Kick start

Synapses, neurons and brains • Great thinkers think about the brain
Idan Segev • How it (us) all started?
• Brain Blossom worldwide
Lesson #1 • Structure of modern brain-research centers
Brain excitements for the 21st century • The problem with “understanding the brain”

• "You, your joys and sorrows, your

memories and your ambitions, your sense “The most
of personal identity and your free will are in incomprehensible
thing about the world
fact no more than the behavior of a vast
assembly of nerve cells and their
associated molecules" is that it is at all
• (Francis Crick, Nobel Laureate 1962 – “the comprehensible.”
father of DNA”).

"Machine think? You bet! We’re machines and we

think, don’t we?"
(Claude Shannon – “the father of information age”)

So what is the route to comprehend the brain?

The start 3.5 Billion years

200,000
70 Million
years
years
Life begins - Bacteria
Or Humans
Primates

3.5 Billion years of life on earth

The Homo sapiens sapiens

&
The ~ 100 years old “Human Brain Project”
 Modern Humans ~ 200,000 years & Cultural Evolution
The development of mammalian “big brains”
Understanding/
200 Million years - TODAY repairing our brain
Today

Cultural evolution
Cell Phones, ICT

weight - gr
Today

weight (gr)
Modern Computers

BrainBrain
70 years

Science
3,000 years

Million years Language/Math

Millions of years ago 5,000 years

Culture explosion of Homo sapiens sapiens

Art
(60,000 - 30,000 ago)

1. Brain Blossom Worldwide

1500

1400

The Jerusalem Brain

1300 (Norman Foster)

1200

1100

1000

900

800
1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0
Millions
 A view from the inside (of the brain) Structure of modern brain centers & central role of theory
(+ new curriculum for “Leonardo da Vinci” brain-researchers)

Neuroscience of
Neurological & cognitive
Disorders

Human
Human&&Primate
Primate
Behavior
Behaviorand
andCognition
Cognition

Plasticity
Plasticity&&Developmental
Developmental
Neuroscience
Neuroscience
Computational
Computational
&&
theoretical
theoretical
Quantitative
QuantitativeAnalysis
Analysis Neuroscience
Neuroscience
of
ofNeuronal
Neuronalcircuits
circuits

The “da Vinci” generation of brain researchers Perspective: Some new dramatic ($ billions) projects for the brain
New Approach: Theory-Driven Brain Research
1. Allen Institute – Seatle, USA (Mouse/Human brain atlas – recently new
focus on mouse vision)

2. Janelia farm – DC, USA (Industrial scale Inst. for connecting network
level anatomy and physiology to s specific behavior)

3. EU Human Brain Project - EPFL, Lausanne Switzerland (ICT-based brain

research platform, integrating data and knowledge from different disciplines,
Neurobiology & and catalyzing world-wide effort to achieve understanding of the brain,
Psychology
Medicine propose new treatments for brain diseases and new brain-like computing
technologies) - Lesson #7.

4. President Obama’s “Brain Activity Map” initiative (Creating revolutionary

Theory/ Computer
Modeling Science
tools to measure/stimulate millions or even billions or neurons
simultaneously)
Applied Physics &
Engineering

Spatial scale

The BIG - difficult question: Meters Recent Brain-Excitements

What does it mean “To Understand the brain?”
From molecules to behavior

1. Connectomics – Complete 3D road-map for the brain

Centimeters
2. Brainbow – Colorful, genetically-designed, brains
Clearly - A THEORY is required to
explains how the brain ingredients Millimeter 3. Brain-machine/computer interface (BMI)
s
(its anatomical units; its electro-chemical signals) 4. Optogenetics – Light-activated brain circuits
generate “high level” phenomena
Micrometers 5. Computer simulation of the brain - “Blue Brain Project”
(perception, action, emotions)

Nanometers
 Beginning of Modern Neuroscience – Cellular Anatomy
The two giants: Camillo Golgi (Italy) & S. Ramon Y Cajal (Spain) – Nobel Prize 1906

Modern neuroanatomy
Mapping/visualizing the wiring diagram of the brain

Connecting fine structure to mental activities in health

and in neuro-psychiatric disorders

Using Golgi staining method

Very small % of cells stained

S. Ramon Y Cajal
Camillo Golgi
Connections (synapses) - not seen

The neuron doctrine (Cajal)

Our brain is built from individual cells
(neurons)

Frontiers 1: Connectomics - modern brain anatomy Connectomics – complete 3D reconstruction a small volume of
mammalian cortex
Electron microscope (EM) reconstruction of a whole piece of brain (nanometers
resolution). All neurons (and other cell types) and all connections (synapses)

Courtesy of Mitya Chklovskii (Janelia Farm)

Based on hippocampus data from Kristen Harris (U. Texas, Austin) Courtesy of Sebastian Seung (MIT)

Frontiers 2. “Brainbow” technology

Genetic staining of neurons in vivo (light microscope – micrometer resolution)
Some prospects for the Connectomics
Courtesy of Jeff Lichtman, Jean Livet and Joshua R. Sanes

1. We will have, for the first time ever, the “blue print” (the
anatomical foundation) of a whole (healthy and sick) brain

2. We may start to bridge the “structure-to-function” problem (lecture

#6) and enable realistic computer simulations (“simulation-based”
research) of the respected (healthy or sick) network (lecture #7)

Brainbow transgenes drive the combinatorial expression of several fluorescent proteins (XFPs) in
neurons, resulting in the colour-tagging of individual cells.

Brainbow-1: stochastic recombination using incompatible lox variants.

 “Brainbow” images – The colorful brain

Some prospects for the Brainbow

1. The structural basis for learning in the brain

2. Tagging and genetic-characterization of the different cell-types
(the building blocks) in a given system (e.g., retina)
3. Tracing short-and-long range connections in brain circuits

From Brain to Machine

Frontiers 3. Brain Machine/Computer Interface (BMI) Spikes in a cell

On-line BMI requires “reading” the electrical activity

(its“electrical language” – its code – lessons #3 & #4)
in well-defined (functional) regions.

Monkey’s brain activity used for self feeding with a robotic arm
Brain-activated robot arm

Courtesy of Miguel Nicolelis (Duke University)

Courtesy of Andrew Schwartz, Univ. Pittsburgh
 From machine (pulses generated by a battery) to brain
Implanting stimulating electrodes in patient’s brain (fully alert)
(the amazing success of BMI for ameliorating Parkinosn’s)
Stimulating
Norma electrodes
The l
Basal
Ganglia

Parkinson
Pulse
generator

Parkinson
Courtesy of Hagai Berman, Hebrew Univ.

Deep Brain Stimulation Future challenges for BMI

)For ameliorating Parkison’s symptoms(
1. Develop chronic brain nano-probes
Post-operation Pre-operation 2. Develop telemetric communication with the brain

3. Develop real-time multi

(millions?) signal processing
methods

Patient: Male, 58 years old (PD Eight years, with extreme on-off) 4. Improving robotic arm and
Courtesy of Hagai Bergman, Zvi Israel, Hadassah University Hospital, Jerusalem “Closing the loop” Stimulation +
recording
Courtesy of Miguel Nicolelis (Duke University)

Frontier 4. Optogenetics Light-activated (~100 neurons) controlling mouse behavior

Frontiers 3: OPTOGENETICS
Optical stimulation (and recording) from single neurons in the living brain

Channel Rhodopsin opens with blue light Natronomonas pharaonis activated with yellow light
Causes spikes Prevents spikes
Hausser and Smith, Nature 2007

Courtesy of Karel Svoboda, Janelia Farm

 Frontier 5. Computer simulation of neuronal circuits The Blue Brain Project
Integrating anatomical and physiological data to provide “understanding”
Using the powerful “Blue-Gene” IBM Computer for realistic
simulation of the cortical circuits

‘I am never content until I have constructed a mathematical model of what I am studying. Courtesy of Henry Markram and the Blue Brain team (EPFL, Switzerland)
If I succeed in making one, I understand; otherwise I do not’ William Thomson (Lord Kelvin)

Step 1 – Mathematical models of neurons’ spiking activity

Connecting model components (modeled neurons) as in real cortical circuit

real

model

Computer voyage into cortical circuit (the cortical column)

Computer simulation of 10,000 neurons and 100 M
synapses in 2 cubic mm of cortical circuit
(electrical activity is color coded)