ERNESTO BURGIO ISDE Scientific Committee ECERI - European Cancer and Environment Research Institute

Fetal programming

1

5

3

2

Ontogenesis

Phylogenesis

Developmental Plasticity

Devo-Evo

4 Mismatch/DOHA 6

7

XX Century Epidemiological

Transition Environment

From Genetics..

FOREWORD : the 7 key words Epigenetic versus genetic origins of health and diseases

Evolutionary Medicine

Is DNA a sort of project inscribed in our cells?

Synaptogénese

Connectome

Cablage fin

Cablage ancestral Homo sapiens

Pre-wired brain

..to Epigenetics

This is a graph taken from a famous article published 10 years ago on NEJM,

showing the rapid decrease of the infectious/acute diseases

and the simultaneous increase of the chronic/inflammatory diseases

in the North of the World

This is a figure taken from the same article, showing the presence

of a South North Gradient concerning this epidemiological transition

ENVIRONMENTAL FACTORS >> DNA

TIPE I DIABETES

X 10

& Non-

Communicable

Diseases

Here we see that environment and lifestyles have, in this epidemiological transition,

a much greater role that the DNA: migrants from the South to the North

will soon get sick of the typical, chronic “Non-Communicable Diseases”

Obesity Trends* Among U.S. Adults 1985

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

In the next 6 slides (taken from JAMA)

we’ll follow, in quick succession, the

dramatic, TRULY EPIDEMIC SPREAD

Obesity Trends* Among U.S. Adults 1987

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. Adults 1993

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. Adults 1995

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. Adults 1997

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. Adults 1999

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10

Obesity Trends* Among U.S. Adults 2001

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10. Today the situation has further deteriorated:

65% of Americans are overweight, 35% morbidly obese

The Childhood Obesity Epidemic

US DHHS, 2001; Hedley et al., 2004; Ogden et al., 2006, 2008

Matthew W. Gillman, MD, SM

in the 70s

childhood

obesity

virtually did

not exist

(it was

associated

with rare

genetic

syndromes):

since then

the increase

has been

rapid and

relentless

Yet the most dramatic increase

concerns children and adolescents

… with a constant anticipation of the age of onset …

The most serious consequence of the epidemic of obesity is the association with many

chronic diseases: first of all with diabetes 2 ( today affecting 180 million people)

The origin of insulin resistance is due both to an accumulation of fat in

adipocytes, and to the related inflammation. But, above all, both conditions

seem to be the product of a poor prenatal metabolic programming…

The link between obesity and

metabolic 2 diabetes is complex …

No one likes to talk about a CANCER PANDEMIC.. But we must

not forget that today, practically all over the North of the world,

one person out of two is likely to have a cancer ..

0

2000

4000

6000

8000

10000

12000

14000

2002 2005 2010 2015 2020

Less Developed More Developed

Th

ou

sa

nd

s p

er

An

nu

m

0

2000

4000

6000

8000

10000

12000

14000

2002 2005 2010 2015 2020

Less Developed More Developed

the significant increase in the Less Developed Countries & in young people all over

the world demonstrates the limits of the SMT (necessary link between aging &CA)

(1) Cancer continuous increase

Poumon 80

60

40

20

4

2

1,5

Sein

Colon

Estomac Lymphôme

10

Leucémie

lymphati

que Leucémie lymphatique

Encéphale

Lymphômes

Neuroblastoma-Retinoblastoma 1

<1 Tessuti molli, rene (Wilms), gonadi

5

Rein Cerveau

It is generally argued that childhood cancers are a rare condition.

But it should be reminded

that CANCER is the main cause of death by disease in childhood

that there is a constant and significant increase of tumors in the world for this age group

that 1 : 5-600 children falls ill with cancer

That more than

13 000 children fall ill with cancer each year in the U.S.

Bleyer A, O’Leary M, Barr R, Ries LA,

editors. Cancer epidemiology in older

adolescents and young adults 15-29

ears of age, including SEER incidence

and survival: 1975-2000. NIH Pub. No.

06-5767. Bethesda (MD): National

Cancer Institute; 2006. Jemal A, Siegel

R, Ward E, et al. Cancer statistics,

2008. CA Cancer J Clin 2008;58:71 – 6.

Alberto Tommasini, Laboratorio Immunologia Pediatrica, IRCCS Burlo Garofolo

is the leading cause of death due to diseases among children over the first year of age

(2) Child cancer increase

Incidenza di tumori (anno/100.000)

We should always consider the epidemiological data in the medium and long term, not to be

deceived by the inevitable fluctuations. It's evident that the incidence rates have increased

dramatically over the past 30 years in the US, from 130 to 170-180 new cases/year per

million inhabitants (to demonstrate the importance of these data, it is useful to remember

that a very similar increase occurred in Europe in the same period)

CA incidence in childhood and adolescence IN EUROPE ( 1970-1999)

mother

latency

A first draft of the report, published on the Lancet in 2004, demonstrated an annual increase of 1-1,5% for all cancers (with more marked increases in lymphomas, soft tissue sarcomas, tumours of the nervous system…) . But the most troubling was the increase - almost the double - for all cancers in the very first year of life (apparently due to transplacental or even trans-generational exposure)

Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, Lacour B, Parkin M. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCISproject): an epidemiological study. Lancet. 2004 Dec 11-17;364(9451):2097-105

http://www-dep.iarc.fr/accis.htm

Many scientists and researchers claim that Autism is

the fastest-growing developmental disorder in the world,

with the prevalence of diagnosis having increased

by 600 per cent over the last 20 years.. And from

1:1200 to 1:90 children in US in the last 30 years

FOREWORD 1 L’autisme, une épidémie ?

http://arstechnica.com/science/2012/04/new-autism-studies-find-new-mutations-many-genes-behind-the-disorder/

2014 1 : 65

L’autisme: une épidémie ?

2014 1 : 65

2008 1 : 88

2006 1 : 110

2002 1 : 150

1980 1 : 1500

L’autisme, une épidémie ?

AUTISME (ASD :Autism Spectrum Disorders)

• Les nouveaux cas d'autisme diagnostiqués (incidence) aux États-Unis sont passés de 15,580 en 1992 à 163,773 en 2003.

• Prévalence estimée: 6-7 12 (2012) cas/1000 enfants

L’autisme, une épidémie ?

Il 17% dei bambini US < 18°a. ha un disturbo dello sviluppo, per lo più a carico del SN Disturbi dell’apprendimento ADHD Disordini dello spettro autistico Ritardo mentale Problemi comportamentali

Analoghe sono le

cifre europee

Il cervello è un organo prezioso e vulnerabile e, poiché il suo funzionamento ottimale dipende dalla

sua integrità, anche danni limitati possono avere conseguenze serie ( Grandjean 2006)

ISDE Palermo - Maria Vittoria Di Matteo

Since 2000 there has been a 66% increase in Alzheimer's diagnoses. 6th leading cause of death in the United States. 5.4 million Americans are living with the disease. 15-20 million more Americans will be diagnosed by 2040

An equally dramatic

trend show

neurodegenerative

diseases and

in particular

Alzheimer's

disease

Interphase chromosomes Mitotic chromosome

Euchromatin

Heterochromatin

...revolving

around it and

playing an

important role

in

transferring

information

from outside

to DNA and

in

modulating

the

response, to

the extent

that some

scientists

have used

the term

natural

genetic

engineering

Multiple levels of packing are required to fit the DNA into the cell nucleus

The first keyword: Epigenetics

DNA double helix (2-nm diameter)

Metaphase chromosome 700 nm

Tight helical fiber (30-nm diameter)

Nucleosome

(10-nm diameter)

Histones

“Beads on

a string”

Supercoil (200-nm diameter)

Campbell NE et al (Eds): Biology: Concepts & Connections 4th Edition, 2003

Euchromatin

Heterochromatin

Multiple levels of packing are required to fit the DNA into the cell nucleus

Nuclear DNA is normally tightly wrapped around histones

The first keyword: Epigenetics

http://news.sciencemag.org/sciencenow/2009/04/21-03.html IN FACT Genes need to be told

to switch “off” and “on”: • Genes need to be told how much expression (protein) is required and where. • Genes need to be regulated – this regulation is not performed by DNA but by many other controls arranged in a complex network • DNA has been called the Book of Life by the Human Genome Project scientists, but many other biologists consider DNA to be simply a random collection of words from which a meaningful story of life may be assembled… • In order to assemble that meaningful story, a living cell uses a second informational system.

(...) The key concept here is that these

dynamic-epigenetic networks have a

life of their own —they follow

network-rules not specified by DNA

From directing the fate of stem cells to determining how.. we grow, the genes in our body act in complex networks.. the whole Genome is a Complex and highly dynamic molecular Network of interacting Genes and non-codifying sequences.. and proteins

Strohman R. , April 2001 Beyond genetic determinism ….Genes Know How to Network…BUT...

Rudolf Jaenisch Whitehead Institute & Dept. of Biology, MIT, Cambridge, MA

Nuclear Receptor DNA Response Element

Histone Lysine Acetylation

Histone Deacetylases.

Histone Acetyltransferases;

Histone Methyltransferases

ATP-dependent Nucleosome Remodeling Complex

Many toxicants cause rapid alterations in gene expression by activating protein kinase signaling

cascades.

The resulting rapid, defensive alterations in

gene activity require the transmission of a signal directly to the histones

present in the chromatin of stress response genes:

within minutes

of exposure the phosphorylation of serine 10 of histone H3

and the acetylation

of lysines 9 and/or 14 take place

H3-K9 H3-S10

P

The “meeting-point” between the information coming from the environment and the information encoded in the DNA (hardware) is the epigenome (software): mimetic molecules (EDCs) and other pollutants or danger-signals induce the epigenome to change

Chromatin itself is the direct target of many toxicants * … toxicant-induced perturbations in chromatin structure may precipitate adverse effects.. Forcing genome to change

TCDD

Viruses

HERVs

EMF

3

2

1

SYNERGISM !!

“FLUID EPI-GENOME”

4

We may represent the environment as a continuous stream of information (simple: photons: individual packages of E = M = Information) or complex (organic molecules, viruses etc) interacting with our cells [membrane /transmembrane receptors, signal transduction proteins, nuclear receptors, genome (DNA + Epigenome)] forcing them to adapt

The second keyword: Environment

Everyday levels matter

At truly low levels … it interferes with gene activation

At high levels… arsenic kills people

At moderately low levels… it causes a range of diseases

Kaltreider et al. 2002

Many of these substances (Dioxins, Heavy Metals, Polycyclic aromatic Hydrocarbons) are dangerous for humans health at very low-every day-doses (which are very difficult to be assessed by the ordinary toxicological studies)

this is not a generic concept, concerning the way in which the "genetic program" contained in DNA is translated, during the nine months of the ontogenetic process, in a specific complex phenotype.

on the contrary,this is a precise technical term that refers to the ability, and at the same time to the necessity, of embryo-fetal cells to define their epigenetic setting in adaptive (and predictive) response to the information coming from the mother and, through her, from the outer world.

Dioxin and Dioxin-like molecules

(Ultra)-fine particles

Heavy Metals

Polycyclic Aromatic Hydrocarbons (PAH)

Benzene

1

2

3

The third key word is fetal programming

Fetal Programming

Differentiation

epi-mutations

Cellular Differentiation: an Epigentic process The actual genetic program of a

particular individual is actually the

product of nine months of

epigenetic adaptive-predictive

“formatting” of billions of cells)..

This is the stage of life which is far more sensitive to

information coming from the environment

(particularly to maternal-fetal stress, to nutritional

errors, to pollutants ..)

1

2

Nature 447, 425-432 (24 May 2007)

PLASTICITY

This image clearly shows the "power" of the epigenome and the

predominant role of environmental information in the phenotypic

shaping of cells, tissues , organisms .. the huge phenotypic (morpho-

functional) difference between a lymphocyte and a neuron is not due to

DNA, which is virtually identical in the two cells , but to the manner in

which the same genome has been utilized by the two cells, on the

basis of the information (positional and environmental) received

during the first months of life (for neuron in the first 2 years) and

processed by the epigenetic networks

The fourth keyword is developmental plasticity

The chimpanzee DNA is for 98.77% identical to the human . On average, a gene encoding a protein in a man differs from its chimpanzee ortholog by only two aa substitutions

.. almost one third of

human genes has exactly the same

protein translation as their

orthologs

in chimpanzee

Species phylogeny

Orangutan Gorilla Chimpanzee Human

From the Tree of the Life Website, University of Arizona

Sanger Institute

We are quite stable (for

millions of years) both

genetically and

phenotypically

Evo

The fifth key word is phylogeny

et de 9 mois de

développement individuel

de 4 milliards d'années de coévolution

moléculaire* (en particulier, notre ADN est

le produit de ce long parcours) ..

Phylogenèse

Nous ne devrions

jamais oublier que

nous sommes

en même temps

le produit

l'ontogenèse

récapitule

la phylogenèse

Devo-Evo

(..notre epigénome est le

produit de 9 mois de

programmation cellulaire

et tissulaire adaptative à un

environnement qui est en

train de changer très vite..

Un risque majeur: les EDCs et d’autres xénobiotiques (n'étant pas le produit de cette coévolution

moléculaire*) peuvent interférer à ce niveau, en agissant comme des pseudo-morphogènes..

Ontogenèse

Mismatch ?

My brain? That's my second favorite organ

Woody Allen

Allen Stewart Königsberg

L’on parle souvent de ce qu'on connaît pas. Ce qui est presque inévitable dans le cas du cerveau. Et pourtant on ne peut parler de l'autisme sans parler du cerveau (notre deuxième organe préféré)

How many research papers about the brain are published each year? For 2013, a PubMed search using the term "brain" shows that 76,945 papers were published For 2012, a PubMed search using the term "brain" shows that 74,303 papers were published For 2011, a PubMed search using the term "brain" shows that 69,927 papers were published For 2010, a PubMed search using the term "brain" shows that 64,929 papers were published For 2009, a PubMed search using the term "brain" shows that 58,459 papers were published. For 2008, a PubMed search using the term "brain" shows that 55,874 papers were published. For 2007, a PubMed search using the term "brain" shows that 53,258 papers were published. For 2006, a PubMed search using the term "brain" shows that 51,163 papers were published. For 2005, a PubMed search using the term "brain" shows that 47,383 papers were published. For 2004, a PubMed search using the term "brain" shows that 42,849 papers were published. For 2003, a PubMed search using the term "brain" shows that 39,964 papers were published. For 2002, a PubMed search using the term "brain" shows that 37,304 papers were published. For 2001, a PubMed search using the term "brain" shows that 36,884 papers were published. For 2000, a PubMed search using the term "brain" shows that 37,000 papers were published. For 1999, a PubMed search using the term "brain" shows that 34,828 papers were published. For 1998, a PubMed search using the term "brain" shows that 33,027 papers were published. For 1997, a PubMed search using the term "brain" shows that 32,112 papers were published. For 1996, a PubMed search using the term "brain" shows that 31,040 papers were published

Key words

Hardware: Devices that are required to store and execute (or run) the software.

Phenotype

Brain (structure)

Ancestral Cablage

Software: Collection of instructions that enables a user to interact with the computer. Software is a program that enables a computer to perform a specific task, as opposed to the

physical components of the system (hardware).

DNA Genome Epigenome Genotype

Individual Cablage - Connectome

Mind/Soul

Input,storage,processing, control, and output devices. CD-ROM, monitor, printer, video card, scanners , label makers, routers , and modems

Quickbooks, Adobe Acrobat, Winoms-Cs, Internet Explorer , Microsoft Word , Microsoft Excel..

Hardware Software

Brain and mind

What interests us here is not the hardware,

that is to say

• the anatomical and physiological structure: the “projective organization of cortex”, formed in millions of years *

• common to all human beings and, to some extent, to all primates

• and also shared, to some extent, by mammals and even by many vertebrates ...

* phylogenesis

The ancestral wiring

The general, species-specific, structure of the human brain/cortex is, indeed, a product of phylogeny:

in particular, the lateralization and the resulting dominance of an hemisphere over the other

and the functional connections between the various regions and areas of the brain are under genetic control (body plans), limiting (channelling) the transformative (evolutionary) potential of the information coming from outside..

On the contrary the fine, individual and soft-wiring structure of the cortex,

(i. e. the individual connectome), is the result of ontogeny and develops under epi-genetic control.

http://www.humanconnectomeproject.org/

The Individual wiring

The ancestral wiring

As with the sensory cortex, Wilder Penfield was responsible for mapping the motor cortex… Chimps also have a motor cortex, but the area of cortex devoted to vocal control is restricted relative to what you see in the human animal. Their brains are just not built for the detailed vocalizations you need to in order to pronounce all the phonemes that comprise linguistic verbal communication. Neurologists knew this, and had the chimp trainers consulted a neurologist before starting, they would have saved themselves years of wasted effort, and moved directly to the more realistic goal of seeing whether chimps could learn sign language

Carroll SB Genetics and the making of Homo sapiens Nature (2003) 422, 849-857

Comme pour le cortex sensoriel, Wilder Penfield est responsable de la cartographie du cortex moteur (Homunculus)... Les chimpanzés ont également un cortex moteur, mais la zone de cortex consacrée au contrôle vocal est limitée par rapport à l'animal humain. Leurs cerveaux sont tout simplement pas construits pour les vocalisations détaillées afin de prononcer tous les phonèmes qui composent la communication verbale linguistique.

Le câblage ancestral

The Human Brain: a Rapidly Evolving Organ

The ancestral wiring

Why Are Our

Brains So

Big?

Science, 2012

Macaques live in complex social

groups and have brains larger

than expected for their body size

Homo Erectus Homo Sapiens

Chimpanzee-human divergence

Chimpanzees Humans

6-8 million years

Hominids or hominins

Brain: a rapidly evolving Organ ?

Evo

The ancestral wiring

La variabilità genetica umana è molto più bassa di quella dei primati più vicini filogeneticamente nonostante che la dimensione delle

popolazioni umane sia di gran lunga maggiore

From Kaessman and Paabo, 2002

Questo è probabilmente dovuto alla recentissima espansione degli umani a

partire da una piccola popolazione e alla scarsa incidenza della selezione in

una specie che si adatta per differenziazione culturale e non genetica.

Marcello Buiatti - UniFI

From 6-2milion years ago

Brain size increase slowly

From 2 milion-800.000 years ago

Brain and body size increase

From 800.000-200.00 years ago

Brain size increase rapidly

Le connectome est un plan complet des connexions neuronales dans un cerveau

http://www.humanconnectomeproject.org/

• Science. 2007 Sep 7;317(5843):1360-6.

• Humans have evolved specialized skills of social cognition: the cultural intelligence hypothesis.

• Herrmann E, , Call J, Hernàndez-Lloreda MV, Hare B, Tomasello M.

• Humans have many cognitive skills not possessed by their nearest primate relatives. The cultural intelligence hypothesis argues that this is mainly due to a species-specific set of social-cognitive skills, emerging early in ontogeny, for participating and exchanging knowledge in cultural groups. We tested this hypothesis by giving a comprehensive battery of cognitive tests to large numbers of two of humans' closest primate relatives, chimpanzees and orangutans, as well as to 2.5-year-old human children before literacy and schooling. Supporting the cultural intelligence hypothesis and contradicting the hypothesis that humans simply have more "general intelligence," we found that the children and chimpanzees had very similar cognitive skills for dealing with the physical world but that the children had more sophisticated cognitive skills than either of the ape species for dealing with the social world.

In the social domain, a very different pattern emerged. Averaging across all of the tasks

in the social domain, the human children were correct on ∼74% of the trials, whereas

the two ape species were correct about half as often (33 to 36% of the trials).

Statistically, the humans were more skillful than either of the two ape species (P < 0.001

in both cases), which did not differ from one another.

• Dev Psychobiol. 2014 Apr;56(3):547-73. doi: 10.1002/dev.21125. Epub 2013 Jun 14.

• Differences in the early cognitive development of children and great apes.

• Wobber V, Herrmann E, Hare B, Wrangham R, Tomasello M

• There is very little research comparing great ape and human cognition developmentally. In the current studies we compared a cross-sectional sample of 2- to 4-year-old human children (n=48) with a large sample of chimpanzees and bonobos in the same age range (n=42, hereafter: apes) on a broad array of cognitive tasks. We then followed a group of juvenile apes (n=44) longitudinally over 3 years to track their cognitive development in greater detail.

• In skills of physical cognition (space, causality, quantities), children and apes performed comparably at 2 years of age, but by 4 years of age children were more advanced (whereas apes stayed at their 2-year-old performance levels). In skills of social cognition (communication, social learning, theory of mind), children out-performed apes already at 2 years, and increased this difference even more by 4 years. Patterns of development differed more between children and apes in the social domain than the physical domain, with support for these patterns present in both the cross-sectional and longitudinal ape data sets.

• These results indicate key differences in the pattern and pace of cognitive development between humans and other apes, particularly in the early emergence of specific social cognitive capacities in humans.

The brain grows at an amazing rate during development. At times during brain development, 250,000 neurons are added every minute! At birth, almost all the neurons that the brain will ever have are present. However, the brain continues to grow for many years after birth. By the age of 2 years old, the brain is about 80% of the adult size

A stegosaurus dinosaur weighed approximately 1,600 kg but had a brain that weighed only approximately 70 grams (0.07 kg). Therefore, the brain was only 0.004% of its total body weight. In contrast, an adult human weighs approximately 70 kg and has a brain that weighs approximately 1.4 kg. Therefore, the human brain is about 2% of the total body weight. This makes the brain to body ratio of the human 500 times greater than that of the stegosaurus

Brain plasticity and modulation of its structure and its functions

Motility of neurons and in particular

the formation of new

connections (synapses) can be

modified (perturbed) by

exposure to environmental

stressors

Wingate Imagining the brain cell: the neuron in visual culture. Nature Rev Neuroscience 2006; 7: 745-752.

The Individual wiring

Early critical periods in the development of SYNAPTOGENESIS and brain functions

Formation of new synapses following stimulation..

The Individual wiring

B Weiss, P J Landrigan The developing brain and the environment: an introduction. Environ Health Perspect. 2000 June; 108(Suppl 3): 373–374.

B Weiss Vulnerability of children and the developing brain to neurotoxic hazards. Environ Health Perspect. 2000 June; 108(Suppl 3): 375–381.

J W Olney, N B Farber, D F Wozniak, V Jevtovic-Todorovic, C Ikonomidou Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ Health Perspect. 2000 June; 108(Suppl 3): 383–388.

E A London The environment as an etiologic factor in autism: a new direction for research.Environ Health Perspect. 2000 June; 108(Suppl 3): 401–404

D C Rice Parallels between attention deficit hyperactivity disorder and behavioral deficits produced by neurotoxic exposure in monkeys.Environ Health Perspect. 2000 June; 108(Suppl 3): 405–408

G J Myers, P W Davidson Does methylmercury have a role in causing developmental disabilities in children? Environ Health Perspect. 2000 June; 108(Suppl 3): 413–420.

S P Porterfield Thyroidal dysfunction and environmental chemicals--potential impact on brain development. Environ Health Perspect. 2000 June; 108(Suppl 3): 433–438.

SG Selevan, CA Kimmel, P Mendola Identifying critical

windows of exposure for children's health. Environ Health Perspect. 2000 June; 108(Suppl 3): 451–455.

These are some articles concerning the

effects of pollutants on the CNS

development during the early stages of

life (windows of exposure)

At birth, each neuron in the cerebral cortex has approximately 2,500 synapses. By the time an infant is two or three years old, the number of synapses is approximately 15,000 synapses per neuron (Gopnick, et al., 1999). This amount is about twice that of the average adult brain. As we age, old connections are deleted through a process called synaptic pruning Ineffective or weak connections are "pruned" in much the same way a gardener would prune a tree or bush, giving the plant the desired shape. It is plasticity that enables the process of developing and pruning connections, allowing the brain to adapt itself to its environment

https://faculty.washington.edu/chudler/plast.html

Developmental Plasticity: Synaptic Pruning

09 A synaptic trek to autism

Schematic representation of the different phases of synaptogenesis in the human brain. During the first three years of life, an excess of cell/synaptic growth rate and inhibitory currents could increase the risk of ASD.

The Epigenome learns from its experiences

• Epigenetic tags act as a kind of cellular memory.

• A cell's epigenetic profile -- a collection of tags that tell genes whether to be on or off -- is the sum of the signals it has received during its lifetime

http://learn.genetics.utah.edu/content/epigenetics/epi_learns/

.. ce qui nous intéresse ici, c'est le software, le logiciel

(qui est essentiellement constitué par des circuits neuronaux et donc par les connexions synaptiques)

et la façon dont - au cours de l'ontogenèse, principalement au cours de la vie fœtale et des deux premières années de la vie (c'est à dire dans la période de plasticité maximale de développement):

des milliards d'arborescences dendritiques se forment pour communiquer entres elles et en réponse à des informations provenant de l'environnement et du reste du "réseau" en cours de construction [ce qui est vraiment difficile est comprendre pourquoi tant de scientifiques préfèrent, même dans ce contexte, un modèle sélectif (néo-darwinien) de l'évolution plutôt qu’un modèle instructive et constructive (Lamarckian et Darwinien au même temps)]

Le câblage individuel

• Early in development, genes are "poised" like runners in the starting blocks, ready to jump to action.

• In a differentiated cell, only 10 to 20% of the genes are active.

• Different sets of active genes make a skin cell different from a brain cell.

• Environmental signals

such as diet and stress can trigger changes in gene expression.

• Epigenetic flexibility is also important for forming new memories.

http://learn.genetics.utah.edu/content/epigenetics/epi_learns/

• A questo proposito si possono ricordare gli studi che hanno dimostrato come un ambiente arricchito permetta un

• maggior sviluppo cerebrale (e in particolare un grande incremento di sinapsi/circuiti)

• negli animali di laboratorio

• e che gli animali che vivono in Natura hanno cervelli più grandi, complessi, attivi, efficienti

Spine plasticity

is implicated in

motivation,

learning

and memory.

In particular

long-term

memory

is mediated

by the growth

of new dendritic

spines (or the

enlargement of

pre-existing

spines)

to reinforce

a particular

neural pathway.

I Neuroni al Microscopio Confocale

Microscopic marvels Nature, 2010

This discovery of a stimulus-dependent alteration in the brain’s macroscopic structure contradicts the traditionally held view that cortical plasticity is associated with functional rather than anatomical changes.

During the learning period, the gray matter increased significantly in the posterior and lateral parietal cortex bilaterally.

Changes in the structure of children's brains may account for some of the risky business of adolescence Nature 442, 865-867 (24 August 2006)

The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects.. volume correlated with the amount of time spent as a taxi driver ( local plastic change in the structure of adult human brain in response to the environment)

Ramón y Cajal

Death of a DOGMA

Scientific American, 2013

Online social network size is reflected in human

brain structures Proc. R. Soc. B, 2012

Gray matter abnormalities in Internet addiction: A

voxel-based morphometry Eur J Radiology 2009

Here, we show a biological basis .. by

demonstrating that quantitative variation in the

number of friends an individual declares on a

web-based social networking service

reliably predicted grey matter density in the

right superior temporal sulcus, left middle

temporal gyrus and entorhinal cortex

Les troubles du spectre autistique De la génétique à l‘ épigénétique

Léo Kanner Hans Asperger

Angelman syndrome

ERNESTO BURGIO ECERI - European Cancer and Environment Research Institute ISDE Scientific Committee

Autism

• Autism and autism spectrum disorders (ADS) are developmental disorders of neural connections and, as we will see, of synaptogenesis

• This affects the way in which the brain "processes information"

The Human Connectome Project

As for the causes of autism

many hypotheses have been advanced:

at present these disorders are usually considered as essentially 'genetic' ..

while all the environmental causes (including vaccines, mercury, heavy metals, pesticides) have been considered as highly improbable

Which is in contrast with the dramatic increase of the autism spectrum disorders ( generally explained with the changing of the diagnostic criteria).

I will try to show why and in what sense this approach is not only simplistic, but also misleading as -the increase of the cases is continuous and alarming, - the traditional genetic risk factors have not so far been found -the most important mutations are de novo (which is to say, they are not found in somatic cells of the parents .. but rather occur - in parents’ gametes or - during fetal development And that makes autism a non-hereditary genomic disease

Beaudet AL Autism: highly heritable but not

Inherited Nature Medicine (2007) 13, 534 - 536

• The fact that these problems usually occur after a latency period (of normal intellectual and motor development) shows that

• the brain basic structures (cerebral neuronal differentiation and migration: definition of the functional areas of the brain), are not changed

• but, so to speak, it is the software (connectome) - synaptic connections .. - neuronal circuits .. to be damaged

Together, results of clinical, neuroimaging, neuropathological, and neurochemical studies show that autism spectrum disorders are disorders of neuronal-cortical organization that cause deficits in information processing in the nervous system, ranging from synaptic and dendritic organisation to connectivity and brain structure

En corrélation avec les déficits fonctionnels observés au niveau comportemental, quelques auteurs auraient relevé que les enfants autistes auraient un cerveau plus gros et un nombre de neurones plus élevé * et ont supposé que l'origine de cette altération est un déficit du pruning à savoir la réduction physiologique des synapses et des circuits redondants qui se produit au cours du développement du cortex

Des travaux récents suggèrent que les synapses inapproprié dans le cerveau en développement sont «marqués» par les protéines du complément (-C3) et ensuite éliminés par la microglie - les macrophages du système nerveux central - dans le cerveau post-natal ..

Kennedy et al. (2007) *ont observé un surcroît de neurones pyramidaux de 58 % chez l’enfant atteint d’autisme.

L’excès de ces neurones (représentant 80 % de l’ensemble des neurones dans le cortex) occasionne un excès d’axones, de dendrites, de synapses et de myéline qui engendre un volume exagéré de substance grise et de substance blanche (Courchesne et al., 2007).

A Silent Pandemic Industrial Chemicals Are Impairing

The Brain Development of Children Worldwide For immediate release: Tuesday, November 7, 2006

Grandjean P. Landrigan Ph

L’autisme, une épidémie ?

1

2

3

1

2

3

L’autisme, une épidémie ?

The Lancet Neurology, Volume 13, Issue 3 , Pages 330 - 338, March 2014

Since 2006, epidemiological studies have documented six additional developmental

neurotoxicants — manganese, fluoride, chlorpyrifos, tetrachloroethylene,

dichlorodiphenyltrichloroethane,, and the polybrominated diphenyl ethers.

We postulate that even more neurotoxicants remain undiscovered

L’autisme, une épidémie ?

The gift our mothers never wanted to give us

http://www.ewg.org/reports/generations/

CHEMICAL FALL OUT

ULTRAFINE PARTICLES HEAVY METALS

ENDOCRINE DISRUPTORS dioxin-like moleculles

1 2

3

That’s why at present many studies in various parts of the world

are evaluating the chemical body burden .. especially in

women, children, embryos / fetuses, providing dramatic results.

Giuseppe Giordano

Monitoring Body-Burdens

700 different synthetic chemicals or heavy metals found in human blood,

POPs

“Diossina di Seveso”: sino a 10 anni negli adipociti !

E’ vero, in particolare, che metalli, diossine e altri inquinati lipofili accumulati nei tessuti materni

possono passare, anche a distanza di anni dal loro assorbimento, nel sangue e raggiungere il feto ?

Is it true that metals, dioxins and other lipophilic pollutants, accumulated in maternal tissue, may pass, even many years after their absorption, into the blood and reach the fetus?

Johns Hopkins Bloomberg School of Public Health April 20, 2007 ENVIRONMENTAL SCIENCE & TECHNOLOGY

•

PFOA perfluorooctanoate

PFOS perfluorooctane sulfonate

300 CAMPIONI DI SANGUE DI CORDONE OMBELICALE

PFOS PRESENTE NEL 99 % DEI CAMPIONI

PFOA PRESENTE NEL 100 % DEI CAMPIONI

SOST. UBIQUITARIE (PELLICOLE x CIBI, TESSILI, MOQUETTE )

http://www.innovations-report.com/html/reports/medicine_health/report-83364.html

Estimating Burden and Disease Costs of Exposure to EDCs in the EU: " The neurodevelopment panel estimated a strong probability (70–100%) that each year in Europe, 13.0 million IQ points are lost (sensitivity analysis, 4.24–17.1 million) due to prenatal organophosphate exposure"

L’autisme, une épidémie ?

Neurodevelopmental Disorders and Prenatal Residential Proximity

to Agricultural Pesticides: The CHARGE Study Janie F. Shelton,1 Estella M. Geraghty Environ Health Perspect; DOI:10.1289/ehp.1307044: 23 June 2014

970 participants, California Pesticide Use Report (1997-2008) linked to the

addresses during pregnancy. Pounds of active ingredient …

aggregated within 1.25km, 1.5km, and 1.75km buffer distances from the home

•Organophosphates higher 3rd trimester expos: 60% increased risk ASD

•Pyrethroid insecticide just prior to conception or for 3rd trimester at

greater risk for both ASD and DD (developmental delay)

•Carbamate: risk for DD increased (Arprocarb di uso anche domestico:

Undene, Propoxur = Baygon).

Giuseppe Giordano ISDE Palermo

Rischio ASDs molto

aumentato (OR > 50%)

ed in modo

statisticamente

significativo tra le

mamme esposte ad

inquinamento

atmosferico da polveri

(PM 2.5) e

non da PM 2,5-10

durante il terzo trimestre

di gravidanza

(sinaptogenesi!) ..

altri due studi caso-

controllo 2013 avevano

mostrato la correlazione

JAMA Psy

2013;70(1):71-7;

EHP 2013;121(3):380-6

JAMA Psychiatry. 2013 January ; 70(1): 71–77. doi:10.1001/jamapsychiatry.2013.266

Living near a freeway, based on the location of the birth,

and third trimester address, and autism PM2.5, PM10, and NO2 at residences were higher in children with autism. The magnitude of these associations appear to be most pronounced during late gestation (OR=1.98, 95%CI 1.20–3.31) and early life / first year of life (OR=1.98, 95%CI 1.20–3.31)

Giuseppe Giordano ISDE Palermo

Nano-tossicologia

Controllo delle emissioni del traffico veicolare

Politiche per una mobilità “sostenibile”

PM 10

PM 2,5 PM 0,1

PARTICOLATO ULTRAFINE

Giuseppe Giordano ISDE Palermo

The frontal cortex of an 11-month-old healthy MC dog exhibits Aβ42 staining of a diffuse plaque, surrounded by a microglia-like nucleus

The frontal cortex of a 17-year-old MC boy… shows a diffuse Aβ42 plaque (red product) and GFAP-negative astrocytes

The frontal cortex of a 36-year-old MC male with an E3/E4 ApoE genotype .. shows abundant mature and diffuse Aβ42 plaques (red stain) along with GFAP-positive reactive astrocytosis

Exposures to particulate matter and gaseous air pollutants have been associated with respiratory tract inflammation, disruption of the nasal respiratory and olfactory barriers, systemic inflammation, production of mediators of inflammation capable of reaching the brain and systemic circulation of particulate matter. Mexico City (MC) residents are exposed to significant amounts of ozone, particulate matter and associated lipopolysaccharides. MC dogs exhibit brain inflammation and an acceleration of Alzheimer’s-like pathology, suggesting that the brain is adversely affected by air pollutants. MC children, adolescents and adults have a significant upregulation of cyclooxygenase-2 (COX2) and interleukin-1β (IL-1β) in olfactory bulb and frontal cortex, as well as neuronal and astrocytic accumulation of the 42 amino acid form of β-amyloid peptide (Aβ42), including diffuse amyloid plaques in frontal cortex. The pathogenesis of Alzheimer’s disease (AD) is characterized by brain inflammation and the accumulation of Aβ42, which precede the appearance of neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD. Our findings of nasal barrier disruption, systemic inflammation, and the upregulation of COX2 and IL-1β expression and Aβ42 accumulation in brain suggests that sustained exposures to significant concentrations of air pollutants such as particulate matter could be a risk factor for AD and other neurodegenerative diseases.

Increased amyloid

A-deposition

Accumulation of hyperphosphorylated

microtubule associated protein “tangles”

(LEARn) model : early environmental factors such as

exposure to Pb, nutritional deficiencies (e.g., folate or

B12), or oxidative stress alter DNA epigenetically, by

reducing the activity of enzymes as DNMTs…

Copyright ©2008 Society for Neuroscience

No Caption Found

Alzheimer’s Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

Environmental Trigger

Early life exposures

DOHA -Developmental (Embrio-Fetal) Origin of AD.

The cause for most Alzheimer's

cases is still essentially unknown

(except for 1% to 5% of cases

where genetic differences have

been identified)………….

The Journal of Neuroscience, 2008 • 28(1):3–9 • 3

A marked reduction in DNA

methylation was observed

in post-mortem brain (Mastroeni et al., 2010)

Epigenetics and Alzheimer disease

Folate and vitamin B12 restriction

induced demethylation of PSEN1

gene and increased a production

in both mice and neuronal cell

cultures (Fuso et al., 2008)

Aberrant methylation of genes related to

a production and deposition (PSEN1,

APOE) and to DNA methylation

(DNMT1, MTHFR) was found in DNA

from blood or brain of AD patients

(Wang et al., 2008)

Prenatal exposure of monkeys

to lead resulted in epigenetic

modifications of genes related to a

Production (APP, PSEN1) and increased

a deposition later in life (Wu et al., 2008)

Several studies point to a possible contribution

of epigenetic modifications in AD

Lucia Migliore Università di Pisa

1

2

3

Des études scientifiques prouvent que l'exposition du fœtus à 800-1900 MHz

utilisés dans les radiofréquences des téléphones cellulaires peut conduire à des

altérations comportementales et neurophysiologiques qui persistent chez l’ adulte

• Les souris exposées pendant la grossesse avaient une déficience demémoire, étaient hyperactifs et ont troubles de anxiété, ce qui indique que l'exposition in utero aux radiofréquences est une cause potentielle de troubles neurocomportementaux.

• Nous avons aussi démontré une augmentation de la transmission synaptique glutamatergique sur les cellules pyramidales dans le cortex préfrontal associés à ces changements de comportement, suggérant un mécanisme par lequel l’exposition aux radiations de téléphone cellulaire in-utero peut conduire à l'augmentation de la prévalence des troubles neurocomportementaux

Fetal Alcohol Spectrum Disorders (FASD)

Behavioral effects of acute, binge-like ethanol exposure

K. Mantha, M. Kleiber - Mouse Model of Fetal Alcohol Spectrum Disorder, J. of Behav. Brain Sc., Vol. 3 No. 1, 2013

1. Delay of development of basic motor skill reflexes and coordination

2. Spatial learning and memory impairment

3. Observed changes in activity and anxiety-related behaviors

Ethanol disrupts biological processes that are actively occurring at the time of

exposure.

Morgan L Kleiber, Katarzyna Mantha, Journal of Neurodevelopmental Disorders 2013, 5:6

Trimester one: Cell proliferation microcephaly

Trimester two: Cell migration and differentiation agenesis of the corpus callosum, cerebellar hypoplasia

Trimester three: Cellular communication and neurotransmission hippocampus

COSTUME

Giuseppe Giordano ISDE Palermo

Maternal cigarette smoking during pregnancy and effects on child neurodevelopment

behavioral and psychiatric

disorders later in life

Affecting placental vasculature, and also by nicotinic

acetylcholine receptor binding in fetal membranes Nicotine Tob Res. 2008, Feb; 10(2): 267-78 Shea AK Steiner M

Epigenetic changes: altered DNA methylation and dysregulated expression of MicroRNA

(Knopik VS, Maccani MA, Dev. Psychopathol. 2012 Nov;24(4)

reduced birth weight

“thrifty phenotype

Brown LA, Khousbouei H, et al Down-regulation of early ionotrophic glutamate

receptor subunit developmental expression as a mechanism for observed

plasticity deficits following gestational exposure to benzo(a)pyrene.

Neurotoxicology. 2007; 28(5):965–78. [PubMed: 17606297]

dysregulation of the nicotinic and muscarinic, catecholaminergic and serotonergic

Neuro-transmitter systems

long-term neurotransmitter

involvement in dysregulation of

emotion and attention

Giuseppe Giordano ISDE Palermo

Prenatal exposure to stressful life events is associated with

significantly increased risk of Autistic Disorders (AD), as well

as other disorders, such as schizophrenia and depression..

Prenatal stress can produce both

(a) abnormal postnatal behaviors that resemble the defining

symptoms of AD, and

(b) other abnormalities that have elevated rates in AD, such as

learning deficits, seizure disorders, perinatal complications,

immunologic and neuroinflammatory anomalies, and low

postnatal tolerance for stress

Early life experience can

persistently alter

expression levels of key

genes through epigenetic

marking which can

underpin changes in

behavior, neuroendocrine,

and stress responsivity

throughout later life.

Collectively, this process is

referred to as epigenetic

programming. The nature

of the environment

throughout later life, in

addition to the impact of

biological processes

associated with aging and

genetic sex, may

exacerbate the effects of

programming established

during early life resulting

in increased vulnerability

to mood disorders.

Encore faut-il activer une portion bien précise de ce gène, grâce à un interrupteur épigénétique. L'analyse des cerveaux de rats n'ayant pas reçu une ration suffisante de léchage l'a démontré : l'interrupteur lié au gène NRC31 était défectueux dans les neurones de l'hippocampe des rats. Conséquence: même en l'absence d'éléments perturbateurs, ils vivent dans un état de stress constant..

Les bébés rats que leur maman lèche souvent

-le léchage remplissant chez le rat la même

-Fonction que la caresse chez l'humain- sont

-plus calmes que les rats mal léchés.

Sur le site vous pouvez voir directement comment l'Amour maternel peut libérer l’ADN ... Expérience 1: mère anxieuse, sans amour: les marques épigénétiques (partiellement réversibles) sur le gène du GR.. ont la tendance à produire des souris caractérisés par anxiété, désarroi, angoisse.. tout au long de leur vie (et même pour quelques générations!)

Expérience 2: mère tranquille, aimable: les caresses "suppriment" les groupes méthyle, libérant le gène du récepteur en permettant son expression. Les petits souris seront rassurés , aimables, résistants au stress tout au long de leur vie (et même pour quelques générations).

Maternal care influences the programming of the hypothalamic-

pituitary-adrenal Axis (HPA) through

epigenetic programming of glucocorticoid receptors expression...

We found a greatly increased methylation of cytosine in the

promoter of a gene codifying for a Glucocorticoids-Neuro-Receptor

(NR3C1) in the hippocampus of suicide victims with a history

of childhood abuse .. (post-mortem examinations)

..our results clearly show that periodic maternal separation decreases hippocampal granule cell neurogenesis beginning in early postnatal life. These alterations take place without chronically increasing basal HPA axis activity during the SHRP. We suggest that MS causes alterations in the development of the central nervous system that are related to the long term HPA axis dysregulation and contributes to increased depressive-like behavior in the adult.

Adults who experienced abuse or neglect as children seem to have an

enhanced emotional sensitivity to stress; they are more likely to

develop psychiatric disorders when confronting subsequent

stressors than adults who did not have a similarly troubled history

Childhood maltreatment is a particularly potent risk factor for depression

in adults, especially when individuals encounter stressful life events

Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link

between childhood trauma and depression: insights from HPA axis studies

in humans. Psychoneuroendocrinology 2008;33:693–710

McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM,

Kessler RC. Childhood adversities and adult psychiatric disorders in the

national comorbidity survey replication II: associations with persistence

of DSM-IV disorders. Arch Gen Psychiatry 2010;67:124 –32

A recent study suggested that early maltreatment might

even accelerate cell aging; young adults with an average

age of 27 years who reported childhood maltreatment had

shorter telomeres in peripheral blood mononuclear

cells (PBMCs) than those who reported no maltreatment…..

A growing literature has linked shorter telomeres with

health behaviors, including physical activity, obesity, and

smoking, as well as aging and age-related diseases,

including cancer, coronary heart disease, diabetes and

heart failure.

Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA, Carpenter LL.

Childhood maltreatment and telomere shortening: preliminary

support for an effect of early stress on cellular aging. Biol

Psychiatry 2010;67:531– 4.

Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD,

Cawthon RM. Accelerated telomere shortening in response to

life stress. Proc Natl Acad Sci U S A 2004;101:17312–5

Willeit P, Willeit J, Mayr A, Weger S, Oberhollenzer F, Brandstatter A,

Kronenberg F, Kiechl S. Telomere length and risk of incident

cancer and cancer mortality. JAMA 2010;304:69 –75

Front Neurosci. 2013; 7: 123. Published online Jul 22, 2013. doi: 10.3389/fnins.2013.00123 PMCID: PMC3717511 Autism spectrum disorder in children born preterm—role of exposure to perinatal inflammation Suzanne J. Meldrum, T. Strunk, A. Currie, S. L.

Prescott, K. Simmer, A. J. O. Whitehouse

Schendel D, Bhasin TK., Birth weight and gestational age characteristics of children with autism, including a comparison with other developmental disabilities. Pediatrics., vol. 121, maggio 2008, pp. 1155-1164.

… a markedly increased prevalence of ASD in children born

preterm, who are at highest risk of exposure to perinatal inflammation. However, the mechanisms that underpin the

susceptibility to infection-driven inflammation during pregnancy and risk of preterm birth, and how these intersect with the

subsequent development of ASD in the offspring, is not understood …. .

Autism spectrum disorder in children born preterm & role of exposure to perinatal inflammation

Giuseppe Giordano ISDE Palermo

Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions

This activation of the inflammatory response system may be suggestive for microglia activation, as these cells are the macrophages of the brain

Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis

Hypothesized Model of the Modulation of Adult Brain and Behavioral Functions by Imbalances in Fetal Brain Cytokines.

Meyer U et al. Schizophr Bull 2008;35:959-972

© The Author 2008. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Maternal immune activation and abnormal brain

development across CNS disorders

Nature Reviews Neurology 10, 643–660 (2014)

Epidemiological studies have shown a clear association between maternal infection

and schizophrenia or autism in the progeny.

Animal models have revealed maternal immune activation (mIA) to be a profound

risk factor for neurochemical and behavioural abnormalities in the offspring.

Maternal immune activation and abnormal brain

development across CNS disorders

Nature Reviews Neurology 10, 643–660 (2014)

Microglial priming has been proposed as a major consequence of mIA representing

a critical link in a causal chain leading to the wide spectrum of neuronal dysfunctions

and behavioural phenotypes observed in the juvenile, adult or aged offspring.

Nature (2010)

An emerging and

intriguing trend is the

identification of rare

CNVs in the same

genes implicated

across

neurodevelopmental

disorders, including

schizophrenia, ADHD,

and intellectual

disability.

What is most striking is that the same

CNVs have been found, at least in some

cases, in the semen of parents, showing

that autism could be the consequence

of a parental exposure to pollutants

and a transgenerational transmission:

which could provide an explanation for the

unremitting "pandemic" increase of

these disorders.

All that said .. it is absolutely necessary to reconsider

the problem of many early environmental exposures

or even gametic, and their possible synergy ..

which can induce an epigenetic instability,

In autism many CNVs

involve genes controlling

- Cell proliferation

- Synapse formation

- cell motility and - cell signaling ..

The CNVs are, in fact, in several

species defensive and reactive

changes

(.. deletion or amplification

of some sequences had been

discovered in the seventies of the

last century in animals and plants

exposed to situations of stress

and pollution)

All these CNVs were associated with genes already known to be involved in autism.

A similar study documented the importance of rare CNVs in different loci associated with schizophrenia.

Deletions and duplications de novo were present in 5% of controls versus 15% of

cases (20% younger) highly significant differences. The association was replicated

independently in patients with schizophrenia beginning in childhood compared to

their parents. Mutations in genes controlling the neurological development of

networks, including neuregulin and glutamate pathways were frequent

CNVS FROM THE AUTISM CHROMOSOME REARRANGEMENT DATABASE (ACRD) ARE PLOTTED TO THE RIGHT OF EACH

CHROMOSOME (BLACK). CNV DATA FROM THE AUTISM-SPECIFIC STRINGENT DATA SET FROM THE CURRENT STUDY

ARE SHOWN TO THE LEFT OF THE CHROMOSOME AND IS CATEGORIZED AS DE NOVO (BLUE),

OVERLAPPING/RECURRENT (GREEN), CNVS OVERLAPPING WITH STRUCTURAL VARIATION FROM THE ACRD (YELLOW),

AND SINGLETON CNVS (RED).

A similar situation is emerging from CNV studies of schizophrenia. There is a high frequency of de novo CNVs.. a large heterogeneity in rare variants… Which indicates that similar pathways may be involved in phenotypically distinct outcomes

Trends in Neuroscience Vol 32, 2, 2009, 69–72

Epigenetics and mental disorders

• Fragile X disease is associated

with an expanded (N250 copies)

number of hypermethylated CGG

repeats 5′ of the FMR1 gene that

results in downregulation of the

gene

• Disease severity in fragile X is

directly correlated with the

extent of methylation in the 5′

region of the FMR1 gene

• Rett syndrome, on the other

hand, is linked to mutations in

the gene encoding the

methylated cytosine binding

protein (MECP2)… which

recruits a variety of proteins

that form a complex..

repressing gene expression

Both fragile X and Rett syndrome are responses to well-established alterations

to a single gene. However, recent work in autism spectrum disorders suggests

a major epigenetic component to the origin of the(se) disease(s)

Free Radical Biology & Medicine 46 (2009) 1241–1249

the severity of the disease is directly related to the number of methylation in the 5 'region of the FMR1 gene

méthylations

Fragile X disease

Rett syndrome

• In at least 95% of Rett syndrome cases, the cause is a de novo mutation in the child. Parents are generally genotypically normal, without an MECP2 mutation.

• In sporadic cases of RTT, the mutated MECP2 is usually thought to be derived from the male copy of the X chromosome.

• It is not yet known what causes the sperm to mutate, and such mutations are rare.

Trappe R, Laccone F, Cobilanschi J et al MECP2 mutations in sporadic cases of Rett's

Disorder are almost exclusively of paternal origin

American Journal of Human Genetics 2001; 68 (5): 1093–101

Starting from the new models of (epi)genetic fluid genome

autism and other neurodevelopmental disorders (as well as neurodegenerative diseases such Alzheimer's disease)

are the most emblematic

- epigenetic diseases (ie genetic and environmental at the same time) - trans-generational diseases (owing to genetic and epigenetic changes that occur in gametes) and/or

- disorders of fetal programming: that is, so to say, changes in the embryo-fetal development related to early transplacental exposure to genotoxic agents (especially heavy metals) with the possible assistance of other epigenotoxic agents ( including EDCs and electromagnetic fields).

CONCLUSION

It is obvious that this requires a total change of perspective:

instead of looking into the DNA for pre-disposing causes (mutations and polymorphisms)

we should search for epigenetic marks and active genetic modification (reactive and defensive)..

which can explain much better the pathogenesis and symptoms that characterize behavioral and neuropsychiatric diseases

CONCLUSION

How Music shapes our Brain

"You are your synapses. They are who you are." --- Joseph LeDoux, 2002 (in Synaptic Self)

Un caso estremamente interessante è quello del cervello del musicista che presenta una struttura alquanto particolare, almeno nei casi in cui lo studio della musica ha avuto inizio nelle primissime fasi della vita..

Music training can significantly improve our motor and reasoning skills We generally assume that learning a musical instrument can be beneficial for kids, but it’s actually useful in more ways than we might expect. One study showed that children who had three years or more musical instrument training performed better than those who didn’t learn an instrument in auditory discrimination abilities and fine motor skills.

08 PLOS ONE Practicing a Musical Instrument in Childhood is Associated with Enhanced Verbal Ability and Nonverbal Reasoning

Music affects many different areas of the brain

http://blog.bufferapp.com/music-and-the-brain

Some of the brain areas that have been found to be enlarged in musicians in

morphometric studies based on structural magnetic resonance imaging. Red,

primary motor cortex; yellow, planum temporale; orange, anterior part of the

corpus callosum.

http://www.nature.com/nrn/journal/v3/n6/fig_tab/nrn843_F2.html#figure-title

Structural brain differences between different musician groups (e.g., keyboard and string players) are consistent with a “nurture” hypothesis (Bangert and Schlaug 2006). The omega sign, an anatomical landmark of the precentral gyrus associated with hand and finger movement representation, was found to be more prominent on the left hemisphere for keyboard players but was more prominent on the right hemisphere for string players

Everybody know that Albert Einstein, when he was young, did extremely poor in school… and that his grade school teachers told his parents to take him out of school because he was "too stupid to learn" and it would be a waste of resources for the school to invest time and energy in his education. The school suggested that his parents get Albert an easy, manual labor job as soon as they could. His mother did not think that Albert was "stupid". Instead of following the school's advice, Albert's parents bought him a violin. Albert became good at the violin. Music was the key that helped Albert Einstein become one of the smartest men who has ever lived. Einstein himself says that the reason he was so smart is because he played the violin and loved the music of both Mozart and Bach ..

Many thanks for your attention