Module 1 Lesson 02: History of Neuroscience Overview

Home , Franz Nissl, Jean Pierre Flourens, Neuron doctrine

1 - Students will be able to state early views of the brain. 2 - Students will be able to explain Galen’s views on ventricular localization of brain function. 3 - Students will be able to explain the ideas set forth by Rene Descartes. 4 - Students will be able to describe contributions towards the notion of electrical signaling in nerves to the brain. 5 -Students will be able to describe the discovery of localization within the cerebral cortex. 6 - Students will be able to explain the Nissl and Golgi stains. 7 - Students will be able to explain the neuron doctrine and its signiﬁcance. 8 - Students will be able to describe the contributions of Otto Loewi to understanding of neurotransmission.

2 Growing Views of the Brain

As history has progressed, our understanding of the brain has continued to develop

● Ancient scholars proposed theories addressing the role of the brain ● Renaissance scholars explored the nature of the mind and experience ● 19 and 20th century scholars studied detailed properties of the nervous system Mind Body Dualism Chris Palmer Science wikipedia Writer Growing Views of the Brain

As history has progressed, our understanding of the brain has continued to develop

Hippocrates 500 B.C. Aristotle 380 B.C. Galen 130 A.D. Descartes 1500s What is the role of the What is the role of the How does the structure How do we reconcile brain? brain? of the brain give rise to the non-physical mind its function? and physical brain? Brenton Bussinger (2015) Curious John Kaag (2019) New York Times Systems ‘Need a New Self-Help Guru? Try Lapham's quarterly Andrea Borghini (2019) ThoughtCo Aristotle’ ‘René Descartes' "Proofs of God's Existence.”’ Trepanation

● Over 7000 years ago, trepanation was used as a medical treatment ○ Boring holes into skull of living patients ○ Thought to be used as a treatment for headaches and psychiatric disorders ● Image shows a healed skull

Bear, Mark F. Neuroscience: Exploring the Brain Edwin Smith Surgical Papyrus: The Brain

● It contains the ﬁrst written form of “brain” and describes what we Egyptian hieroglyphic recognize as the meninges and for “brain” cerebrospinal ﬂuid.

● It noted "the pulsations of the exposed brain" and compared the Egyptian hieroglyphic surface of the brain to the rippling for “cerebrospinal fluid” surface of copper slag.

Eric Chudler Neuroscience for kids What is the role of the brain?

Aristotle: The heart is the center of intellect, and the brain is a radiator for cooling blood.

Hippocrates: The brain is involved in sensation and is the seat of intelligence.

John Kaag (2019) New York Times ‘Need a New Self-Help Guru? Try Brenton Bussinger (2015) Curious Aristotle’ Systems 2 Galen: Ventricular Localization of Brain Function Who Was Galen?

● Claudius Galenus, a Roman physician, lived from 129 A.D. to 201 A.D. ● He regarded anatomy as the foundation of medical knowledge, countering the religious and supernatural explanations for illness. ○ Advocated for the Hippocratic view of brain function ● Gained access to human tissue as a physician to gladiators

Lapham's quarterly What is the role of the brain?

● Sought to elucidate brain function by analyzing structure ○ Proposed that cerebrum must receive sensations and the cerebellum must command muscles

● Studied eﬀects of brain lesions in both animal and human subjects ○ “Squealing pig” demonstration - cut live pig/caused it to squeal, then cut nerves innervating vocal Mindvalley (2018) ‘Cerebrum Vs cord to make it stop Cerebellum: What Is The Diﬀerence?’ Galen and the Ventricular Theory

● How does the brain receives sensations to move limbs? ● To answer this, Galen opened up the brain ○ Discovered that it was hollow ● Believed the ﬂuid here was the medium for communication between the brain and body ● Claimed that sensations were registered and motions willed via the movement of ﬂuid through the ventricles Ibn Sina (980) Ventricular theory of sensation and perception De generatione embryonis Growing Views of the Brain

As history has progressed, our understanding of the brain has continued to develop

● Born in France, he initially pursued a career in law before discovering his passion for engineering and mathematics.

● He studied a wide variety of topics such as dualism, physiology and psychology, moral philosophy, religion, natural science, and animals.

● Most widely remembered for the development of Cartesian geometry and pioneered “standard mathematical notation” Andrea Borghini (2019) ThoughtCo ‘René Descartes' "Proofs of God's Existence.”’ René Descartes and Mind-Body Dualism

● Believed the Galen’s ideas on the role of the ventricles and CSF were a good way to describe mechanistic aspects of the brain ○ Unable to describe the workings of the mind ● Believed the mind is spiritual and received commands from the brain via communication with the pineal gland ● Introduced the idea of mind-body dualism

Mind Body Dualism wikipedia René Descartes and Animal Spirits

● Proposed that liquid ﬂows through hollow nerves to control motor function ○ Previous scientists thought weightless/non-physical spirits ﬂowed through

● No diﬀerence between humans and animals other than complexity and soul ○ Believed that mechanisms of neuronal function could and should be studied mechanistically

Mind Body Dualism wikipedia New Anatomical Descriptions

Dissections done during the Renaissance gave rise to new anatomical descriptions detailing matter types, lobes, and subdivisions of the nervous system.

Bear, Mark F. Neuroscience: Exploring the Brain 4 Contributions to Electrical Signaling in Nerves Growing Views of the Brain

As history has progressed, our understanding of the brain has continued to develop

Galvani (DATE) Charles Bell (DATE) Magendie (DATE) How does electricity Do sensory and motor nerves How do sensory nerves activate nerves? use the same pathways to travel? transmit information? The Electrical Revolution

● In 1751, Benjamin Franklin published Experiments and Observations on Electricity

● Provided a new understanding of electricity

● Motivated experiments that studied electrical properties of biological systems The Top 10 Signiﬁcant Figures Who Helped Found America Luigi Aloisio Galvani

● In the late 1700s, Galvani discovered that muscular movement in a frog can be induced by electricity.

● He knew artiﬁcial sources of electricity could cause muscle twitching but proved that natural electricity (lightning) can too.

Luigi Aloisio Galvani wikipedia Experiment

● Galvani prepared nerves and connected them to long wires directed towards the sky ● He realized that the muscles contracted in correspondence with lightning , making the frogs “dance” Hypothesis: Negatively-charged muscles form a complete circuit with our positively-charged surroundings, creating an electric ﬂow that contracts muscle. Luigi Aloisio Galvani wikipedia “Discussion Question After his ﬁrst experiment, Galvani wanted to test whether or not electrical information can

be transmitted between nerves without

metals. He attached two sciatic nerves and

stimulates one. What eﬀect (if any) do you “ think this had on the second nerve?

26 Experiment

● Galvani prepared another set of frog legs each with sciatic nerves attached (nerves connected two legs) ● Realized when the ﬁrst nerve was in contact with the second, muscle contraction occured in both simultaneously Hypothesis: Nerve cells can communicate via biological electricity. Sir Charles Bell

In the early 1800s, Bell studied the functions of different nerves. ● Wanted to know if signals to muscles used same wires as sensory signals ● Cut each root individually and observed effect ● Found that cutting the ventral root only caused muscle paralysis ● Bell identified the functions of motor and sensory nerves Bell C (1798): Vol. 1. Edinburgh: Mundell & Son; Glasgow: J Mundell. Bell - Magendie

● After Bell’s experiments, french physiologist Magendie contributed this idea ● Showed that dorsal roots carry sensory information to the spinal cord ● Bell and magendie concluded together that each nerve contains a mixture of wires that bring information to and from the brain

5 Localization of Brain Function Anatomical Views of the Brain

Gall 1700s Broca 1800s Nissl 1800s Golgi 1800s Ramon y Cajal What do bumps on How does brain How can neurons How are 1800s the brain say about damages cause in the brain be neurons How are neurons personality? aphasia? visualized? anatomically anatomically structured? Franz Gall wikipedia structured? Encyclopedia Britannica Franz Nissl Camillo Golgi Santiago Ramon y Pierre Paul Broca wikipedia wikipedia Cajal wikipedia Franz Gall and Phrenology

● Franz Gall known for his work on phrenology ○ Correlating the structure of the head with personality traits ● Believed that bumps on the brain were characteristic of certain traits ● Used to justify racist beliefs and assert the superiority of Western Europeans

Encyclopedia Britannica Franz Joseph Gall Flourens and Functional Localization

● Jean Pierre Flourens challenged Gall’s view of phrenology ○ Ideas not backed by experimentation

● Conducted lesion studies in pigeons to more rigorously characterize the functions of diﬀerent brain regions ○ Cerebellum controls motor coordination ○ Brainstem necessary for life-sustaining functions ○ Semicircular canals in inner ear control balance Broca and Localization in Humans

Pierre Paul Broca demonstrated that some brain functions are localized in humans through post-mortem studies of patients with aphasias (speech deﬁcits)

Right: Paul Pierre Broca: A Brief Biography Patient Tan

● Louis Leborgne lost the ability to speak at 30 years old ● Only syllable he could pronounce was “Tan” ○ Became known as “Patient Tan” ● Post mortem, Broca discovered that Tan had a lesion within his left frontal lobe ● Broca went on to ﬁnd autopsy evidence from more cases to support the localization of spoken language Bear, Mark F. Neuroscience: Exploring the Brain Broca’s Legacy

● The area aﬀects language comprehension and speaking through communication with other regions of the brain. ● Revolutionized the understanding of language processing as well as what disorders are caused by damage to this area. ● Following Broca, many others investigated localization of function through lesion studies Christian Gonzalez IYNA Journal ‘Broca’s Aphasia: At a Loss for Words’ Observing the Cells of the 6 Nervous System Histology Stains

● In the late 1800s, two stains were developed to visualize cells in the nervous system ● The Nissl stain is typically cresyl violet acetate or toluidine blue, both capable of binding to nucleotides ○ Allows scientists to visualize cell bodies/nuclei ● The Golgi stain utilizes silver nitrate ○ Allows scientists to visualize the Marc Dingman (2017) entire neuron (cell body and Brain stuﬀ: What is a Nissl Neuroscientiﬁcally neurites) stain 2018 Challenged: History of neuroscience Nissl Stain

● This technique is useful for observing the structure of regions of the brain (how they are layered and organized).

● Genetic material is found in the cell body so the orientation of neurons can be determined.

● Orientation can give insights into the transmission of impulses and how neurons communicate.

NSA Thionine (Nissl) Cell Body Stain Golgi Stain

● Golgi’s largest contribution is his use of a silver nitrate stain

● The advantages of this technique over Nissl’s is that the entire neuron can be seen instead of just the parts housing genetic material

● Only stains about 3% of the total neurons in a sample of tissue Marc Dingman (2017) Neuroscientiﬁcally Challenged: History of neuroscience 7Neuron Doctrine Santiago Ramón y Cajal

● Cajal was a Spanish neuroscientist and pathologist who won a Nobel Prize in neurophysiology

● Studied the anatomy of cells in the nervous system using Golgi stain and reﬁned methods

Psychology today: Does the Cerebellum Fine-Tune Complex Cerebral Functions? (2016) The Neuron Doctrine

● Development of Golgi Stain allowed Cajal to see connections between neurons ● Observed that individuals neurons are the fundamental (and discrete) units of the nervous system ● Neurons connect together to form networks ● Conﬁrmed decades lasted with electron microscopy

Mitch Glickstein (2006) Current biology Golgi and Cajal: The neuron doctrine and the 100th anniversary of the 1906 Nobel Prize Reticular Hypothesis vs. Neuron Doctrine

● Golgi believed that neurons formed interconnected syncticium (continuous network, single cell) ● Ramon y Cajal used Golgi’s own staining method but developed the opposite conclusion ● Shared the Nobel Prize in 1906, despite substantial disagreements

Santiago Ramon y Cajal Camillo Golgi wikipedia wikipedia Ramon y Cajal’s Prescience

● Based on brain structure alone, predicted many aspects of nervous system function ○ Neurodevelopment ○ Cellular Neuroscience

● Left incredibly detailed drawings of micrographs for future scientists to observe

Quanta magazine: Why the First Drawings of Neurons Were Defaced Structures Observed in Chick Embryo During Development

Castro et al. (2007) Brain Research Reviews Neuroanatomy of the Retina

Near pupil

Away from pupil

Santiesteban et al. (2017) Frontiers in Neurology Cerebellar Neuron

Chris Palmer (2013) The scientist magazine: The Neuron Doctrine, circa 1894 8 Otto Loewi: Neurotransmission Views of Signaling in the Brain

Loewi 1900s Huxley 1900s Hodgkin 1900s Is neurotransmission How does ion ﬂow govern How does ion ﬂow govern chemical or electrical? the action potential? the action potential? Otto Loewi

Are synapses electrical or chemical? How does transmission happen?

● Pharmacologist and psychobiologist ● Discovered the role of acetylcholine as a neurotransmitter ● Proved the neurotransmission is chemical ● 1936 - Nobel Prize in Physiology or Medicine

Otto Loewi wikipedia Loewi experiment

Sankari Arunachalam (2015) Physiology of Neuromodulation and neuromodulators