History of neuroscience: Julien Jean Cesar Legallois

The idea that different parts of the nervous system are specialized for specific functions has been a pervasive concept in brain science since ancient times, perhaps best exemplified by the belief---dating back to the 4th century CE---that the four cavities of the brain known as the ventricles each were responsible for a different function, e.g. perception in the two lateral ventricles, cognition in the third ventricle, and memory in the fourth ventricle. By the early 1800s, however, there was still no definitive experimental evidence linking a particular function to a circumscribed area of the brain.

Image showing the medulla oblongata, the region of the brainstem that Legallois found was essential to respiration.

Image showing the medulla oblongata, the region of the brainstem that Legallois found was essential to respiration.

This changed with Julien Jean Cesar Legallois, a young French physician who was driven to identify the parts of the brain and body that were essential for maintaining life. The thinking at the time was that the heart and brain were both integral to life, but there was some debate about where the life-sustaining centers in the brain were located. Some, for example, considered the cerebellum to be the organ that controlled vital functions like heartbeat and respiration. Research conducted in the second half of the 18th century by the French physician Antione Charles de Lorry, however, had suggested that the area of the brain most critical to life was found in the upper spinal cord. Legallois would take Lorry's research a step further by conducting a series of gruesome experiments with rabbits that would help him to specifically pinpoint the center of vital functions in the brain.

Before detailing these experiments, it's important to mention that Legallois' studies were done at a time when the ethical treatment of animals in research---and indeed ethics in research at all---were not given much thought. Legallois was a vivisectionist, meaning that he performed surgery on living animals in his experiments. Legallois' work would not be likely to be approved by a university or research institution today, and indeed when you read Legallois' own impassive descriptions of his grisly experiments they sound like something a budding serial killer might have dreamed up before he moved on to human victims. But this was a different time, when thoughts about animal welfare were not as well formulated as they are now---and Legallois was far from the only vivisectionist of his day. Indeed, a great deal of our current neuroscience knowledge was developed using experimental methods we would consider unjustifiably cruel today. 

Legallois' method of exploring the centers of vital functions in the brain primarily involved the decapitation of rabbits. Legallois observed that after a decapitation made at certain levels of the brainstem, the headless body of a rabbit could still continue to breathe and "survive" for some time (up to five and a half hours according to Legallois). Decapitation further down the brainstem, however, would cause respiration to cease immediately. This observation was in agreement with Lorry's. Legallois then set out to isolate the particular part of the brainstem where these respiratory functions were located.

To do this, Legallois opened the skull of a young rabbit (while the rabbit was still alive), and began to remove portions of the brain---slice by slice. He found that he could remove all of the cerebrum and cerebellum and much of the brainstem, and respiration would continue. But, when he reached a particular location in the medulla oblongata---at the point of origin for the vagus nerve---respiration stopped. Thus, Legallois surmised that respiration did not depend on the whole brain but on one circumscribed area of the medulla. He concluded that the "primary seat of life" was in the medulla, not the cerebellum or cerebrum.

Legallois published the details of his seminal experiment in 1812. We now consider the medulla to be a critical area for the control of respiration as well as the regulation of heart rate, and the region is often considered to be a center of vital functions in the nervous system. Indeed, Legallois was influential in establishing the hypothesis that the brain is involved in the regulation of heart rate as well (prior hypotheses had emphasized the ability of the heart to act alone---without the influence of the brain). While Legallois was not the first to hypothesize that vital functions are localized to the medulla (he was preceded by Lorry), he was the first to provide clear experimental evidence linking the medulla to such functions, and he greatly refined Lorry's estimation of where the vital centers were located. In the process, Legallois gave us our first clear evidence that linked a function to a localized area of the brain.

Cheung T. 2013. Limits of Life and Death: Legallois's Decapitation Experiments. Journal of the History of Biology. 46: 283-313.

Finger, S. 1994. Origins of Neuroscience. New York, NY: Oxford University Press.

For more about the medulla oblongata's role in vital functions, read this article: Know your brain - Medulla oblongata

History of neuroscience: Charles Scott Sherrington

sherrington.jpg

To many, Charles Scott Sherrington is best known for providing us with the term synapse, a word we still use to describe the junction where two neurons communicate. While Sherrington's work to understand synapses and neural communication was important, however, his studies of reflexes, proprioception, spinal nerves, muscle action, and movement were much more expansive and probably even more influential.

Regardless, his observations concerning synapses are representative of the meticulous care with which he investigated and made deductions about the nervous system and its function. His writings on the synapse came at a time when Santiago Ramon y Cajal was beginning to convince the scientific community that the brain consists of separate nerve cells (which became known as neurons in 1891) rather than a continuous "net" of uninterrupted nerves. One thing missing from this theory was an understanding of how neurons might communicate with one another.

In writing on that issue, Sherrington proposed a specialized membrane---which he termed a synapse---that separates two nerve cells that come together. Microscopes of the day couldn't actually observe the separation found at synapses (which is minutely small), so Sherrington was forced to describe the synapse as a purely functional separation---but a separation nonetheless. He based his hypothesis on observations he made in his own research like the fact that reflexes (which he studied extensively) weren't as fast as they should be if they involved simply conducting signals along continuous nerve fibers. Sherrington had originally planned to use the term syndesm to describe the functional junction between neurons, but a friend suggested synapse, from the Greek meaning "to clasp," since it "yields a better adjectival form." 

Thus the term synapse was born, but for Sherrington his observations about the synapse were really just one part of a much greater investigation into reflexes and nerve-muscle communication. He made an important contribution in this area when he helped to elucidate the mechanism underlying the famous knee-jerk reflex (which you've likely experienced when a doctor has tapped just below your kneecap to cause your leg to kick outwards).

His work on spinal reflexes also led Sherrington to another seminal hypothesis. He proposed that muscles don't just receive innervation from nerves that travel to them from the spinal cord but that they also send sensory information about muscle length, tension, and position back to the spinal cord. Sherrington believed that this information is important for things like muscle tone and posture. He hypothesized that there are receptors in the muscle that convey this type of information, and he specifically identified muscle spindles and golgi tendon organs as potential receptors that send information about stretch and tension, respectively (this would later be confirmed). To describe the information these muscle receptors send, Sherrington coined another termproprioception. He chose this term because proprius is Latin for "own" and he wanted to emphasize that the sensory information sent from these muscle receptors comes from an individual's own body, and is not initiated by an external stimulus (as is common with other receptors).

Among Sherrington's many other contributions to understanding movement and muscle function, he also helped to develop a better understanding of the mechanism underlying something called reciprocal innervation. Reciprocal innervation refers to the way in which the activation of one muscle influences the activity of other muscles. This is a common and necessary response. As we walk across the floor, for example, when the muscles involved in the extension of one leg are activated, the muscles involved in the retraction of that same leg must be inhibited. Otherwise, our muscles would constantly be competing with one another, which would result in complete rigidity and make movement (or even standing in one place) impossible. Sherrington didn't discover the phenomenon of reciprocal innervation, but he spent years studying it and in the process gave us a better understanding of how it works. His investigations of reciprocal innervation led to a number of experiments on complex reflexes involved in movements like walking, running, and even scratching. His work helped us to understand how some reflexes involve chaining together several simple reflexive actions to create a seemingly complicated behavioral display.

Sherrington's focus on spinal nerves and reflexes led him to map the motor nerves traveling from the spinal cord to the muscles and the sensory nerves traveling from the muscles to the spinal cord---a task which took him almost ten years. He also explored the functionality of these nerves, helping to create a map of the area of the body served by a single spinal nerve (areas known as dermatomes). And he mapped the ape motor cortex, expanding on previous maps that had been made with dogs and monkeys.

Thus, although Sherrington may be best known for his naming of the synapse, his other work---which was broad but focused a great deal on muscles, movement, and reflexes---was probably even more valuable to our overall understanding of the nervous system. Sherrington won the Nobel Prize for Medicine in 1932 just as he was entering into his retirement, as recognition for his wide-ranging contributions to neuroscience. He continued to write into retirement, and branched out from scientific writing to publish a collection of poems as well as a book that focused on philosophical themes like the relationship between the mind, brain, and soul. He died in 1952 at the age of ninety-five.

Finger S. Minds Behind the Brain. New York, NY: Oxford University Press; 2000

2-Minute Neuroscience: Neurotransmitter Release

In this video, I describe the mechanisms underlying neurotransmitter release. I discuss how calcium influx is thought to play a role in mobilizing and preparing synaptic vesicles for neurotransmitter release, and I cover the hypothesized mechanism by which vesicles fuse with the cell membrane of the neuron to empty their contents into the synaptic cleft.

Know your brain: Preoptic area

Where is the preoptic area?

the preoptic area is highlighted in blue.

Functionally, the preoptic area is considered to be a region of the hypothalamus even though its embryological origins are as part of the telencephalon (rather than the diencephalon like the rest of the hypothalamus). It consists of the area of the hypothalamus that is situated at the very anterior (i.e. front) of the structure, and it extends back from the anterior of the hypothalamus to the posterior edge of the optic chiasm, the point where the optic nerves from the two eyes meet.

The preoptic area, like the rest of the hypothalamus, is a very functionally diverse region. This diversity is represented by the division of the preoptic area into a collection of distinct nuclei. The majority of the research into the preoptic area, however, has been done in rodents; it is not as well understood in humans. This has caused the anatomical differentiation of the preoptic area to not be completely consistent when applied to the human brain and has generated some disagreement, for example, as to which areas of the human preoptic area are homologous to those of the rat brain.

What is the preoptic area and what does it do?

As mentioned above, the preoptic area consists of several nuclei (each of which are often divided into subnuclei), and thus is a very functionally heterogeneous region. To attempt to simplify it, I will discuss the functions most commonly attributed to what are generally considered the major nuclei of the preoptic area (e.g. the median, periventricular, medial, and ventrolateral nuclei). The preoptic area is still not very well understood in humans, however, so the functions listed here will not be a comprehensive list of all that the preoptic area is involved in. Additionally, because most of the attempts to elucidate the function of the preoptic area has been done in rodents, it is still unclear if some of the functionality I will discuss can be said to describe the preoptic area in humans. 

The median preoptic nucleus is found near the midline of the brain and at the very anterior end of the hypothalamus, where it borders the third ventricle. It merges and is neurally connected with a structure called the organum vasculosum, and it also receives input from another structure called the subfornical organ. The organum vasculosum and the subfornical organ are both part of a group of structures known as circumventricular organs. These structures lack a blood-brain barrier and thus can detect the levels of substances (e.g. sodium, hormones) in the blood, then pass this information on to the brain. The median preoptic nucleus is thought to receive such information from the organum vasculosum and subfornical organ and then seems to be involved in using that information to help regulate blood composition and volume, both through mechanisms of hormone release and through behavior like drinking.

The median preoptic nucleus also appears to play a role in the regulation of body temperature. Rodent studies suggest neurons in the median preoptic nucleus receive information regarding skin temperature and then send projections to neurons in the medulla that are involved in mechanisms that influence body temperature.

Just below the median preoptic nucleus is the preoptic periventricular nucleus. The preoptic periventricular nucleus is poorly defined anatomically (its boundaries vary depending on species) and poorly understood functionally. Some consider it to be equivalent to an area called the anteroventral periventricular nucleus, which is thought to be involved with sex-specific physiology and behavior, but according to other sources it is a separate location. There is limited information available on the preoptic periventricular nucleus as a stand-alone structure when it is not considered as part of the anteroventral periventricular nucleus or other nuclei nearby.

Lateral to the median preoptic nucleus is the medial preoptic nucleus. The medial preoptic nucleus is the largest collection of preoptic area neurons. It has been linked to a list of actions ranging from regulation of cardiovascular function to regulation of body temperature and fluid balance and water intake. This region, however, is best known for its association with reproductive and parental behavior.

The medial preoptic nucleus is often divided into subnuclei, and the central medial preoptic nucleus in the rat is sometimes called the sexually dimorphic nucleus, as it has been found to be larger in males than females. This observation has also been replicated in a number of other species. Although this has not been seen as consistently in humans, researchers have identified potential homologous regions in the human medial preoptic area that also have been observed to exhibit sexual dimorphism.

The sexually dimorphic nucleus in rodents has been linked to male sexual behavior and male partner preference. Lesions to different parts of this region have been found to eliminate male copulatory behavior and inhibit sexual desire. Additionally, damage to the sexually dimorphic nucleus in male ferrets was associated with their sexually-motivated seeking of same-sex males rather than females. In a study of sheep (which are unique in that ~8% of rams display a consistent preference for male sexual partners), it was found that the sexually dimorphic nucleus was twice as large in female-oriented rams than in male-oriented (i.e. homosexual) rams.

These findings, of course, have led to speculation that the sexually dimorphic nucleus in humans may also be linked to sexual preference. Although there has been some debate as to what the human homolog of the rat sexually dimorphic nucleus actually is, there have been studies that have found sexual dimorphism among preoptic regions in humans. Some studies have also observed differences in size in these regions between heterosexual and homosexual men. These findings, however, have not been seen consistently from study to study, and need to be confirmed before we can be confident in them.

Additionally, the central medial preoptic nucleus has been linked to parental behavior in rodents, sheep, and other mammals. For example, damage to the connections of the medial preoptic nucleus can disrupt parental behaviors like nest building and pup retrieval (i.e. collecting stray pups when they wander from the nest) in rodents. And activation of medial preoptic neurons mitigates male aggression toward pups as well as stimulates the grooming of pups.

Just above the optic chiasm is another nucleus that is known as the ventrolateral preoptic nucleus in rodents. It is generally considered to be homologous with a nucleus in the human brain called the intermediate nucleus, and this cell group actually overlaps with the nuclei discussed above that are thought to be sexually dimorphic in the human brain. This region is thought to play an important role in sleep regulation. Damage to the ventrolateral preoptic nucleus can cause sleep disruptions in a variety of mammalian species. One hypothesis is that ventrolateral preoptic neurons extend to brain regions involved in arousal; through the release of inhibitory neurotransmitters like GABA, the ventrolateral preoptic nucleus can inhibit the activity of these regions to promote sleep. The median preoptic area (discussed above) is also thought to potentially contribute to the induction of sleep.

The preoptic area consists of a collection of nuclei that are interconnected with numerous other hypothalamic regions and other regions of the brain. The anatomy and function of the preoptic area is still being worked out, and the functions presented here are just a short and very abridged list of everything the preoptic region is likely involved in. Additionally, due to the inconsistency in definitions of preoptic nuclei in the human hypothalamus, it is possible some of the definitions discussed above will change with further research into the preoptic area. 

Saper, BS. (2012). Hypothalamus. In JK Mai and G Paxinos (Eds.) The Human Nervous System, 548-583 DOI: https://.org/10.1016/B978-0-12-374236-0.10016-1

History of neuroscience: John Hughlings Jackson

In 1860, when John Hughlings Jackson was just beginning his career as a physician, neurology did not yet exist as a medical specialty. In fact, at that time there had been little attention paid to developing a standard approach to treating patients with neurological disease. Such an approach was one of Jackson's greatest contributions to neuroscience. He advocated for examining each patient individually in an attempt to identify the biological underpinnings of neurological disorders. This examination, Jackson asserted, should be guided by the tenets of localization of function, which had been popularized by Franz Joseph Gall in the decades before Jackson was born. Concordant with these tenets, Jackson believed that neurological dysfunction could be traced back to dysfunction in specific foci of the nervous system, and the ability to identify the part of the nervous system that was affected to produce a disease was critical for making an accurate diagnosis.

Jackson's perspective on understanding neurological diseases is exemplified by his efforts to elucidate the neurobiological origins of epilepsy---the work he is probably best known for. Jackson's observations on epilepsy date back to the very beginning of his medical career. At that time, the most popular explanation for epileptic seizures was that they were associated with abnormal function in a region of the brain known as the corpus striatum, a term that refers to a composite structure consisting of the striatum and the globus pallidus. The corpus striatum was known to be involved with motor functions, which caused it to be implicated in epileptic seizures as well.

Jackson, however, began to suspect that the cerebral cortex participated in creating the convulsions that epileptics suffered from during seizures. To support this hypothesis, he cited cases where patients experienced convulsions that primarily struck one side of the body. Very often, Jackson argued, these patients upon autopsy would display damage to the cerebral hemisphere on the opposite side of the body that was affected by seizures.

Watch this 2-Minute Neuroscience video to learn more about epilepsy.

Jackson approached the idea that there were certain areas of the cortex devoted to movement with hesitancy for multiple reasons. First, at the time the prevailing view was still that the cortex was unexcitable, and thus would be unlikely to be affected by what Jackson considered to be a disease of increased excitability. Additionally, it was still common in Jackson's time to consider the cortex to be homogenous. Although the concept of localization of function was challenging this idea, many still held the belief that all gray matter in the cortex was equivalent and there were no areas of functional specialization. According to this view, the entire mass of the cortex had to act together to produce some sort of response. Jackson's idea that seizures could be linked to increased excitability in one half of the cortex did not conform to this perspective.

In addition to his observations about the link between hemispheric damage and seizures on the other side of the body, Jackson also noted a unique feature of some of the seizures he observed. He pointed out that in certain patients convulsions started in one specific area of the body and then proceeded to travel outward from that area in a predictable fashion. For example, convulsions might begin in the hand and then move up the arm to the face, and then down the same leg on the same side of the body. Or they might start in the foot and travel up the leg, then down the arm and into the hand on the same side of the body.

This process, later called the Jacksonian march, would help Jackson to formulate some of his most important ideas about the brain. He hypothesized that there were areas of the cortex that were devoted to controlling the movement of different parts of the body. When excitation spreads throughout the cortex, Jackson posited, it stimulates these different areas one by one, creating the Jacksonian march of convulsions through the patient's body. Furthermore, Jackson suggested that the parts of the body that were capable of the most diverse movements (e.g. hand, face, foot) likely had the most space in the cortex devoted to them.

With his observations on epilepsy Jackson was essentially predicting the existence of the motor cortex as well as anticipating the functional arrangement of the gray matter that the motor cortex is made up of. His hypothesis that there was a distinct region of the cerebral cortex devoted to motor function was confirmed in 1870 when Gustav Fritsch and Eduard Hitzig provided experimental evidence of a motor cortex in dogs. The arrangement Jackson envisioned, where one part of the cortex is devoted to one part of the body, we now call somatotopic arrangement. It has been verified by a series of experiments, capped by Wilder Penfield's electrical stimulation studies of the 1930s. It is now common neuroscience knowledge that there are regions of the motor cortex that seem to be devoted specifically to movement of the hands, other regions devoted to the movement of the face, and so on. As Jackson predicted, areas of the body that are involved in more diverse movements generally have more cortical area devoted to them.

Jackson's clinical observations of epilepsy and his hypotheses about the motor regions in the cortex accurately predicted what would soon be discovered through experimentation, and acted as a guide for researchers like Fritsch and Hitzig. Thus, Jackson's work contributed significantly to a better understanding of the organization of the cortex, a region that we now consider to be functionally diverse and intricately arranged---a far cry from the idea of cortical homogeneity common in Jackson's time. Additionally, Jackson's development of a more formalized methodology of observation in neurology has caused him to be considered one of the founding fathers of the field.

Jackson's contributions to neuroscience, however, were much more extensive than there is room to cover here. He wrote copiously on diverse topics ranging from the evolution of the nervous system to aphasia. At a time when our understanding of the brain was still so lacking in comparison to today, Jackson had a brilliant mind that seemed capable of comprehending brain function in a way that has rarely been replicated in the history of neuroscience.

Finger, S. Origins of Neuroscience. New York, NY: Oxford University Press; 1994.

York GK, Steinberg DA (2007). An Introduction to the Life and Work of John Hughlings Jackson. Med Hist Suppl. (26), 3-34