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The initial views of the nervous system were adopted by Pythagoras and Plato. Plato stated that there was a clear association and interaction between the soul and the body (1). Up to that point, the soul was known as something called the "psyche", and was thought to be composed of spherical particles that were located in the brain (1). Plato echoed these ideas and said that the soul-body interaction took place in the nervous system (1). In one of his works, called Timaeus, he said that there was a bond between the soul and a substance called "marrow" which was found in the brain and spinal cord (1).

Plato's major contribution was to eventually propose the idea that the soul, which rested in the body, represented rationality and that this "soul" was located in the nervous system (1).

Source:
1.https://damienadupont.wordpress.com/2010/03/27/plato-on-how-the-brain-and-body-influence-each-other-

2.https://www.britannica.com/biography/Plato

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Galen had revolutionary ideas about the nervous system and its structure. For starters, Galen believed that the brain was the origination point for nerves (2). He re-iterated the concept of a "vital pneuma" that was put forth by Aristotle that stated that this "vital pneuma" gave life to the organs of the body and helped those organs carry out their functions (1). However, Galen added the point that this vital pneuma would be converted to psychic pneuma by the brain and conducted to the rest of the body via nerves (1).

Galen was the first to introduce the concept of 2 types of nerves: sensory and motor (2). He also believed that these functions of nerves were coordinated by 2 types of nerves which he deemed "hard" and "soft (2). His quote illustrating these concepts says, "All muscles require to receive a nerve from the brain or from the spinal cord and this nerve is small to behold but by no means slight in power" (1).

Galen also had a hypothesis on the mode of transmission of this psychic pneuma (1). He hypothesized that the psychic pneuma would travel through the nerve, and get pushed out the end of the nerve, where it would then act on the muscles to conduct a specific function (1). These hypotheses would serve as a precursor to synapse research over the next 1500-2000 years.

Sources:
1.https://www.sciencedirect.com/science/article/pii/S0361923099000945#BIB41

2.https://web.stanford.edu/class/history13/earlysciencelab/body1/nervespages/nerves.html#:~:text=Galen%20believed%20that%20the%20brain,carried%20sensation%20to%20the%20limbs.

3.https://www.sapaviva.com/claudius-galen-of-pergamon/

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Descartes would go against the grain and fly in the face of the previous teachings of Aristotle which had been in place for a significant period of time up to that point (1). He disregarded the idea of the "psychic pneuma" as the driving force behind muscle activation and nerve conduction (1). To answer the question of conduction and transmission, Descartes presented a mechanistic view of man. “I suppose the body to be nothing but a statue or machine made of earth, which God forms with the explicit intention of making it as much as possible like us." (1).

In this new view presented by Descartes, the pineal gland was at the center of perception and muscle activation and movement (1). Descartes proposed that the pineal gland was filled with animal spirits, and the pattern in which these animal spirits flowed through the pineal gland would determine sensation, and imagination (1). He also said that the pineal gland was instrumental in muscle movement as well (1).

One type of muscle movement proposed by Descartes was that when the pineal moved, it moved closer towards valves in the walls of the ventricles in the heart (1). The animal spirits in the pineal gland would travel into these valves and flow to the muscles via nerves, which carried these "animal spirits" (1). These spirits would control particular valves near the target muscles which would control the tension of said muscles, causing contraction and/or relaxation, and movement (1). To illustrate this idea, he says,  “And note that if we have an idea about moving a member, that idea—consisting of nothing but the way in which spirits flow from the gland—is the cause of the movement itself" (1).

Sources:
1.https://plato.stanford.edu/archives/sum2011/entries/pineal-gland/#2.1

2.https://www.itcamefromthepond.com/tag/history-and-philosophy-of-science/

This picture was taken from one of Descartes's work , called Traité de l’Homme, which was published in 1644. In it, he describes the pea-shaped pineal gland and tackles the mind-body problem (2).

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Hans and Zacharias Jansen are credited with building the first microscope in 1595 (1).  However, there were a lot of flaws with the design so, in the 17th century, it was perfected by scientists such as Robert Hooke, and Anton Van Leeuwenhoek (1). Leeuwenhoek's microscope, specifically, was extremely potent, and could magnify up to 300X (1). He used this power to discover never before seen microscopic organisms such as protozoa and spermatozoa (1). Also, in 1674, he used this microscope to cut open and observe a cow's optical nerves (1). He then discovered that they were not hollow tubes as proposed by Descartes (1).

However, even these first microscopes were very rudimentary, and did not allow for high quality observations (1). In the 19th century, the invention of the achromatic lens allowed scientists to see structures in high magnifications without spherical aberrations (1).

Sources:
1.https://cerebromente.org.br/n17/history/neurons1_i.htm

2.https://cerebromente.org.br/n17/history/neurons1_i.htm- Picture

This is a drawing of a cross section of a nerve by Van Leeuwenhoek in 1719 (2).

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With the discovery of the microscope by Van Leeuwenhoek in 1668, there was an effort in the scientific community to understand the composition of these so-called "nerves" (1). Felice Fontana, in the late 18th century, performed nerve dissections (which are pictured below) to shed more light on this problem (2). He concluded that these vessels were not hollow, and contained the same "animal spirits" referenced by Descartes (1). Specifically, in 1781, he had this to say on the structure of the axoplasm that made up the cut end of an axon (1). He described them as "… glutinous, elastic, transparent material, insoluble in water, that decomposed itself into very little round grains of a diameter four or five times less than a red blood globule" (1).

These discoveries were made at approximately the same time that Galvani was drawing his conclusions on the nature of the conduction material between nerves (1). This represented a shift towards looking at electricity being the conduction material for nerves and not these "animal spirits" (1).

Sources:
1.https://www.sciencedirect.com/science/article/pii/S0361923099000945#BIB25

2.https://www.researchgate.net/figure/Panel-A-Structure-of-nerve-tissue-by-Felice-Fontana-1781-Part-a-A-primitive-nerve_fig3_272076102-Picture

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Between 1781 and 1791, Galvani created many different experiments to show that nerves used electrical conduction to transmit information (1). His frog experiment, arguably his most famous undertaking, provided evidence for the existence of "nervous electric fluid" (1). He also proved that this electric fluid would flow along nerves, in addition to flowing through the spinal cord as well (1).

Furthermore, Galvani's experiments also proved the existence of endogenous animal electricity (1). Another famous frog experiment he did to prove this is when he showed that frog legs would twitch when they were hung from brass hooks even when a thunderstorm was not present (1). A further experiment Galvani did to prove this fact was to put a severed end of a nerve, obtained from a frog leg, adjacent to an intact portion of a nerve (1). When he did this, he observed movement of the leg associated with the severed nerve (1).

The impact of Galvani's experiments cannot be understated. Rather than continuing the notion of "animal spirits" conducting along nerves, Galvani conducted experiments to show that nerves conduct electricity (1).

Sources:
1.https://www.sciencedirect.com/science/article/pii/S0361923099000945#BIB25

2.https://www.neuroscientificallychallenged.com/blog/history-of-neuroscience-luigi-galvani-Picture

This picture is from Galvani's 1791 publication detailing the setup of his frog experiments and some of the instruments used in his lab.

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Okay, what do these neurons even look like? (7)

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Okay, what do these neurons even look like? (7)

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The advent of good staining techniques in the 19th centuries allowed for the initial descriptions and classifications of neurons (1). C.G. Ehrenberg classified single nerve cells in the leech nervous system and Purkinje classified nerve cells in the cerebellum of mammalian nervous systems (1). Kuhne discovered differences in the structure between the end of a motor neuron and the adjacent neurons it synapses onto (1). Kuhne proposed that the electrical current discharged by the nerve would enter the muscle at the neural endplate (1).

In 1865, Dieters illustrated that dendrites originated from nerve fibers (1). He did this through his illustrations of an ox spinal cord. He speculated that the many finger-like projections on the surface of these dendrites could play a role in signaling, and that inputs would be received by the dendrites through these projections (1). In 1898, Auerbach demonstrated with a silver stain the "end bulbs" of nerve fibers, which he believed to be continuous with adjacent nerves, a fact that would be disproved with the advent of better staining techniques in the coming decades (1).

Sources:
1.https://www.sciencedirect.com/science/article/pii/S0361923099000945#aep-section-id22

2.https://www.sciencedirect.com/science/article/pii/S0361923099000945#aep-section-id22

In this picture, (A) was the ox neuron analyzed by Dieters in 1865 that proved to him the presence of dendrites (2).

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Sherrington's research on spinal reflexes in the 1890's shined light on the concept of conduction across nerve terminals to nerves in the spinal cord and the difference between this and the transmission of an action potential through a nerve (1). Sherrington stressed the fact that there was a gap between the end bulb of a neuron and the beginning of an adjacent neuron (1). He says, "The evidence of Wallerian secondary degeneration is clear in showing that process observes strictly a boundary between neurone and neurone in the reflex arc" (1).

Through further research , Sherrington embraced the term "synapse" as a way to describe this gap between the end bulb of a neuron and the beginning of the adjacent neuron (1). This research went against the research of Boerhaave, Kuhn, and Golgi, who were adamant in their opinion that neurons were continuous with each other (1). These conclusions were supported by Cajal's research (1). Cajal's stains showed that conduction was only possible in one direction down an axon, and across a synapse (1).

Sources:
1.https://www.sciencedirect.com/science/article/pii/S0361923099000945#BIB25

2.https://www.nobelprizemedicine.org/selecting-laureates/history/the-nobel-prizes-in-the-field-of-neuroscience/

This picture is from a publication by Sherrington, in which he demonstrates his idea of the "synapse" (2).

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With the revelation that the synapse was a gap between neurons, the next question was concerning the nature of the materials that crossed the synapse and allowed the neurons to communicate with each other (1). In his book, Tale of the Dueling Neurosurgeons,  Sam Kean discusses this fierce debate (1). The "sparks", a group of scientists who believed that neurons used pulses of electricity to send signals across the synapse, initially were the dominant thought group in the field (1). According to Kean, this is because that chemical transmission across the synapse, an idea proposed by the "soups", seemed old and outdated, very similar to the concept of "humors" proposed by the Ancient Greeks (1). In addition to disfavorable opinions against soups, there were experiments that were on the sparks' side (1). Probes, a recently developed technology at the time, showed that neurons conducted and discharged electricity whenever they fired an action potential (1). The sparks reasoned that if electricity was used for internal use in a neuron, electricity could also be used as a signalling mechanism between neurons (1).

The soups, however, rejected these claims by the sparks and maintained that there were chemicals involved in the signalling processes between neurons (1). However, a scientist named Otto Loewi conducted experiments with frogs and provided a tremendous victory for the soups (1). His experiments  proved that in animals, chemicals were used to transmit messages (1). His work was instrumental in the discovery of all the different neurotransmitters (1).

Sources:
1. KEAN, S. (2014). TALE OF THE DUELING NEUROSURGEONS. GRAND CENTRAL.

2. https://www.amazon.com/Tale-Dueling-Neurosurgeons-Revealed-Recovery-ebook/dp/B00GG0GIXQ

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THE FINALE: Otto's Loewi's grand conclusion (10)

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THE FINALE: Otto's Loewi's grand conclusion (10)

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Otto Loewi was part of the science community known as the "soups", scientists who thought that the signaling between neurons involved chemicals (1). His now famous experiment with frogs, conducted in 1920, was the knockout punch in this soups vs sparks debate that opened the door for many different avenues of neuroscience research (1).

He used two beating frog hearts, and placed them in two separate chambers (1). One of the hearts had a supplied vagus nerve intact, and one of them had no supplied vagus nerve (1). He then stimulated the intact vagus nerve supplying one of the hearts and observed that the heart slowed down (2). However, when he took the liquid associated with the first heart and applied it to the second heart, he saw that the second heart slowed down as well, even though there was no vagal innervation to that second heart (1). He termed this inhibitory material "vagusstoff". Today, that is known as acetylcholine (1). On the contrary, he also saw that excitatory material from a stimulated heart also caused a second heart to beat more quickly (1). This proved to the scientific community that chemicals were involved in the cell communication between neurons, and Loewi was awarded the Nobel Prize in 1936 (1).

Sources:
1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291908/pdf/SMJ-55-3.pdf

2.https://cerebromente.org.br/n17/history/neurons5_i.htm

Otto Loewi's original experiment, done in 1920 (2).

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Otto Loewi was a German-born pharmacologist born in Frankfurt in 1873 to wealthy wine merchant parents (1). As a young boy, he was enamored with the arts, and originally wanted to go to graduate school to study art history (1). However, that idea was shot down by his father , who persuaded him into becoming a physician (1). At university, his passion for the humanities and arts did not fade, as he would regularly skive off his own classes to attend humanities lectures (1).

After a lot of trials and tribulations, Loewi completed his medical degree in 1896 (1). His early research in the lab of Dr. Hans Meyer was concerned with drugs and their effects on different systems (1). In 1902, Loewi traveled to the lab of Dr. Ernest Starling, an English physiologist (1). It was there that he met Henry Dale, a fellow scientist and Loewi's future friend (1). He also met a medical student named Thomas Renton Elliot, who was studying cell communication at Cambridge under the tutelage of Dr. John Langley (1).   Loewi and Elliot had deep and interesting discussions regarding nerve cell communication, and Elliot proposed that adrenaline might be the chemical involved in nerve cell communication at the synapse (1). It was these interactions that pushed Loewi into conducting experiments to illuminate more about this issue, and eventually he would conduct his famous frog experiment, and shed light on the chemicals involved in nerve cell communication (1).

Sources:
1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291908/pdf/SMJ-55-3.pdf

2. http://lymberis.com/oLoewi.html

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A recent study done by Peking University in China looked at the effect of glutamate dysfunction on drug-seeking behavior (1). Glutamate is an endogenous excitatory neurotransmitter that is involved in many neuronal signalling pathways in the brain (1). Specifically, impairment in the glutamate homeostasis pathway in the nucleus accumbens, the reward center for the brain, led to an increase in negative drug-seeking behavior (1).

There is an increase in the presynaptic levels of glutamate and there is a scarcity of glutamate outside the synapse in cocaine-treated rats (1). This dysfunction in glutamate has been linked to a dysfunction in the mGluR2/R3 glutamate receptors (1). However, sustained infusions in the nucleus accumbens of the cannabinoid AEA has been shown to reverse this glutamate dysregulation and restore glutamate homeostasis even after cocaine self-administration (1).

Sources:
1.https://www.nature.com/articles/s41386-021-00955-1.pdf

2.https://www.nature.com/articles/s41386-021-00955-1.pdf-picture

This is a visual representation of the effects of the infusion of the cannabinoid AEA on glutamate homeostasis (2).