate bony or cartilaginous capsule which opens into the base of the nasal cavity. It is a tubular crescent shape and split into two pairs, separated by the nasal septum. It is the first processing stage of the accessory olfactory system, after which chemical stimuli go to the accessory olfactory bulb, then to targets in the amygdala and hypothalamus. The VNO has two separate types of neuronal receptors, V1R and V2R, which are seven-transmembrane receptors that are coupled to GTP-binding proteins. The receptors are distinct from each other and from the large family of receptors in the main olfactory system. Evidence shows that the VNO responds to nonvolatile cues which stimulate the receptor neurons. Its presence in many animals has been widely studied and the importance of the vomeronasal system to the role of reproduction and social networking in animals has been shown in many studies. Its presence and functionality in humans is widely controversial.

Structure
The vomeronasal organ (VNO) is found at the base of the nasal cavity. It is split into two, being divided by the nasal septum, with both sides possessing an elongated c-shaped, or crescent, lumen. It is encompassed inside a bony or cartilaginous capsule which opens into the base of the nasal cavity. The vomeronasal receptor neurons possess axons which travel from the VNO to the accessory olfactory bulb (AOB) or, as its also known, the vomeronasal bulb. These sensory receptors are located on the medial concave surface of the crescent lumen and have a density of approximately 92 x 103  mm-2. The lateral, convex surface of the lumen is covered with non sensory ciliated cells, where the basal cells are also found. At the dorsal and ventral aspect of the lumen are vomeronasal glands, which fill the vomeronasal lumen with fluid. Sitting net to the lumen are blood vessels that dilate or constrict to pump the lumen.

Function
In mammals, the sensory neurons of the vomeronasal organ detect specific chemical compounds contained within scents that are often, but not always, large non-volatile molecules. Notably by way of the vomeronasal organ, some scents act as chemical-communication signals (pheromones) from other individuals of the same species. Unlike the main olfactory bulb that sends neuronal signals to the olfactory cortex, the VNO sends neuronal signals to the accessory olfactory bulb and then to the amygdala and hypothalamus, which may explain how scents influence aggressive and mating behavior. However, it is key to note that the vomeronasal organ detects other compounds in addition to pheromones and that some pheromones are detected by the main olfactory system.

Sensory Epithelium & Receptors
The VNO is a tubular crescent shape and split into two pairs, separated by the nasal septum. The crescent lumen is lined with receptor neurons on the medial concave side and is filled with fluid from the VN glands. There VN neurons are isolated from the nasal cavity and therefore isolated from the air stream that passes during normal respiration. This means that a stimulus requires arousal of the vascular pump which is lateral to the lumen. The medial, concave area of the lumen is lined with a pseudo stratified epithelium that has tree main cell types: receptor cells, supporting cells, and basal cells. The supporting cells are located superficially on the membrane while the basal cells are found on the basement membrane near the non sensory epithelium. The vomeronasal sensory cells form in the olfactory placode along with other sensory olfaction neurons. The vomeronasal sensory neurons communicate with the hypothalamus to change neuroendocrine function. These sensory receptors are often referred to as pheromone receptors since vomeronasal receptors have been tied to detecting pheromones.

The receptor cells are G-protein-coupled receptors which detect the pheromones, which are frequently referred to as pheromone receptors. The receptor neurons possess apical microvilli whose axons merge together to form VN nerves which move from the paired olfactory bulbs to the MOB, entering the posterior dorsal aspect through the AOB. There have been two different G-protein-coupled receptors identified in the VNO, each found in distinct regions. These are V1 and V2. V1 and V2 are seven transmembrane receptors which are not closely related to the main olfactory receptors.


 * V1 receptors, V1Rs, are linked to the G protein, Gαi2. V1Rs are located on the apical compartment of the VNO.  They have a relatively short NH2 terminal and have a great sequence diversity in their transmembrane domains.


 * V2 receptors, V2Rs, are linked to the G-protein, Gαo. These have long extracellular NH2 terminals which are thought to be the binding domain for pheomonal molecules.  V2Rs make up a large family of around 140 different genes that are known for this long extracellular amino terminus.  V2Rs are located on the basal compartment of the VNO.     V2R genes can be grouped in to four separate families, termed A, B, C (also known as V2R2), and D.  Family C V2Rs are quite distinct from the other families and they are expressed in all basal neurons of the VNO.

The vomeronasal organ’s sensory neurons act on a different signaling pathway than that of the main olfactory system’s sensory neurons.
 * The main olfactory system signals using G protein-coupled receptors that activate adenylyl cyclase which opens cyclic nucleotide gated ion channels (CNGs).
 * The vomeronasal organ’s sensory neurons, however, activates 1,4,5-triphosphate (IP3) signaling upon stimulation by pheromones.

Upon stimulation activated by pheromones, IP3 production has been shown to increase in VNO membranes in many animals, while adenylyl cyclase and cyclic adenosine monophosphate (cAMP) remain unaltered. This trend has been shown in many animals, such as the hamster, the pig, the rat, and the garter snake upon introduction of vaginal or seminal secretions into the environment.

V1Rs and V2Rs are suggested to be activated by distinct ligands or pheromones. The evidence that Gi and Go proteins are activated upon stimulation via different pheromones supports this.
 * Gi proteins are activated upon stimulation with lipophilic volatile oderents.
 * Go proteins on the other hand is activated by nonvolatile proteins, suggesting that V2Rs are activated by non volatile proteins.

Sensory Neurons
Vomeronasal sensory neurons are extremely sensitive and fire action potentials at currents as low as 1 pA. Many patch-clamp recordings have confirmed the sensitivity of the vomeronasal neurons. This sensitivity is tied to the fact that the resting potential of the vomeronasal neurons are relatively close to that of the firing threshold of these neurons. Vomeronasal sensory neurons also show remarkably slow adaptation and the firing rate increases with increasing current up to 10 pA. The main olfactory sensory neurons fire single burst action potentials and show a much quicker adaptation rate. Activating neurons that have V1 receptors, V1Rs, cause field potentials that have weak, fluctuating responses that are seen the anterior of the accessory olfactory bulb, AOB. Activation of neurons that contain V2 receptors, V2Rs, however, promote distinct oscillations in the posterior of the AOB.

In animals (other than humans)
The functional vomeronasal system is found in many animals, including many mammals, such as mice, rats, snakes, elephants, cow, dog, goat, pig etc.


 * The organ is also well developed in some primates such as the Nycticebus tardigradus or the Cebus capucinus.


 * Snakes use this organ to sense prey, sticking their tongue out to gather scents and touching it to the opening of the organ when the tongue is retracted.


 * Elephants transfer chemosensory stimuli to the vomeronasal opening in the roof of their mouths using the prehensile structure, sometimes called a "finger", at the tips of their trunks.


 * House cats often may be seen making this grimace when examining a scent that interests them.

In some other mammals, the entire organ contracts or pumps in order to draw in the scents.


 * Salamanders perform a nose tapping bahavior to supposedly activate its VNO.


 * Dogs lick urine deposits of others to direct the stimulus to the VNO. This behavior is especially seen if the urine is produced by female dogs in heat.

Some mammals, particularly felids and ungulates, use a distinctive facial movement called the flehmen response to direct inhaled compounds to this organ. The animal will lift its head after finding the odorant, wrinkle its nose while lifting its lips, and cease to breathe momentarily. Flehmen behavior is associated with “anatomical specialization”, and animals that present flehmen behavior have incisive papilla and ducts, which connect the oral cavity to the VNO, that are found behind their teeth.

Behavioral Studies
Kudjakova et al. performed exploratory behavioral studies on non purebred rats by extirpating the VNO. The study showed that the exploratory behavior of the rats with extirpated VNO’s were significantly different from both control groups of rats. These results suggest that removal of the VNO removed the experimental rats from important social information. This is seen in the reduced exploratory activity in the experimental animal and the lower number of species-specific reactions.

Another study conducted by Beauchamp et al. investigated the role of the VNO in male guinea pigs social behavior. Half of the guinea pigs vomeronasal systems were removed, while the other half were put under fake surgeries with their vomeronasal systems left intact. The findings suggested that the VNO in the male domestic guinea pig is necessary for the maintenance of normal responsiveness to sex odors. However, “in its absence, other sensory systems are capable of maintaining normal sexual behavior under conditions of laboratory testing.”

These behavioral studies show the importance of the vomeronasal system in animals’ social networks and everyday activities. The importance of the vomeronasal system to the role of reproduction and social networking has been shown in many studies.

In humans
Anatomical studies demonstrate that in humans the vomeronasal organ regresses during fetal development, as is the case with some other mammals, including apes, cetaceans, and some bats. In fact, the human embryonic VNO possesses bipolar cells and luteinizing hormone releasing hormone (LHRH) producing cells, both that are characteristics of developing vomeronasal systems in other animals. The presence of a VNO in human embryos goes undisputed. It is debatable, and somewhat controversial, whether or not there is a presence of the vomeronasal system in adult humans.

Many studies have been performed to find if there is an actual presence of a VNO in adult humans. Trotier et al. estimated that around 92% of their subjects that had no septal surgery had at least one intact VNO. Kajer and Hansen, on the other hand, stated that VNO structure disappeared at later stages in development. Won (2000) found evidence of a VNO in 13 of his 22 cadavers (59.1%) and in 22 of his 78 living patients (28.2%). Many studies have shown that there is a structure in adult humans in the septal mucosa inside the nasal septum that opens from the VNO pit. This structure is found in the same location of the VNO of human embryos and is thought by many to be the adult human VNO.

Given these finding, many believe that there is a VNO in many adult humans, however this does not suggest that the VNO is functional in adult humans. The human VNO is absent of neurons that show characteristics of active sensory neurons that can be seen in working vomeronasal systems of other animals. Furthermore, there is no evidence to date that suggests there are nerve and axon connections between any existing sensory receptor cells that may be in the adult human VNO and the brain. Likewise, there is no evidence for any accessory olfactory bulb in the adult human. Monti-Blonch et al. in 1996 put forth data that suggested the existence of functional vomeronasal pituitary pathway in adult humans by administering vomeropherin to male subjects and measuring changes in electrodermal activity and EEG patterns. This was the first study to provide any support for the existence of a functional VNO in adult humans.

Given these findings, it is unlikely, though still debatable, that the adult human VNO is functional. However, the absence of a vomeronasal system in humans does not suggest that there is no detection of pheromones since some are detected by the main olfactory system as well.