User:Lildevil3221/Area Postrema Project Proposal

Area Postrema Project Proposal
The initial research for the area postrema project was divided into four major categories for each student in the group to explore. After assessing these first findings we will divide up the remaining research, adjusting where necessary, in order to equalize each group member’s work load. The four major categories were “Anatomy and connectivity,” “Function,” “Pathology/disease,” and “History of research/Current research.” The categories were explored by Jess, Danielle, Nick, and Lauren, respectively.

Anatomy and Connectivity
The area postrema is located within the medulla oblongata of the brain stem. More specifically, it is a protuberance found on each side of the fourth ventricle, one of four fluid-filled cavities within the human brain. This location situates this circumventricular organ outside of the blood-brain barrier. The area postrema is connected via nerve fibers to the solitary nucleus, spinal cord and other areas of the medulla.

Function
The area postrema is a critical homeostatic integration center for humoral and neural signals. Recent studies have implicated its role as a chemoreceptor trigger zone for vomiting in response to emetic drugs. Its position outside of the blood-brain barrier makes this particular region of the medulla a key player in the control of autonomic functions, including the cardiovascular system and systems controlling feeding and metabolism. Area postrema is now being considered as the initial site for integration for various physiological signals in the blood as they enter the central nervous system.

Pathology and Disease
Since the area postrema acts as an entry point to the brain for information from the sensory neurons of the stomach, intestines, liver, kidneys, heart, and other internal organs, a variety of the physiological reflexes rely on the area postrema to transfer information. The area postrema also acts to directly monitor the chemical status of the organism. Lesions of the area postrema are sometimes referred to as ‘central vagotomy’ because of their ability to eliminate the brain’s ability to monitor the physiological status through its vagus nerve. These lesions also serve to prevent the detection of poisons and consequently prevent the body’s natural defenses from kicking in. For example, studies in rats and rabbits indicate that angiotension II- dependent hypertansion is abolished by lesioning of the area postrema. In another experiment with rats, the area postrema lesions prevented the detection of Lithium Chloride, which can become toxic at high concentrations. Since the rats could not detect the chemical, they were not able to employ a psychological procedure known as taste aversion conditioning, causing the rat to continuously ingest the toxic chemical when added to its food.

History of research and Current research
The area postrema was first named and located in the gross anatomy of the brain by Magnus Gustaf Retzius, a Swedish anatomist, anthropologist and professor of histology at the Karolinska Mediko-Kirurgiska Institutet in Stockholm. In 1896 he published a two-volume monograph on the gross anatomy of human brain in which the area postrema was mentioned. This work was one of the most important works published in the 19th century on the anatomy of the human brain.

In 1937, a publication by King, L.S. claimed that the area postrema was made up soley of glial cells, but this was later disproved by the research of several scientists including Jan Cammermeyer, Kenneth R. Brizzee and Herbert L. Borison who demonstrated the presence of neurons in the area postrema of several mammal species.

Scientists became increasingly interested in the research of of vomiting in the 1950s, perhaps in part due to society's heightened awareness of radiation sickness, a condition in which many patients who vomited after radiation exposure died. Intensive studies on vomiting began in the 1950s at the University of Utah College of Medicine where Borison held a strong presence as both a professor and a researcher. . He had received his doctorate in 1948 from Colombia University, establishing himself as an authority on brainstem and neurophysiology. Prior to the research of Borison and his well-known colleague S.C. Wang, a doctor and assistant professor from Columbia University, it was believed that the human body's chemodetection and coordination of vomiting, or emesis, were controlled exclusively by the dorsal vagal nucleus. Yet this idea was "incompatible with the observation that emesis could still be induced by gastrointestinal irritants in dogs with chronic lesions of the dorsal vagal nucleus", and so Borison and Wang dedicated their research to solving this puzzle. Borison eventually explained that their results showed the existence of two areas in the brain related to emesis; one, a chemosensor for vomiting with no coordinating function, located in the fourth ventricle and two, a coordinator of vomiting with no chemosensory function, located in the lateral reticular formation of the medulla oblongata.

In 1953 Borison and Wang determined that the chemosensor area acted as a vomiting trigger zone in the brain stem and they named it the chemoreceptor trigger zone (CTZ) for emesis. Using cats and dogs as model organisms, they found that the removal of this trigger zone from the brain allowed for the prevention of emesis in the animals directly following injection of certain chemicals into the blood stream, demonstrating the existence of a relationship between the trigger zone and the act of vomiting. . The CTZ was anatomically located in the area postrema of the medulla oblongata. The area postrema had been anatomically identified and named nearly 60 years earlier, but its function had remained unknown until the work of Borison and Wang proposed its role in emesis, which was later confirmed by many laboratories.

Borison and Wang created the Borison-Wang model of emesis which includes a diagram illustrating their concept of a vestibular emetic pathway connecting through the area postrema as the obligatory route to the emetic center, however, more recent research has shown this model to be incorrect.

Other scientists noted as pioneers in the field of research concerning the area postrema and the mechanism of vomiting in general are Larry McCarthy, A.D. Miller and V. J Wilson.

Research has continued today around the world on the functions of the area postrema. Beyond its role in emesis, as studied intensely by the researchers of the mid 1900s, the activity of the area postrema has been closely linked to other autonomic functions such as regulation of food intake, body fluid homeostasis and cardiovascular regulation through behavioral studies and electrophysiological studies. In 2007 in Japan, research was performed on the mechanism of excitability of area postrema neurons by extracellular ATP. Voltage clamp whole-cell recording techniques were used on rat brain slices. The results showed that most responses to ATP were excitatory and that they were mediated by particular P2 purinoceptors found in the area postrema. The role of the area postrema in flavor conditioned aversion and preference was studied in 2001 by researchers at the Brooklyn College at the City University of New York. The experiment tested the effect of area postrema lesions in rats on their ability to learn to flavor conditioned aversion to flavors paired with toxic drug treatments, which indeed showed that lesions of the area postrema led to impaired flavor aversion learning.