Mind & Brain in the What Is Neuroscience? 21 st Century - - PDF document

Mind & Brain in the 21st Century

Dr Guy Sutton

Medical Biology Interactive

• To review how and why brain research has

advanced over the past twenty years.

Aims

• To consider particular advances in our understanding
• f brain function; neuroplasticity, neurogenetics, and

neuroimaging.

• To briefly address new technologies, the immediate

future and what is on the horizon for brain research.

What Is Neuroscience?

Multidisciplinary research attempts to understand brain function are collectively referred to as neuroscience. Neuroscience encompasses research methodologies from many diverse scientific disciplines, including anatomy, biochemistry, biophysics, pharmacology, philosophy, physiology, cognitive science and neuropsychology.

Decade of the Brain

The U.S. Library of Congress and the National Institute

• f Mental Health sponsored

this inter-organisational research initiative. The general aim was to raise the profile of research endeavours and ethical issues in brain research with the general public. Kandel & Squire (2000): the main developments in neuroscience were: 1) The transition of the study of nerve development from a descriptive to a molecular discipline, with advances in our understanding of neuroplasticity. 2) The start of the long process of mapping genes to nerve development, differentiation and function in the central nervous system. 3) The development of functional brain imaging and its application to the study of human cognition.

Decade of the Brain

• Neuroplasticity refers to the

capacity of the nervous system to modify its organisation.

• Changes can occur as a consequence
• f many events, including the normal

development and maturation of the

• rganism, the acquisition of new skills

(‘learning’) in immature and mature

• rganisms, after damage to the nervous

system and as a result of sensory deprivation.

Neuroplasticity

The most dramatic changes in the developing brain relate to the growth of axons, dendrites, and the number of synaptic connections between neurons, a process known as synaptogenesis. Synaptogenesis results in a surplus of synapses in the prenatal brain, thus these connections undergo ‘pruning’, a form of neural ‘fine tuning’.

Nerve Cell Growth & Synaptogenesis

The majority of neurons comprising the mature brain develop prenatally and are present from birth. Some new neurons develop after birth in areas of the brain such as the hippocampus.

Experience-Dependent Structural Plasticity

Aydin, K. et al (2007). Increased gray matter density in the parietal cortex of mathematicians: a voxel-based morphometry study. American Journal of Neuroradiology, 28: 1859-1864.

In academic mathematicians, cortical gray matter density in the left inferior frontal lobe and bilateral inferior parietal lobules were significantly increased relative to controls. Increases in gray matter in the right inferior parietal lobule in mathematicians was strongly correlated with duration of time as an academic.

Our mental faculties do not deteriorate as quickly as we sometimes think.

Neuroplasticity & The Ageing Brain

Myths:

• the adult brain is incapable of change
• the adult brain suffers increasing neural

loss with consequent deterioration in learning, memory and performance

• frontal lobe structure and development is

effectively finalised by adolescence

• Although laying down new

information becomes less efficient with age, there seems to be no age limit for learning.

• Neuroplasticity depends critically
• n how much the brain is used. 'Use it
• or lose it' is therefore good advice.
• Evidence from neuroscience that

educational rehabilitation in adulthood is not only possible but well worth investing in.

Neuroplasticity & The Ageing Brain

Sensory and motor areas of the adult brain can adapt very quickly.

Plasticity & Fast Brain Change

In a mere five days, the motor cortex, responsible for movement of body parts (fingers included) increased in size and activity when non-pianist adults learnt a five-finger piano exercise for two hours per day over a five-day

• period. Control participants experience no such

change.

Pascual-Leone, A. (2001). The brain that plays music and is changed by it. Annals of the New York Academy of Sciences, 930: 315-329.

Addiction: A Loss of Plasticity of the Brain?

Fernando Kasanetz, V. et al (2010). Transition to Addiction is Associated with a Persistent Impairment in Synaptic Plasticity. Science, June 24, DOI: 10.1126/science.1187801

• Why is it that only some drug users

become addicts? The transition to addiction could result from a persistent impairment of synaptic plasticity in a key structure of the brain.

• Addiction may result from a form of

anaplasticity, i.e. from incapacity of addicted individuals to counteract the pathological modifications caused by the drug to all users.

Addiction: A Loss of Plasticity of the Brain?

• Chronic exposure to drugs causes many

modifications to the physiology of the brain. Which of these modifications is responsible for the development of an addiction?

• Animals which developed an addiction to

cocaine exhibit a permanent loss of the capacity to produce a form of plasticity known as long term depression (or LTD). It plays a major role in the ability to develop new memory traces and, flexible behaviour.

Fernando Kasanetz, V. et al (2010). Transition to Addiction is Associated with a Persistent Impairment in Synaptic Plasticity. Science, June 24, 2010 DOI: 10.1126/science.1187801

What Do Genes Do In The Brain?

• supervise the construction of neurotransmitters,

receptors, enzymes and the like

• supervise the metabolism of glucose
• supervise the maintenance of synapses,

altering the wiring of the brain

• guide the specialisation and

migration of cells in addition to the initial pattern of neural wiring

Genes & The Nervous System

A number of gene families play a role in the control of CNS development in

• vertebrates. Many of these genes are

homeobox genes.

Genes In Brain Development

The most well- known and best-studied among them are the Hox genes which control regionalisation and cell identity in the developing hindbrain and spinal cord.

Geisen, L. et al (2008). Hox Paralog Group 2 Genes Control the Migration of Mouse Pontine Neurons through Slit-Robo Signaling. PLoS Biology, 2008; 6 (6): e142 DOI: 10.1371/journal.pbio.0060142.

Pontine neurons are generated in the rear part of the brain and ultimately end up in the cerebellum. Pontine neuron migration is controlled by specific Hox genes. Knocking out the expression of the Hoxa2 gene changes the path of the neurons, causing them to end up in the wrong part of the brain.

Hox Genes & Neuron Pathways

BERT & ERNI Proteins Control Brain Development

Papanayotou, C. et al (2008). A mechanism regulating the onset of Sox2 expression in the embryonic neural plate. PLoS Biology, 6(1): e2.doi:10.1371/journal.pbio.0060002.

Two proteins, BERT and ERNI, interact in embryos to control when different organ systems in the body start to form. In vertebrate embryos a few hours old, a sequence of reactions occurs preventing early development of neural cells, conveying a head start to other cells and preventing premature NS development. At the crucial time, BERT binds with the protein ERNI and other proteins to unblock a gene called Sox2, which gives the green light to cells to start forming the brain and nervous system.

A Master Gene For Human Brain Development

Xiaoqing Zhang, C. T. et al (2010). Pax6 Is a Human Neuroectoderm Cell Fate Determinant. Stem Cell, 7, 1, 90-100, 2 July 2010 DOI: 10.1016/j.stem.2010.04.017

• A single gene, Pax6, has been identified

that seems to be a master regulator of human brain development, instructing stem cells at the earliest stages of embryonic development to become the cells of the brain and spinal cord.

• In human, but not lower animal brain

development, Pax-6 plays a very important role, particularly in cortical development. Neurons Developed from Stem Cells Successfully Wired With Other Brain Regions in Animals

Ideguchi, M. et al (2010). Murine Embryonic Stem Cell-Derived Pyramidal Neurons Integrate into the Cerebral Cortex and Appropriately Project Axons to Subcortical Targets. The Journal

• f Neuroscience, January 20, 2010, 30(3):894-904; doi:10.1523/JNEUROSCI.4318-09.2010

Transplanted neurons grown from embryonic stem cells were fully integrated into the brains of young animals. This new finding is the first to show that stem cells can be directed not only to become specific brain cells – those that are damaged in spinal cord injury - but to link correctly.

Rare Variants That Disrupt Gene Activity in Autistic Children

• Some children carry private genetic

mutations that are unique to them, contributing to their susceptibility to autism.

• The problem? Every child showed a different

disturbance in a different gene. Certain categories of genes emerged that were more likely to be influenced by the mutation.

Pinto et al (2010). Functional impact of global rare copy number variation in autism spectrum

• disorders. Nature, DOI: 10.1038/nature09146
• These findings explain only 3.3% of the genetic
• rigins of autism.

More Alzheimer’s Disease Genes

• Recent discovery of 3 gene mutations that

account for nearly 100,000 cases of AD in Britain today.

• One gene, clusterin, helps to protect the brain

from exessive inflammation caused by infections and other illnesses. The gene is also involved in removing clumps of amyloid plaques.

Harold, D. et al (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics, 6 September 2009 | doi:10.1038/ng.440. Lambert, J-C. et al (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genetics , 6 September 2009 | doi:10.1038/ng.439.

More Alzheimer’s Disease Genes

• The second new gene, Picalm, is crucial

for maintaining the health of connections between brain cells. Mutations in the Picalm gene are thought to disrupt the ability of neurons to communicate

• The third gene, CR1 is involved in protecting

the brain by clearing out amyloid plaques that can build up in Alzheimer's patients.

Harold, D. et al (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics, 6 September 2009 | doi:10.1038/ng.440. Lambert, J-C. et al (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genetics , 6 September 2009 | doi:10.1038/ng.439.

Compound Found in Red Wine Neutralises Toxicity of Proteins Related to Alzheimer's!

Ladiwala, A.R.A., et al (2010). Resveratrol selectively remodels soluble oligomers and fibrils of amyloid a into off-pathway conformers. Journal of Biological Chemistry, DOI: 10.1074/jbc.M110.133108

Hurrah! An organic compound found in red wine - resveratrol - has the ability to neutralise the toxic effects of proteins linked to Alzheimer's disease. Deformations of a particular peptide - the Aβ1-42 peptide - have been linked to AD. Improperly folded peptides have been shown to collect in accumulations called plaques within the brain. A single thalamocortical arbor in layer 1 of the neocortex at postnatal days 8, 11, 13 and 17. Note that some branches are added whereas others are eliminated over time.

In vivo two-photon time-lapse imaging

Neuroimaging Mapping Brain Circuits: The Connectome

Diffusion Tensor Imaging

Visualisation of a DTI measurement of a human

• brain. Depicted are

reconstructed fibre tracts that run through the mid- sagittal plane. Especially prominent are the U-shaped fibres that connect the two hemispheres through the corpus callosum (the fibres come out of the image plane and consequently bend towards the top) and the fibre tracts that descend toward the spine (blue, within the image plane).

Neuroimaging - Functional Measures

Current techniques include:

• Positron emission

tomography (PET)

• Single photon emission

tomography (SPECT)

• Functional magnetic

resonance imaging (fMRI)

Functional MRI (fMRI)

In active brain areas, levels of oxyhaemoglobin decrease whilst the levels

• f deoxyhaemoglobin

increase. To meet the metabolic demands of the neurons, the local blood vessels increase the flow of

• xygen-rich blood to the

area, increasing the

• xyhaemoglobin-

deoxyhaemoglobin ratio.

fMRI Studies

“Imagine playing tennis…”

Other New Technologies: Magnetoencephalography (MEG) Synchronization Tomography Near Infrared Spectroscopy

Conclusions

• Significant advances are being made in our

understanding of the brain at a molecular, cellular, systems and psychological level.

• New methods for studying brain structure and

function range from techniques which allow us to visualise gene expression neuroimaging techniques which allow us to visualise the working brain.

• The tradition of the newborn as a blank slate

shaped solely by experience (uninfluenced by genes) is no longer tenable.