Fred Mendelsohn on brain adaptability

This text reflects the contents of Professor Fred Mendelsohn's lecture but is not a word-for-word transcription.

The Honorable John Cain, President of the Library Board of Victoria, distinguished guests. May I also pay my respects to the Elders of the Kulin Nation, on whose traditional lands we stand.

What has neuroscience and neural plasticity got to do with Sir Redmond Barry and the State Library of Victoria? I believe quite a lot. As you've just heard Barry was founder of the State Library and a key figure in the development of Australia's cultural and intellectual life.

Redmond Barry, as well as enjoying a successful legal career in the colony of Victoria, played a significant role in establishing and directing the Melbourne Public Library. He was instrumental in building the tradition of the Library as a public Library, with a strong base in classical and educational literature. He conceived of the Library as the people's university. Barry also had a central roles in the establishment of the University of Melbourne, as well as Victoria's Museum and Gallery.

Given his recognition of the importance of scholarship and learning, I'm sure he would be fascinated to hear how much we have learnt about our brains over the last 150 years, most of it in the last ten. We now know that the richness of our environment has a marked effect on the development of our brains and on how we recover from damage or cope with degeneration of this vital organ. The institutions of learning that Barry initiated are part of the intellectual richness that surrounds us and that has contributed to the development of our own brains.

As Mr Cain mentioned, until recently it was thought that the human brain's wiring and function were fixed from childhood. Now we know the brain can adapt and repair itself, thanks to the plasticity of its connections and its ability to generate new nerve cells.

I would like to show you how nerve cells communicate, how these connections change depending on use and are involved in encoding memories, the implications of the discovery of neural stem cells in the brain, and how advanced neuroimaging is showing us how the brain adapts during learning and recovery from injury.

This is a nerve cell in the brain with its cell body, a number of branches of the cell body called dendrites and a major process leading out of the cell body called the axon. These small orange dots are sites where other nerve cells make specialised contacts ... Each of us has approximately 100 billion of these nerve cells in the brain, nearly 20 times the number of people on earth. Each nerve cell makes approximately 10,000 of these synaptic contacts with other cells. It is the number and strength of the synapses which define pathways in the brain that underlie development learning and plasticity in response to injury.

Here are two nerve cells or neurons making synaptic contacts here. This is a magnified view of this synapse showing packets of specialised chemicals called neurotransmitters that are released in response to an electrical signal transmitted along the axon into this cleft where the neurotransmitter can interact with specialised receptor molecules on the surface of the receiving cell. This process of chemical neurotransmission is an Australian discovery - Sir John Eccles and his group at the John Curtin School of Medical Research, at the Australian National University in Canberra, work for which he shared the Nobel Prize in 1963.

Neurotransmitters – this is a rather technical slide but actually most people have heard of dopamine in PD, serotonin in depression, acetylcholine in memory. At first it was thought that one type of neuron had one type of transmitter but now we know that most nerve cells use several transmitters – often one or two from each class. Australian neuroscientists – John Furness and Marchello Costa – were pioneers in the discovery of cotransmission. This means that chemical neurotransmission is a much more subtle process than formerly believed.

I would like to show you an animated cartoon of this process of electrical and chemical transmission of signals between nerve cells.

The term 'neural plasticity' refers to two separate processes. One is the plasticity of the synaptic connections between nerve cells which depends on the number of synapses and their efficacy; this process is use-dependent so that pathways that are used frequently are reinforced and those that are not used weaken and may disappear. There is also cellular plasticity which refers to the recent discovery that there are two neural stem cells in the adult brain that are capable of providing new nerve cells and supporting cells.

The term 'neural Darwinism' was invented probably separately by the Nobel Prize-winning neuroscientists Jean-Pierre Changeux in Paris and Geral Edelman in New York. It refers to the process whereby nerve cells compete with each other to make connections with other nerve cells or peripheral targets. This phenomenon has major implications for brain development, learning and memory as well as adaptation recovery and rehabilitation following injury.

This shows the growth of a nerve cell in the cerebral cortex showing increased size and complexity of its dendritic branches. Here you can see the remarkable profusion of dendritic branching over the first two years of life.

During childhood with the development of language, motor skills and cognitive ability there is a progressive pruning of this abundant dendritic synaptic connections by the process of neural Darwinism. This enables refinement of the skills in a manner appropriate to the environment that the child finds him or herself in.

A human infant is born with very few skills and is essentially helpless. Over the next few years she or he will rapidly develop extraordinary skills in motor function, speech and cognition. Most importantly these new skills will be appropriate for the social and physical environment she finds herself in. The human brain is a learning machine and is amazingly plastic and adaptable. Many living things are born or hatched with intact skills to survive including standing and running, but humans have traded this wired-in advantage for plasticity which enables us to adapt to widely different environments and acquire skills necessary to survive and thrive in them.

I would like to tell you about some exciting discoveries, made principally in the last 10 years, about how our brains develop, acquire skills and respond to damage in ways previously unsuspected.

Indeed observations of normal development and of individuals with extraordinary skills suggest that in most of us our brains operate somewhat below their capacity. By understanding these processes at a deeper level there is good reason to expect that we will be able to boost the nervous system's capacity for adaptation and repair way beyond what is currently possible.

This remarkable photograph shows nerve cells and their fibres in a part of the mouse brain called the hippocampus that is critical in laying down memory. The different colours represent genetic tags that are labelling neurons containing different neurotransmitters. This major technical advance will greatly help research aimed at studying the patterns of complex connections that underlies learning and memory.

What are the limits of human memory? Strangely the answer to this seems to be coming from people with developmental brain malformations and disability. This is a man called Kim Peek with his father. At birth Kim was found to have multiple developmental brain defects. His father was told that Kim would be severely mentally retarded, unable to walk or talk and would be best cared for in an institution. Kim's father devoted himself to his son's care and education. Over the years extraordinary abilities emerged with spectacular memory for everything he heard and read. I have a short video of Kim that I would like to show you.

What does this mean in terms of memory and capabilities of people with normal brains? I think it is showing us that we all probably have the latent ability to perform like Kim, or other people with Savant Syndrome, but that our brains have normal mechanisms to 'wipe the slate clean' so that we only retain material that is relevant to our daily lives.

How does the brain change when we learn a motor skill? This shows some work from Gary Egan's group at the Florey where they studied brain activity. We have known for many years that motor activity is generated in a part of the brain called the motor cortex, right here on the opposite side of the body. What this video shows is that a whole network of brain regions are involved in different stages of the process and that the pattern of activity changes as skill develops.

Professor Leanne Carey at FNI has been studying patients recovering from a stroke affecting their right arm. In healthy volunteers there is the expected activation of the primary motor cortex here, as well as the supplementary motor area. In patients two weeks after the stroke there is less activity in the primary motor cortex, much more marked activation of the supplementary motor cortex on both sides and recruitment of activity in the pre-motor cortex on the opposite side. As the patient's rehabilitation progresses this pattern starts to shrink down to resemble that in the normal subjects. We used to think that recovery of function after brain injury represented recovery of activity at the injured site. What these studies are telling us is that the brain is able to recruit additional areas to restore function, illustrating dramatically the plasticity of the brain.

So far my message has been that plasticity is a good thing. However exactly the same processes seem to be invoked in situations such as addiction, pleasure pathway, dopamine, addictive drugs, down regulation, loss of normal pleasure.

I would now like to turn to the other side of brain plasticity which revolves around the discovery of neural stem cells in the adult brain and factors, called neurotrophic factors, that regulate their behaviour.Sources of neural stem cellsMost people have heard of embryonic stem cells and the ethical controversy surrounding whether they should be used in an attempt to treat illnesses like diabetes or spinal cord injury. There are a number of places in the body where stem cells reside and provide a constant source of specialised cells such as blood cells. However it came as a great surprise to most of us the adult brain contains neural stem cells that are capable of generating new nerve cells and supporting cells.

This line is taken from a paper by Fred Gage and co workers at the Salk Institute in California and shows neural stem cells in two regions of the rat brain – this one called the subventricular zone, and here in part of the hippocampus – a region involved in laying down memory. The same is true of the human brain.

In a collaboration between the Walter and Eliza Hall Institute, lead by Dr Rod Rietze, and the Howard Florey Institute, lead by Professor Song-Sent Tan, scientists succeeded in isolating neural stem cells from the rat brain and here in a culture dish the stem cells have produced a neuron and a  supporting cell. Now that these cells can be isolated in culture it is possible to study the factors which makes them divide and replenish or to develop into particular cell types. This knowledge means that the sky is the limit in terms of boosting the brain's ability to regenerate and repair. Some of you may have heard Dr Rietze, who is now at the Queensland Brain Institute, talking about the beneficial effects of physical exercise on stem cells on ABC news recently.

Neurotrophins are specialised molecules which regulate the production, growth  and function of cells in the nervous system. The first discovered, nerve growth factor or NGF, by the Italian Scientist, Rita Levi-Montalcini lead to a Nobel Prize in 1986. Subsequently several more nerve growth factors have been discovered, each with unique actions, and one of which, BDNF, I will talk more about in a moment.

This slide shows that mouse ES cells in a culture dish have been transformed into dopamine containing neurons ... a mixture of growth factors. Similar results have now been achieved with human ES cells. These developments raise the exciting prospect of curing Parkinson's disease, a condition due to loss of dopamine cells in the mid-brain. This would involve grafting such cells into the midbrain, or alternatively using appropriate factors to regenerate the patient’s owner dopamine cells. However, there is still quite some way to go to do so safely in human grafts, but this is an exciting area which is likely to develop dramatically in the future.

Recently an additional source of stem cells has been obtained by introducing four particular genes into adult cells such as skin cells. These cells are called induced pluripotent stem cells or iPPCs.  This remarkable discovery means that it may be possible to generate stem cells from the patient's own cells and use these to repair the brain or other organs. Once again there is much work that needs to be done before this becomes a practical reality.

I would now like to tell you about some remarkable work by Dr Tony Hannan at the Florey onto the inherited neurodegenerative disorder, Huntington's disease. Some of you may have heard me talk about this work before but I bring it up again because of its great importance in understanding the interactions of neurotrophins, stem cells and a rich environment in combating neurodegenerative disease. The genetic cause of Huntington's disease is known and it is possible to introduce this genetic abnormality into a strain of mice which then develop the disorder with motor and cognitive defects. Dr Hannan's group has taken and housed them in an enriched environment containing toys and objects to explore. Compared to mice housed under routine conditions, the mice exposed to enrichment showed a remarkable delay in the onset and severity of the disorder. Hannan believes that there is a defect in neurogenesis, probably due to reduced levels of BDN, that can be, at least partially, reversed by an enriched environment.

In fact ... the possible involvement of impaired neural stem cell function goes much further than neurodegenerative disease. There is evidence in humans that depression may be associated with impaired neurogenesis secondary to lower levels of BDNF. Interestingly physical exercise boosts BDNF, neurogenesis and has antidepressant effects.

Illustrations of the new $220 million Neuroscience Facility buildings in progress at Parkville and Austin.

In summary:

• The brain is much more plastic than we previously believed
• Genes acting through many trophic and guidance factors determine the basic wiring pattern of the brain
• During development initially there is an excess of neurons and synaptic connections
• These are pruned by use-dependent mechanisms
• Similar processes are invoked in recovery of function after injury

Exercise, both physical and mental, have beneficial effects on the brain in terms of:

• aiding development
• fighting depression
• helping repair mechanisms
• combating neurodegeneration

Contrary to the dogma that the adult brain cannot repair itself, neural stem cells do exist in the adult brain and are capable of regenerating new nerve cells. Understanding the molecular mechanisms of neurogenesis and synaptic plasticity holds the promise of greatly enhancing repair after injury or degeneration.