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1. Ancient Greek Hypotheses on Sensation

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1. Ancient Greek Hypotheses on Sensation

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As we have learned in lecture, the Ancient Greeks had many theories on nerve conduction that we know to be untrue or incomplete today, but they laid the groundwork for future findings related to synaptic transmission. Greek physician and philosopher Alcmaeon of Croton had theories on the nervous system that were relevant during the late 5th Century. His findings showed that the mind and brain were intertwined and not distinct entities. In regards to nerve conduction and sensation, Alcmaeon believed that senses were understood through the brain.

Alcmaeon also believed that every sense organ (eyes, ears, mouth, nose, skin) was connected to the brain via channels he called "poroi" (1). For instance, he theorized that when air is inhaled through the nostrils, its smell was directly transmitted to the brain through poroi. The concepts of neurons, synapses, and electrical conduction of signals were not even remotely in existence at this point, but Alcmaeon's research was significant because it put the brain at the center of the nervous system as a relay system for stimuli, an idea that evidently still applies to neuroscience today.

As we have learned in class, another notable Greek figure, Galen, believed that the brain and spinal cord dictated much of sensation, and that nerves carried pneuma that facilitated communication between the brain and body (2). This theory dominated over the second long-reigning theory that the heart facilitated sensation, but was limited by a lack of physiological experimentation in favor of anatomical dissections.

The artifact pictured above is in reference to Galen's identification of nerves themselves - he found that nerves not only existed but were specialized to dictate sensation (soft nerves) and movement (hard nerves) distinctly through transmission of various pneuma to the brain as signals (2). Galen's findings also certainly paved the way for further discoveries related to nerve conduction.

Sources: (1) https://www.itmedicalteam.pl/articles/the-ancient-greek-discovery-of-the-nervous-systemalcmaeon-praxagoras-and-herophilus-107334.html

(2) https://pubmed.ncbi.nlm.nih.gov/8046725/

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2. Anatomical Drawings from the Renaissance

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2. Anatomical Drawings from the Renaissance

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During the Renaissance, many anatomists passionate about uncovering the secrets of the human body performed detailed dissections on both animals and people in hopes of pinning down the structure.

For instance, in the 15th century, renowned artist Leonardo Da Vinci conducted numerous dissections and created intricate drawings of many body systems, including the nervous system. His drawings included images of the skull, brain, and cerebral ventricles.

Scientist Andreas Vesalius took depictions of the nervous system a step further, by drawing detailed images of the brain in his famous book "De Humani Corporis Fabrica" (On the Fabric of the Human Body), published in 1543. Before this, nobody had ever produced images of the nervous system with such accuracy, including cross-sections of the brain, dura, and vessels leading to the brain (2). While he did not directly identify nerve tracts, this was a landmark in the quest to learning about synaptic transmission years later. Without an understanding of the layout of the central and peripheral nervous systems, it would be difficult to lay the groundwork to discover the organization of nerves and connections to different areas of the brain. For example, the image above is one of Vesalius' drawings, including fiber tracts that connect to the brain (3). The fact that he understood that so many connections exist within the body shows an understanding of communication before reaching the brain, which is consistent with the communication between neurons even though this was not an explicit concept.

Sources: (1) https://www.rct.uk/sites/default/files/file-downloads/9781909686834_High%20Res..pdf

(2) https://www.ajnr.org/content/35/1/19

(3) https://artsandculture.google.com/asset/nervous-system-of-the-human-body/IgFQ6JSMmRve9Q?hl=en

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In the late 19th Century, scientists identified the neuron as the discrete cell of the nervous system, with distinguishable structure and mechanics.

One scientist, Camillo Golgi, laid the foundation of neurohistology with the introduction of cell staining techniques. He led an active laboratory and was fixated on perfecting the visualization of various cells including the neuron. Above is a photo of him in the lab in 1920, surrounded by different chemicals and substances used to produce various stains (1). Golgi finally created an image of a neuron with a soma, dendrites, axon, and axon terminals.

From, here fellow scientist Santiago Cajal popularized the neuron doctrine, which stated that the nervous system was made up of many discrete cells known as neurons (2). This finding was instrumental to neuroscience - obviously. Without this discovery, we would have to have a wildly incomplete understanding of the way the the nervous system functions and communicates so quickly and efficiently.

There was now an understanding requires thousands of neurons working together to relay messages and sensations to the brain so quickly. The discovery of the neuron certainly laid the groundwork for the discovery of the synapse considering that so many individual cells exist in this system - they must have a means to communicate with one another in order to be functional. With so many advanced images of the neuron, there was no lack of anatomical evidence of the action potential and synaptic transmission. At this point, experimentation was required to actually see a neuron firing in action.

Sources: (1) https://www.frontiersin.org/articles/10.3389/fnana.2019.00003/full

(2) https://embryo.asu.edu/pages/neuron-doctrine-1860-1895

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Austrian neuroscientist Otto Loewi led a landmark investigation that demonstrated that nerve cells communicate using neurotransmitters in 1921. Loewi had long hypothesized chemical transmissions between neurons but wanted to show this process in action.

Before his experiment, it was known in the scientific community the vagus nerve, which innervates the heart, slowed down heart rate when electrically stimulated. Loewi believed that this change was facilitated via the release of a substance through the end of the vagus nerve.

To prove his theory, he used two isolated, beating frog hearts. He electrically stimulated the vagus nerve of the first heart, and expectedly, the heart's beat slowed. Upon collecting and transferring the solution of the first heart to the second heart, its rate also decreased (1).

It could then reasonably be concluded that there was some sort of chemical substance in the solution of the first heart that could have the same effect on the second heart - without direct stimulation of the second heart's vagus nerve. The experimental set-up is shown in the image above, with the two hearts hung on either side of a pole (2).

Loewi's findings were revolutionary as they proved the existence of the molecules that facilitate all of neuronal communication. We now know there molecules as neurotransmitters, and in the case of the frog heart experiment specifically, acetylcholine. The missing piece of the puzzle of neuronal communication at this point was the way that these molecules traveled from neuron to neuron, activating each one at their dendrites via synapses.

Sources: (1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291908/

(2) https://link.springer.com/article/10.1007/s00424-021-02580-9

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By the 19th century, many anatomists and neuroscientists had an understanding that there was an electrical element to nerve cell communication. A German physiologist, Emil du Bois-Reymond, significantly contributed to this finding. He developed instruments, one being the galvanometer, that could measure small electrical currents produced by biological cells, including nerve cells (1).

While little was actually known about the structure of the neuron, the fact that du Bois-Raymond demonstrated that nerve cells generate electrical impulses was a monumental milestone in neuroscience. We know today that redistribution of ion charge causes a change in voltage across the neuron cell membrane - a very important concept in understanding synaptic communication because the voltage of the neuron is a large indicator as to which point of the action potential a neuron is in.

Du Bois-Raymond also identified the "law of unchanging total current", which states that the current flowing through a nerve cell remains constant during the generation of an action potential. This law would be important in understanding the all-or-nothing response of neurons, and how a neuron will surely fire and release neurotransmitters into the synapse after a threshold voltage is reached.

The image above is one of du Bois-Ray using a galvanometer to measure his entire bodily current. The tool had many applications, and measuring neuronal currents was only one of them (1).

Source: (1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588001/

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In the early 20th century, the term "synapse" was finally coined by Sir Charles Sherrington, a British physiologist. Sherrington had been intrigued by reflex arcs, and more specifically by the neural pathways involved in spinal reflexes. As we know, reflexes are the rapid responses of muscles to stimuli without conscious thought. The attached image shows Sherrington and his colleague C.S. Roy at the door of the Old Pathological Laboratory in Cambridge, where he conducted much of his research regarding reflex arcs (2).

Sherrington identified a couple of key takeaways. First, he quickly realized temporal summation to be true. For instance, if two stimuli were applied to a muscle in quick succession, the reflex was much more precise than if just one stimuli was applied. This indicated his second takeaway - that there must be a delay between the sensory nerve receiving the signal and muscle moving. He also found that the speed of different types of nerve fibers varied, with sensory fibers conducting more slowly than motor fibers (1).

All of this pointed to a bigger conclusion for Sherrington. He realized that this slight delay in motor output was due to the transport of biomolecules released from neural tracts from the cell to the muscle. This area was named the synapse - or the gap between two neurons or a neuron and effector organ (1). Essentially, he had identified the site of communication between neurons.

Sources: (1) https://jnnp.bmj.com/content/75/4/544

(2) https://en.wikipedia.org/wiki/Charles_Scott_Sherrington

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In the mid-20th century, many technological advancements surfaced that were pivotal in the build-up to the discovery of synaptic transmission.

To start, the invention and refinement of the oscilloscope greatly improved electrophysiology. This device graphically displays and analyzes electrical signals. It enabled researchers to see the electrical patterns of neurons in real time, and pin down the different properties of neuronal firing based on the portion of the action potential it was measuring. Scientists were hence able to see electrical events occurring in individual neurons and neuronal networks alike (1).

Another technique known as the "patch clamp technique" allowed for the study of ion channels by creating a seal between a glass microelectrode and a tiny patch of neuronal membrane. This isolates electrical currents and allows for the measurement of currents flowing through individual ion channels (2).

These innovations continue to be used in investigations of neuroscience today, and provide critical insights into neuronal communication, synaptic transmission, and ion channel function, laying the foundation for modern neuroscience research. The graph above shows early records of voltage-activated single channels taken using the patch clamp technique (3).

Sources: (1) https://www.ncbi.nlm.nih.gov/books/NBK11069/

(2) https://www.leica-microsystems.com/science-lab/life-science/the-patch-clamp-technique/

(3) https://www.nobelprize.org/uploads/2018/06/neher-lecture.pdf

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8. Discovery of the Neuromuscular Junction

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8. Discovery of the Neuromuscular Junction

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During the late 1800s, British researcher John Newport Langley explored the mystery surrounding the neuromuscular junction. At this point in time, the scientific community was very interested in learning more about the relationship between nerve conduction and muscle contraction.

Langley developed experiments using isolated nerve-muscle arrangements, usually from frogs and mammals, and was able to identify the region when nerve fibers make contact with muscle fibers. He termed this area the "neuromuscular junction" (1).

Further, Langley was able to characterize the neuromuscular junction and identify what exactly made it so unique. He described it as a specialized synapse in which the axon terminal of the motor neuron is able to communicate with the muscle fiber through release of neurotransmitters, later referred to as acetylcholine, and prompt muscle contraction. Information about muscle contraction can be found in a book of his findings titled "The Autonomic Nervous System" and pictured above (2).

The identification of the neuromuscular junction was a huge feat. It is the most popular example of a synapse today and serves as a model for studying synaptic communication and neurotransmitter release.

Sources: (1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC546337/#:~:text=Langley%20suggested%20that%20a%20cell,of%20these%20two%20receptor%20types.

(2) https://openlibrary.org/books/OL24179879M/The_autonomic_nervous_system

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In the 1930s and 40s, scientists Henry Dale and Otto Loewi together proposed the quantal hypothesis of neurotransmitter release, which states that neurotransmitters in the synapse are released from presynaptic nerve terminals in transmitter packages known as quanta.

Both scientists conducted experiments on neuromuscular transmission, and realized that some nerve impulses developed more precise muscle contractions while other created weaker muscle contractions. This observation indicated that neurotransmitter release at the neuromuscular junction might not be continuous but rather occur in discrete packets (1).

After statistical analysis of the frequency and amplitude of muscle responses, the pair found that neurotransmitter release could be described using a quantal model (1). The graph included above is not historical, but displays how neurotransmitters are released in different events over a period of time, consistent with the quantal model (2). The quantal model has revolutionized our understanding of synaptic transmission and mechanism of neurotransmitters in the synapse.

Sources: (1) https://www.ncbi.nlm.nih.gov/books/NBK11028/

(2)https://www.researchgate.net/figure/The-histogram-of-the-quantal-release-times-and-the-curve-of-the-TCS-obtained-from-the_fig1_5424860

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10. Sir Bernard Katz Displays Evidence of Synaptic Transmission and Wins the Nobel Prize

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10. Sir Bernard Katz Displays Evidence of Synaptic Transmission and Wins the Nobel Prize

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Sir Bernard Katz won the Nobel Prize in Physiology in the year 1970 for his discoveries in neuroscience during the 1940s to 50s. His experiments also largely utilized the frog neuromuscular junction as well as intracellular recording to compute the response of muscle fibers to electrical stimulation. What he found was consistent with the quantum model - that there were discrete increases in membrane potential (later named miniature end-plate potentials (MEPPs)) (1).

What Katz identified specifically is that even when a nerve wasn't stimulated, MEPPs still occurred. So, it made sense that quantal release occurred in nerve conduction. What he added with his findings was that neurons fire in an-or-nothing response because no signaling occurred until a voltage threshold was achieved.

Further, Katz was able to identify the specific ions that facilitate the action potential and consequently synaptic transmission. His work highlighted the job of the calcium ions in promoting synaptic vesicle fusion and neurotransmitter release, helping to create the foundation for future research on presynaptic calcium channels and exocytosis (1). The image above displays his findings - that neurotransmitters are stored in vesicles, released discretely in vesicles, and reabsorbed by the pre-synaptic cell as a means of inactivation (2).

Source: (1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151334/

(2) https://openbooks.lib.msu.edu/neuroscience/chapter/neurotransmitter-clearance/

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Today, mental illness is rampant, including disorders like chronic depression, anxiety, bipolar disorder, schizophrenia, and eating disorders just to name a few. Many of these illnesses are caused by imbalances in or a lack of neurotransmitters.

Depression, for example, can be a caused by a factor of things including environmental factors, life events, an abnormal sleep cycle, and like mentioned above, an imbalance of neurotransmitters. Chemicals in the brain such as seretonin and noradrenaline are mood-boosting and allow us to be alert, respectively. When our bodies fail to produce ample amounts of these hormones, we can experience a series of symptoms - a common one being depression (1).

Antidepressants are thought to work by not only increasing neurotransmitters, but increasing their concentration in the synaptic junction. A specific class of antidepressants, known as Seretonin-noradrenaline reuptake inhibitors (SNRIs) bind to the channels on the presynaptic cell membrane specialized to bind to neurotransmitters and cause reuptake. By doing this, they inhibit these channels, allowing seretonin and noadrenaline to remain in the synapse and bind to post-synaptic cell for a longer amount of time (1). The image in this post show oral antidepressants (how they are typically taken) as well as an exam - a mental status exam typically used to see if someone can clincally be diagnosed with depression (2).

Source: (1) https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/antidepressants/

(2) https://pharmanewsintel.com/features/understanding-serotonin-and-norepinephrine-reuptake-inhibitors-snris

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Sir Bernard Katz is the docent and Nobel prize winner in this exhibit. He was born on March 26, 1911 in Leipzig, Germany. He's known for his work on synaptic transmission in England, however, in neuroscience in 1940-50. He studied medicine at the University of Leipzig, and received the Siegfried Garten Prize for physiological research in 1933 (1).

Katz won the Nobel Prize for his work in quantal neurotransmitter release and synaptic transmission in 1970, along with biophysiologists Julius Axelrod and Ulf von Euler. He's pictured above looking into a microscope (1).

As a PhD student, Katz was passionate about the workings of the nervous system and dedicated his life to discovering the mechanics of nerve conduction after acquiring both his PhD and MD.

Source: (1) https://www.nobelprize.org/prizes/medicine/1970/katz/lecture/