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History of neuroscience

Sarah Olesen, Peter Vincent

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History of neuroscience: a journey toward the mystery of intelligence

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Ancient views of intelligence and the brain
Neuron Doctrine and Cellular neuroscience
Modern neuroscience (or methods of neuroscience)

Lecture overview

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The heart is the seat of intelligence

(Ancient Egypt and Aristotle)

Aristotle

(c. 384 BC – c. 322 BC)

The brain was not always held in high regard. The ancient Egyptians did not think much of the brain. In fact, when creating a mummy, the Egyptians scooped out the brain through the nostrils and threw it away. However, the heart and other internal organs were removed carefully and preserved. These organs were then placed back into the body or into jars that were set next to the body.

The Greek philosopher, Aristotle, thought the heart, not the brain, was the location of intelligence and thought. He considered the brain to be a secondary organ that served as a cooling agent for the heart and a place in which spirit circulated freely. He designated the space in which all the spirits came together as the sensus communis – the origins of our modern-day metaphorical term, “common sense”.)

(In Ancient Egypt, the concept of heart included three constituents: heart-haty, heart-ib, and the spiritual seat of intelligence, emotion and memory)

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The brain is the seat of intelligence

(Hippocrates, Galen)

Galen

(129 AD – c. 200 AD)

Hippocrates

(c. 460 BC – c. 370 BC)

On the other hand, other greek scholars did not agree with Aristotle.

Hippocrates, the "Father of Medicine, believed that the brain is the seat of intelligence. He also discusses epilepsy as a disturbance of the brain.

After Hippocrates, the next significant physician was Galen, a who lived from AD 129 to AD 200. His observations of the effects of brain injuries on mental activity formed an important practical basis for his conclusions. Galen concluded that the brain was the seat of the animal soul – one of three “souls” found in the body, each associated with a principal organ. He believed the brain was a cold, moist organ formed of sperm. One of his experiments showed that

Galen dissected the brains of sheep, monkeys, dogs, swine, among other non-human mammals. He concluded that, as the cerebellum was denser than the brain, it must control the muscles, while as the cerebrum was soft, it must be where the senses were processed. Galen further theorized that the brain functioned by movement of animal spirits through the ventricles. "Further, his studies of the cranial nerves and spinal cord were outstanding. He noted that specific spinal nerves controlled specific muscles, and had the idea of the reciprocal action of muscles.

Galen's principal interest was in human anatomy, but Roman law had prohibited the dissection of human cadavers since about 150 BC.^[39] Because of this restriction, Galen performed anatomical dissections on living (vivisection) and dead animals, mostly focusing on primates.^[6] This work was useful because Galen believed that the anatomical structures of these animals closely mirrored those of humans. Galen clarified the anatomy of the trachea and was the first to demonstrate that the larynx generates the voice

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Brain anatomy: from ventricles to functional areas

Traditionally, people believe that intelligence lies into the ventricles in the brain, such as imagination was located in the anterior ventricle memory in the posterior ventricle, and reason located in the middle

Renaissance physicians began to dissect the brain with greater frequency.

(Middle top picture) Da vinci, for example, began to examine the relationship between the brain and the olfactory and optical nerves through experimenting with wax injections that helped him to model the ventricles. He sketched the brain from many different perspectives, looking closely at the ventricles and the origins of the nerves in the medulla.

(Middle bottom picture) In

(right picture) With advances in techniques, people started to map the function of the brain in their areas. This is also how we often view and study the brain.

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Ancient views of intelligence and the brain
Neuron Doctrine and Cellular neuroscience
Modern neuroscience (or methods of neuroscience)

Lecture overview

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A system of small neurons (Neuron Doctrine) or

a system of a big neuron (Reticular Theory)

CAJAL'S REPRESENTATION OF THE LAYERS OF THE CEREBRAL CORTEX..

At the time, the widely held view of the brain was that it was made up of a single network of nerve fibers that were all physically connected to one another. In other words, the nerves of the brain were thought to make up one big, continuous nerve net. In 1873, however, Camillo Golgi had developed a new stain (a stain is simply something added to cells for microscopy that allows the cells or their structures to be seen) that allowed nerve cells to be visualized more clearly under a microscope. When the processes of neurons could be seen with better resolution using the Golgi stain, some began to suggest that nerve cells were just that: individual cells that were not actually connected to each other.

In the end, both Golgi and Ramón y Cajal shared the Nobel Prize in Physiology or Medicine in 1906 for their extensive observations, descriptions and categorizations of neurons throughout the brain.

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Neuron doctrine: the nervous system is made up of discrete individual cells

CAJAL'S REPRESENTATION OF THE LAYERS OF THE CEREBRAL CORTEX..

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Galvani: electrical transmission (1791)

How does it work?

As we saw in previous slides, neurons are not in physical contact, they are individual cells. So how can these cells communicate? And not just how neurons communicate with eachother, but hou they send signals to other tissues?

Scientific community had been wondering what caused muscles to contract. Several theories existed but with no physical /scientific proof.

Nowadays we know electricity exists and is responsible by muscles contraction in our bodies. But the first to propose that and prove it was Luigi Galvani (Italy 1780).The theory that animals generate electricity was already in Galvani mind for a while. He did experiments in the lab that started to prove electricity caused muscle contraction. But in the case it was used static electricity(). So a new experience outdoor proved that natural electricity could induce the same effect. A frog corpse lay on the table. A storm was coming. All that remained was the final touch: connecting the lightning rod to the frog. Then, after making the connection, it was time to wait.

At long last, the storm came. Whenever lightning flashed nearby, energy coursed down the rod and the frog’s leg twitched!

He had already shown that his static electricity generator made frog legs twitch in controlled laboratory conditions. Here was a piece of evidence to improve his theory: a connection between naturally occurring electricity and movement

https://helix.northwestern.edu/article/experiment-shocked-world

How does this work?

This animated figure shows Galvani’s understanding of animal electricity. When the bronze (yellow wire) is connected to iron (silver wire), charges flow between the frog’s positively-charged outside and the frog’s negatively-charged inside. This circuit completion causes the frog’s muscles to contract. (Figure credit: Andrew Lai)

Unfortunately Galvani had a very sad ending. His findings were not immediately accepted by scientific community and later because of political issues (Napoleonic invasions) he lost his job as an academic. He died poor one year after losing his job. But today we know that he catalyzed change in medical and physical science.

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Henry Dale (1913) and Otto Loewi (1921):

chemical transmission

neurotransmitters

Henry Dale received the Nobel prize in physiology or medicine in 1936 with Otto Loewi for their research which proved chemical synaptic transmission in the peripheral nervous system.

It was already known the existence of neurons. But how the stimulation of a nerve influenced the effector organ’s function was not well understood yet. It was though that the transmission at synapses was too fast to be a chemical processes. This debate and its final resolution was one of the most crucial in the history of neuroscience in the 20th century.

In 1914 Henry Dale found that acetylcholine generated stimuli in part of the nervous system, the parasympathetic nervous system, which has a dampening effect on heart activity and other functions. After Otto Loewi demonstrated acetylcholine's function as a messenger between nerves and organs, Dale and other researchers refined the understanding of acetylcholine's role in the nervous system.

Nowadays we all know acetylcholine is a neurotransmitter:chemical messengers that transmit a signal from a neuron across the synapse to a target cell

Otto Loewi stimulated the heart of a frog with electrical impulses and had it pump a small amount of nutrient solution. When the fluid was transferred to another heart, it operated in a similar way. This provided proof that chemical substances convey nerve signals to organs.

http://faculty.washington.edu/chudler/chnt.html

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Hodgkin and Huxley (1939): the action potential

Figure on the left - cover of the 1963 Nobel Prize Programme: Huxley is on the left as Hodgkin on the right adjusts an oscilloscope.

Now, by the last 1930s, researchers had come to understand several important things about the conduction of signals within neurons, e.g., they knew that conduction of signals within neurons is electrical in nature, while signaling between neurons is usually chemical. We also knew that electrical transmission in neurons occurs in bursts of activity called action potentials. But the full details of what is going on during an action potential were not made completely clear until Alan Hodgkin and Andrew Huxley started collaborating on the issue in 1939. This is because neurons are incredibly small, and so it’s very hard to insert a recording device to measure voltage changes during an AP.

Briefly - during an action potential, the cell membrane potential rapidly changes, and this happens by the movement of positively-charged sodium channels from the outside to the inside of a neuron through ion channels.

Hodgkin and Huxley famously got around this problem by studying APs in the enormous axons of the squid. They inserted a fine capillary electrode into the squid giant axon and were able to measure electrical changes within the axon during an AP. The found that the membrane potential of the neuron actually reversed during an action potential, causing the neuron to momentarily have a positive membrane potential. This rapid reversal of membrane potential was the impetus for the generation of the electrical signal underlying the AP.

Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell.

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Ancient views of intelligence and the brain
Neuron Doctrine and Cellular neuroscience
Modern neuroscience (or methods of neuroscience)

Lecture overview

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The methods in neuroscience:

techniques differ in their spatial and temporal resolution

Principles of Cognitive Neuroscience 2nd Edition

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Pharmacological Stimulation of the Brain: chemicals

Depression

Epilepsy

Pain relief

Parkinson’s disease

...

and many more!

Chemicals help us understand the brain

Chemicals help us treat brain disease

--- not sure if this is too simple, happy to change it but really not sure how deep to go with short time

One major advance in modern neuroscience was the development of pharmacology as a biomedical science in the 19th century. Pharmacology is the study of the interactions between biological organisms and chemicals (naturally or artificially derived) that affect them. Pharmacology has its’ origins in the middle ages but it only developed into a proper scientific discipline in the 19th century.

Neuroscientists use chemicals/drugs to understand how the brain works:

By studying how different drugs affect mechanisms inside neurons that control neurotransmitter release for example
By using drugs that activate or block normal function of receptors

Studying how chemicals affect brain function has led to major advances in how we treat brain disease in modern medicine - there are drugs that can reduce symptoms of major brain disroders like Depression, etc etc

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Electrical Stimulation of the Brain: electrodes

Deep brain stimulation as therapy

So we can perturb the brain chemically but we can also do it electrically. During the 19th century, many scientists used electric stimulation of the cortex in animals and humans to study motor function for example (Eduard Hitzig, Gustav Fritsch, David Ferrier, Friedrich Goltz, Robert Bartholow , Fedor Krause)

In the 20th century, this technique was improved by the development of the stereotactic method (which allows precise targeting of brain locations in a 3d coordinate system) AND chronic electrode implants made up of straight insulated wires that could be inserted with precision deep in the brain of humans and other animals, such as cats and monkeys, and more recently rats and mice for example. (refer to human figure in the first image)

With electric stimulation, neuroscientists made very important discoveries such as that there exist pleasure centers in the brain, that some parts of the brain represent and control certain parts of the body, and that we can create the illusion of seeing something that isn’t really there just by changing the activity of neurons with electrodes(James Olds, Wilder Penfield).

One of the main use of direct electric stimulation in the brain in recent years has been in the treatment of Parkinsonian tremors using deep brain stimulation, by placing electrodes in the desired brain regions that are connected to an implanted pulse generator via an extension - a portable mechanism.

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Genetic perturbation of the brain: optogenetics

So about 20 years ago, a major revolution occurred in the way that neuroscientists perturb the brain of animals to study brain function - and that was the development of a technique called optogenetics.

Optogenetics refers to the use of light to control neurons. But we just told you that neurons have electric and chemical communication, so how do we control them with light?

The first thing you need to know is that many organisms like some bacteria and algae have ion channels that will open or close when light of a certain wavelength is present (for example blue light), letting different ions pass in or out of their cell membranes.

Then, neuroscientists figured out that they could take the DNA from those algae or bacteria that made up those light-sensitive receptors and put it into neurons in the brains of flies and that when they shined light they could see electric current changes. Later, scientist tried it in mice and it also worked. So these ion channels can now be expressed in the membranes of neurons in many species and if we shine light on them they will open and for example trigger action potentials or shut down the activity of cells.

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Recording Neural Activity:

Whole Cell Patch Clamp in Brain Slices

Electrophysiology

in Injured Tissue

Electrophysiology

in Behavior

So, not only can we change the activities of neurons now, but we can also record from single neurons too. One way to do this is in slices of brain - we prepare slices in such a way that they stay in artificial CSF, or the fluid that surrounds your brain normally, so the cells remain alive for the duration of the recording, and this allows us to measure the voltage, and therefore the activities of these neurons, which is super useful for identifying which parts of the brain talk to which other parts.

ANother interesting thing you can do is look at injury - both in the nervous system, for example after spinal cord injury, but also muscles because there are loads of neurons in there as well. This is just an image of some electrical potential recordings in injured and un-injured spinal cord tissue, and this kind of thing is super useful for diagnosing extent of injury and also for researching potential therapies for repair.

Lastly, we can measure electrical activity in brain regions using optic fibers and fluorescence, essentially allowing us to measure the level of activity of certain brain regions in mice while the mice are doing certain tasks, which is super useful for understanding the activity of various brain areas. Because neurons are so small, this method actually only allows measurements of groups of the same type of neurons buuuuut...

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Recording Neural Activity:

Electrophysiology

in Behavior

Neural Probes

can record whole groups of individual neurons

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Recording Neural Activity:

Hubel & Wiesel’s experiment on cat’s cortical neuron in primary visual cortex

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Recording Neural Activity: fMRI

(Magnetic Resonance Imaging)

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Recording Neural Activity: fMRI

Mind-Reading…?

Lie Detector…?

(Magnetic Resonance Imaging)

In fact, some studies show that fMRI might be more efficient at lie-detection than a standard polygraph, as you have to engage more regions of your brain in order to invent a lie, on the right, than you do to tell the truth, on the left. Also, a handful of labs are looking at using fMRI to “decode” your thoughts, which is kind of a fancy way of saying “mind-reading.” They show the patient the images on the top, and then use the signals picked up by an MRI machine to reconstruct what images the patient sees. They can do this at an extremely high accuracy, all things considered - the output on the bottom is the computer-generated interpretation of what images were shown.

They also apply this to action-based video games, and can use fMRI to predict what move the person will make in the game next, sometimes half a second before the person actually makes it.

https://pubmed.ncbi.nlm.nih.gov/21945275/

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Recording Neural Activity: fMRI

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Studying Innate Behavior

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Studying Learned Behavior

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Recording Neural Activity:

Electroencephalography (EEG)

Normal

Seizure

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