What is the Goal of Cognitive Neuroscience?

Background image from: https://cogneuro.phhp.ufl.edu/

Understanding the mind:

Philosophical introspection

Empirical analysis

Experimental psychology

Kandel, Eric R. Principles of Neural Science. 5th ed., p. 371-2.

Before 19th

CenturyMiddle 19th

CenturyEnd of 19th

Century

Stimulus response1 Genesis of

behavior2

https://www.canva.com/learn/gestalt-theory/

“…our knowledge of the world is based on our biological equipment for perceiving the world, that perception is a constructive process that depends not only on the stimulus but also on the mental apparatus of the perceiver—the organization of the sensory and motor systems in the brain.”

Kandel, Eric R. Principles of Neural Science. 5th ed. Print. p 372

UCSDCognitive Science

Images from Amazon.com

What are emergent properties?

Mary ET Boyle, Ph. D.

Department of Cognitive Science, UCSD

Basic elements: Neurons and Glia

“An emergent property is a new behaviour or phenomenon which is found at higher levels of organization as a result of

interactions at a lower level.”

http://www.nature.com/scitable/blog/accumulating-glitches/selfish_genes_emergent_properties

Molecular networks

Local circuits

Complex cellular networks

Increasing hierarchic level of integration

Decreasing level of miniaturization

The nervous system is a hierarchical system.

Each level has its own emergent properties

New characteristics and functions result from the complex organization of

the entire system.

Interactions and arrangements between the

components produce behavior that cannot be

performed by the individual parts.

Study cells individually

How do they work together

What are the emergent properties

Create the mind

Focus on structure,

chemistry and function of the

cells in the nervous system

High level learning objectives

Differentiate the basic classes of cells found in the central nervous system (CNS)

Characterize the anatomy of a neuronCell body, dendrites, axons and synapses

Understand and describe the elements of the CNS

Continued:

Describe the basic classes of cells found in the central nervous system (CNS)

Describe the basic functions of the three types of glial cells found in the CNS

Characterize the blood brain barrier.

“Neurophilosophy-mind/body”

??Relationship

between mind and brain

Glia and NeuronsNeuroglia (glia)

Insulates, supports, and nourishes neuronsElectrical and chemical functionality

Neurons:• Primary processors of neural

information• Sense environmental changes • Communicate changes to other

neurons• Command body response

Nervous system components:

Neurons • Primary processors of neural signals

Neuroglia • Support the electrical and chemical functions of neurons

Vascular endothelium

• Involved in the blood supply to brain tissue

• Difficult to study• Neuron size range: 0.01-0.05mmSmall size

• Microscopic study of tissue• Cytoarchitecture important for understanding

function and gross anatomy • Tissue preparation• Visualization levels– light and electron

Histology

• Fiber tract tracing• Identification of receptor types• Mapping distribution of a particular gene

Histochemistry

Pencil tip is about 0.7mm

Microscopes are our

window to life

reveal the inner

workings of cells

with stains and dyes.

Images: Nature

Nissl stain• Named for German neurologist:

Franz Nissl (1860-1919)• Methylene blue – Cresyl violet – Neutral red –

Toluidine blue (cationic dyes)

• Nissl bodies/substance = cytoplasmic granules in neuronal soma

• By 1950’s Nissl bodies are aggregations of rough ER– Staining the high concentrations of rRNA

• Good for distinguishing neurons from glia more rough ER in neurons

• Great to visualize the cytoarchitecture of neurons in different brain regions

• Under pathological conditions Nissl bodies dissolve or disappear (chromatolysis.)

Image from Wikipedia(top) Nissl-stained horizontal section through the mouse hippocampus showing various classes of cells.

http://hubel.med.harvard.edu

rER is where mRNA is translated and proteins are

synthesized. Nissl stains these structures due to high

concentrations of rRNA.

What is the most important function of the rough endoplasmic reticulum? Choose the correct option.

a RNA splicing.

b Post-translational protein processing

c Site of protein synthesis

d Cellular respiration

http://www.westernhistological.com.au/

Soak the brain in silver chomatesolution –only a small percentage of neurons become darkly colored in their entirety.

“The gain in brain is mainly in the stain!”

GOLGI

CAJALvs

Umemoria, H and Hortsch, M. (Eds.) 2009 In: ”The Sticky Synapse: Cell Adhesions Molecules and Their Role in Synapse Formation and Maintenance”

Santiago Ramon y Cajal’s 160th birthday May 1, 2012 - Google Doodle:http://www.google.com/doodles/ramon-y-cajal-160th-birthday

Golgi v. Ramón y Cajal

Reticular Theory-Golgi• Continuous syncytial network• Nerve fibers, dendrites and neuronal cells

directly connected to each other by cytoplasmic bridges

• Neuronal cell bodies provide nourishment.• Ironically, Golgi stain led to demise of theory

Neuron Doctrine-Ramón y Cajal• Neurons are not continuous• Neurons communicate by contact, not

continuity• Golgi stain – identification of subcellular units

of the neuron• Soma• Axon• Dendrite

– Circuitry• Electron microscopy

– Synapse (not gap junctions)• Neurons were not continuous

“Same data; different conclusion.”

“This drawing by Santiago Ramon y Cajal first appeared in volume two, part two of Cajal's Textura del SistemaNervioso del Hombre y de los Vertebrados, published in Madrid in 1904.

The image shows the six layers of the mouse neocortex, labeled A through F, in Cajal's hand.

Cajal's drawings provided the foundation of modern neuroanatomy by showing that the nervous system is composed of individual nerve cells, as opposed to a web of continuous elements”

http://www.sfn.org -- History of Neurosciene

What does the “neuron doctrine” state? Choose the correct option.

a Neurites of different cells fuse together to form a continuous reticulum.

b Individual cells communicate by contact and not continuity.

c The cell body of a neuron contains organelles.

d The elementary functional unit of all tissues is the individual cell.

Who had the insight about the neuron doctrine?Choose the correct option.

a Camillio Golgi

b Franz Nissl

c Santiago Ramon y Cajal

d Mario Capecchi

Fundamental functional unit

Metabolic machinery

MorophologyBioelectric

Intercellular communicationun

ique

Input zone

Conducting zone

Output zone

dendrites

cell body

axon

axon terminal

Many input sites

Neurons can receive input from other neurons on

many regions

Axon – process to send output to other neurons

Only a small part of interconnections between neurons takes place at the soma;

the majority takes place between different processes.

Grey matter

White matter

Grey matterImage from : http://www.uthsc.edu/neuroscience/imaging-center/

Cytosol: Watery fluid inside the cell

Organelles: Membrane-enclosed structures within the

soma

Cytoplasm: Contents within a cell

membrane (e.g., organelles, excluding

the nucleus)

The SomaFundamental

functional unit

Metabolic machinery

MorphologyBioelectric

Intercellular communicationun

ique

Neuron internal view

Neuronal membraneMitochondrionRough ERRibosomesNucleusPolyribosomesGolgi apparatusSmooth ERAxon hillockMicrotubulesAxon

Within the soma: The nucleus

– Gene expression– Transcription– RNA processing

transcription

translation

Rough endoplasmic reticulumMajor site for protein synthesis

Rough ER abounds in neurons, far more than in glia or most other non-neuronal cells.

Fun facts:

• Way more rER in neurons than in glia

• Another name for rER is ______.

• Your protein fate is determined by ____.

• If you are synthesized by ribosomes on rERthen you are destined to _____.

What is the most important function of the rough endoplasmic reticulum? Choose the correct option.

a RNA splicing.

b Pre-transcription DNA processing

c Site of protein synthesis/assembly

d Cellular respiration

Protein synthesis also on free ribosomes;

polyribosomes

Protein destined to reside in the cytosol

Protein likely to be inserted in membrane

Smooth ER and Golgi ApparatusSites for preparing and sorting proteins for delivery to different cell regions (trafficking) and regulating substances

Who do you think first described this structure?

The Golgi apparatus _____Choose the correct option.

a Was first described by Camillo Golgi in 1898.

b Is the site of post-translational processing.

c Acts like a protein sorting device for the cell.

d All of the above.

Mitochondrion

Mitochondria(plural)

Abundant in soma

ATP production

Energy currency for cell

Lin, M. T. & Beal, M. F (2006)

Difference in gene expression…

• “Post-genomic era”–Information about the genes expressed in our tissues

can be used to diagnose and treat diseases.• Biological basis for neurological and psychiatric

disorders.

December 11, 2007 vol. 104 no. 50

Transcriptome analysis of the brain and liver after sleep deprivation in three inbred mouse strains indicates that Homer 1a is specifically upregulated in the brain.

Maret S et al. PNAS 2007;104:20090-20095

accessexcellence.org

Mitochondrion• Site of cellular respiration

(inhale and exhale)• Pyruvic acid (inhale)• 17 ATB (exhale)

– Krebs cycle– ATP- cell’s energy source

“Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative

diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.”

NATURE REVIEWS | NEUROSCIENCE VOLUME 13 | MAY 2012

Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as ‘neurochemical diseases’, it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses.

“

”

http://www.nature.com/scitable/definition/translation-rna-translation-173

Which of the following is the largest of the cytoskeletal elements? Choose the correct option.

a microfilament

b neurofilament

c microtubule

d tubulin

The Neuronal Membrane• Barrier that encloses cytoplasm• ~5 nm thick• Protein composition in membrane varies• Structure of discrete membrane regions

influences neuronal function

• The Cytoskeleton• Not static• Internal scaffolding of neuronal membrane• Three “bones”

• Microtubules• Microfilaments• Neurofilaments

Big and run longitudinally along neurite

Composed of strands of tubulin

Microtubule-associated proteins regulate microtubule assembly

and function

MAPs serve as anchors. Dissociated tau proteins are seen in neurodegenerative diseases.

AKA Intermediate filaments in other

cells.

Structurally resembles bones and ligaments

Mechanically very strong structure.

MicrofilamentBraids of two thin strands of

actin

Important role in cell shape –also anchored to the

membrane

run longitudinally down the core of a neurite

? What are the functions of each of the following structures:

Nucleus, mitochondria, rough ER, synaptic vesicle, Golgi apparatus, MAP, neurofilament, microtubules, microfilament

Which are specialized for neurons?

Check your understanding…know for EC Quiz and Midterm:

nature reviews | neuroscience volume 8

“In the case of neurodegenerative tauopathies — a group of disorders that includes Alzheimer’s disease (AD) and the frontotemporal dementias (FTDs) —neurofibrillary tangles (NFTs) … twisted ribbons or other conformations of aberrantly phosphorylated forms of the microtubule-associated protein (MAP) tau are the diagnostic hallmark lesions in the CNS.”

“Moreover, added complexity may come from the fact that, aside from its well-established role in promoting the stabilization of microtubules (MTs), tau may have additional functions as a result of its interactions with other structures and enzymes”

Ballatore, C., et al (2007)

Tau (also known as MAPT) facilitates microtubule stabilization within cells and is particularly abundant in neurons.

Microtubules serve as 'tracks' that are essential for normal trafficking of cellular cargo along the lengthy axonal projections of neurons.

b | It is thought that tau function is compromised in Alzheimer's disease and other tauopathies. This probably results from both tau hyperphosphorylation, which reduces the binding of tau to microtubules, and the sequestration of hyperphosphorylated tau into neurofibrillary tangles (NFTs), which reduces the amount of tau that is available to bind microtubules.

The loss of tau function leads to microtubule instability and reduced axonal transport, which could contribute to neuropathology.

Kurt R. Brunden, John Q. Trojanowski & Virginia M.-Y. LeeNature Reviews Drug Discovery 8, 783-793 (October 2009)

• The Axon– Axon hillock (beginning)– Axon proper (middle)– Axon terminal (end)

• Differences between axon and soma– ER does not extend into axon– Protein composition: Unique– Structural differences =

functional differences– No protein synthesis import

all proteins down the axon.

• Differences between the cytoplasm of axon terminal and axon – No microtubules in

terminal– Presence of synaptic

vesicles– Abundance of membrane

proteins– Large number of

mitochondria

The Synapse

• Synaptic transmission• Electrical-to-chemical-to-

electrical transformation• Synaptic transmission

dysfunction – Mental disorders

Transportation• The Axon

–Axoplasmic transport–Anterograde

• (Kinesin protein: soma to terminal)

– Retrograde• (Dynein protein: terminal to soma)

Kinesin: the legs that walk the vesicle down the axon –soma terminal

• Dendrites are the “Antennae” of neurons

• Dendritic tree• Synapse - receptors• Dendritic spines

– Postsynaptic– Structurally different– Sensitive to synaptic

activity

Image from Wikipedia

Example of a projection neuron

Cortical pyramidal neuron

Pyramidal cell

Local axon collateral (local circuitry)

Dendrites

Descending axon (output)

Stellate cell

Knee Jerk (mytactic) Reflex

Classifying Neurons

• Classification Based on the Number of Neurites– Single neurite

• Unipolar

– Two or more neurites• Bipolar- two• Multipolar- more than

two

• Classification Based on Dendritic and Somatic Morphologies – Stellate cells (star-

shaped) and– pyramidal cells

(pyramid-shaped)– Spiny or aspinous

• Further Classification– By connections within the CNS

• Primary sensory neurons, • motor neurons, • interneurons

– Based on axonal length• Golgi Type I – projection neurons

(from one part of the brain to the other)

• Golgi Type II – local circuit neurons

– Based on neurotransmitter type• e.g., – Cholinergic = Acetylcholine at

synapses

Projection neurons

Local circuits

Golgi I Golgi II

What are they called?

Prefrontal cortical circuits; Example of Golgi Type I and Golgi Type II neurons.

Figure adapted from: Ioan Opris, and Manuel F. Casanova Brain 2014;137:1863-1875© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Count the many functions of Glia…

Support neuronal

functions -chemical

Support neuronal metabolic function

Make myelin –insulating the axon to make

neuronal signaling more

efficient.

Participate in neuron circuit formation and

synaptic plasticity

Participate in the inflammatory response in

injured neural tissue, including phagocytosis of cellular debris

Contribute to the formation of scar

tissue in damaged brain and spinal cord.

Blood brain barrier

Astrocytes

• Found primarily in gray matter• Closely associated with neuronal cell bodies, dendrites and synapses• Help maintain ionic balance of extracellular fluids• Take-up and process neurotransmitters from synaptic clefts

• Assist in the formation of new synapses and circuits

• Contribute to the formation of the blood brain barrier and brain ependymal (ventricular) barrier

• Contribute to the formation of scars following injury.

Astrocytes

• Most numerous glia in the brain

• Fill spaces between neurons• Influence neurite growth • Regulate chemical content of

extracellular space

Myelinating glial cell in CNS: oligodendrocyte

• A Specialist among glia• found in white matter – because it is

the white matter!• Peripheral nervous system myelin:

Schwann cells• Myelin aids in the propagation of

neural signals along myelinated axons• Pro: Present antigens that influence the

outgrowth of axons in developing and recovering brain to regenerate lost connections

• Con: present antigens that can attack CNS – Multiple sclerosis.

Glia

• Myelinating Glia– Oligodendroglia (in CNS)– Schwann cells (in PNS)– Insulate axons

Oligodendrocyte

Node of Ranvier

Myelin sheath

Ion channels and pumps are concentrated at nodes

• Insulate axons by generating layers of membrane that wrap around axon segments• Myelin makes the passive flow of current along the axon more efficient.• Having gaps between myelin segments enables the neuron to conserve its resources by

having ion channels and pumps concentrated in and around the myelin gap.

– Oligodendro-glial cells

– Node of Ranvier• Region where the

axonal membrane is exposed

Other Non-Neuronal CellsMicroglia as phagocytes (immune

• Special type of mononuclear phagocyte in CNS• Migrate to brain during embryonic development• Two forms – dormant and active

• Ramified is dormant – lying in wait for injury or inflammation• Amoeboid is active – mobile and ready to phagocytize debris

and release cytokines that modulate local inflammatory responses

Injury or inflammation

Existing neurons

New neurons

Glial stem cell

Blood vessel

True stem cells give rise to more stem cells, astrocytes,

oligodendrocytes and neurons!

Subset of astrocytes located near vessels adjacent to the ventricles

Proliferate

self renewal

Potential to make all the cells of a given tissue (e.g. CNS)

Key properties of somatic stem cells

WHAT IS THE BLOOD BRAIN BARRIER?

In 1885, the German scientist Paul Ehrlich (1854–1915) injected vital dyes using parenteral routes in adult animals. All organs were stained, except the brain and spinal cord [1]. The first conclusion was that the central nervous system (CNS) possessed specific features that resulted in a lack or low affinity for vital dyes.

Barichello T., Collodel A., Hasbun R., Morales R. (2019) An Overview of the Blood-Brain Barrier. In: Barichello T. (eds) Blood-Brain Barrier. Neuromethods, vol 142. Humana Press, New York, NY

The BBB (blood brain barrier) is the gatekeeper to the central

nervous system (CNS).

The BBB controls the flow in both directions – in and out.

THREE TYPES OF CAPILLARY VESSELSContinuous/Tight Fenestrated/Pores Sinusoidal

Impermeable and only allows for the passage of water, ions and glucose.

The pores (or fenestrations) make the capillary permeable

to larger molecules.

There are extensive intercellular gaps that allow large molecules

(plasma) to cross.

Nervous system, skin, muscles

Small intestine, kidneys

Lymph nodes, bone marrow

THE BLOOD BRAIN BARRIER (BBB)

A direct comparison of CNS with non-CNS capillaries.

CNS non-CNS

CNS non-CNS

Tight Junctions (TJ)prevent a pathway between

endothelial cells.

endothelial cells

Paracellular route allows water soluble

substances (polar) to be transferred between

endothelial cells. (Note: tight junctions (TJ)

are not present.)

An important comment about tight junctions (TJ):

Disruption of the tight junctions (TJs) of the blood–brain barrier (BBB) is a hallmark of many CNS pathologies, including stroke, HIV encephalitis, Alzheimer's disease, multiple sclerosis and bacterial

meningitis.

*

Huber, J. D., Egleton, R. D., & Davis, T. P. (2001). Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci, 24(12), 719-725. doi:10.1016/s0166-2236(00)02004-x

CNS non-CNS

Very little transcytotic

vesicular transport.

endothelial cells

Transcytotic vesicular transport

Continuous basement

membrane.

CNS non-CNS

CNS non-CNS

Astrocytic footprocesses are up

against the basement membrane.

These astrocytes provide the chemical signal to maintain the tight junctions (TJ).

Oligodendrocyteprecursor

Differentiates into oligos, astrocytes,

neurons

Myelinatingoligodendrocyte

• Oligodendroglialprecursors are located in and around white matter

• Mostly give rise to oligos but can generate neurons and astrocytes

capillarynucleus

brain capillary endothelial cell

tight junctionastrocyte foot

process

Specialized permeability

barrier between the

capillary endothelium

and the extracellular

space in neural tissue.

Blood brain barrier

? Classify the following neuron based on:

(a) Number of neurites(b) Dendritic spines(c) Connections(d) Axon length(e) All of the above

Check your understanding…

? How does information flow through a neuron?

a. Dendrite synapse cell body axon dendriteb. Synapse dendrite axon cell body synapsec. Synapse dendrite cell body axon synapsed. Axon dendrite synapse cell body axone. None of the above

Check your understanding…

? Consider a patient that has suffered a stroke – consequently it caused damage to a region in the brain. Which of the following glial cell activities occurred first? a. Microglia were stimulated to convert from ramified to amoeboid states.b. Astrocytes formed scar tissue to fill-in space vacated by damaged tissue.c. Microglia phagocytosed cellular debris.d. Glial stem cells repopulated region of damage neural tissue.e. None of the above – what was it?

Check your understanding…