Tag Archives: Wiring the brain

Eye Plasticity


Is how the eye remodels itself during foetal development providing a model for changes in our plastic brain?

KEY POINTS

  • Early development in the eye provides a model for neuronal plasticity.
  • Elucidating the mechanisms of normal neuronal development will help understand disease processes.
  • Innate immunity mechanisms through the HLA Class I molecules seem to have shared roles in both fighting the foreign and neuronal recognition processes. 

Elucidation of remodelling processes as complex human vision pathways develop in the foetus may provide clues to the mechanisms of neural plasticity that drive nervous system adaptation.

  • Clues to the Normal and Disease

The processes of plasticity in neuronal circuits and cells are not only significant for normal functioning but also they play a role in complex and diverse brain and nervous system disorders. An increased understanding of these processes may help in the future treatment of disease and also, for example, aid the recovery from brain damage by conditions such as stroke.

To understand disease it is important first to understand what is normal. Our understanding of how the brain works and how it remodels itself is key to our understanding of brain complexity and normal- and disease-related plasticity.

  • Throwing Light on Vision

The development of our highly evolved vision system provides an ideal model for how neural circuits and cells connect and how they remodel.

We start off in the womb with a primitive non-light dependent system. Then biochemical processes trigger activity that leads to the development of our complex visual sensory pathways. In early development, there is neuronal activity with spontaneous firing leading to the remodelling of the circuits involved in vision. It is this activity that leads to the development of the more complex adult wiring.

  • Role for the Immune

Analysis of the molecular mechanisms driving this early sophistication has surprisingly shown the involvement of similar molecules to those with a central role in innate immunity – the MHC class 1 molecules – the distinguisher of what is self and non-self. The MHC1 molecules in neurons seem to bind to a similar receptor molecule to the T-cell receptor called PirB. This interaction has been found to play a role in the switch from the more primitive in utero visual system to our more complex final adult wiring.

The optic tract leads from the retina and ends in the lateral geniculate nucleus (LGN), which is a sensory relay nucleus in the thalamus brain region. Maturing of the optic circuits occurs, so they up the normal pattern and organisation.

  • Foetal Development

In the foetus, there are initially no layers in the LGN. The ganglion cell inputs from the two eyes are intermixed and then gradually sort out to form the layers. In adult wiring, there is ocular dominance manifest in the LGN, and it is highly ordered such that ganglion cells from opposite eyes form connections within separate but adjacent interdigitated, eye-specific layers.

Blocking the neuronal activity in utero or preventing vision after birth disrupts rewiring plasticity of optic circuits and the immature pattern persists.

The rewiring involves elimination of inappropriate ganglions through  a process of weakening and regression and those that are made in the appropriate area are strengthened and stabilised.

  • Therapeutic Clues

Elucidation of the mechanisms involved in synaptic plasticity may offer a range of therapeutic options for behavioural disorders such schizophrenia and autism.

Cell and circuit changes accompany these disorders and there may be commonality between the processes in the development of wiring in the eye.

Even if we know all of the genes and the mutations or deletions involved in development disorders, such as schizophrenia or autism, then we will not know everything about these diseases until we understand the detailed circuit and cellular changes that occur in the disease state.

  • Conclusion

The way the immune and nervous system interact through the function of the MHC1 genes may partially explain some of the aetiology of these developmental disorders.

It seems as it the immune and nervous system share a common molecular language. This is important because when the immune system is in the brain it needs to communicate to have an effect on the neurons. Immune cells interact directly with neurons by interrogating their MHC1 proteins. The release of cytokines in the microenvironment of cells within the nervous system and brain may have profound effects in health and disease.

Conor Caffrey is a medical and science writer.

After a presentation by Carla Schatz at the Wiring the Brain Conference held in Powerscourt, County Wicklow.

Toys for Boys and Girls


Boys like trucks; girls like dolls. Is a liking for truckin’ all down to the hormone testosterone?

KEY POINTS

  • Testosterone levels in girls during early development can alter sex-type behaviours such as playing with toys.
  • Gender specific behaviours are altered by a range of factors, many still unidentified, and not just hormone levels.
  • Epigenetic mechanisms may in the future identify factors that determine sex differences between boys and girls.

 One thing is clear; the reason for the differences between the sexes is not yet clear. Whether you are from Venus or Mars or your favourite colour is pink or blue, or whether you are a more manly woman or womanly man is certainly not black and white.

  • A Host of Differences

It is not just genetics that determines whether the differences between men and women. There are a host of factors, some of them innate, some of them conditioned by the individual’s environment and learned experiences, and some of them socio-cultural, that make up whether an individual boy or girl is more masculine or feminine in their behaviours.

Sex difference, both structural and behavioural, is to some extent under hormonal control during early development and later during puberty changes.

  • The Androgen Factor

Testosterone and other hormones in the androgen family seem to be the main drivers of early development divergence in the sexes.

In humans, gender specific body traits, including height, and specific structures including the sex organs and specific parts of the brain, are under considerable influence of sex hormones and in particular testosterone levels but they can be influenced by the environment too.

Manipulation of testosterone levels in mammals other than humans also alters juvenile and adult behaviour with different impacts in males and females. It does this by altering brain structure permanently but also at critical times when sex differentiation evolves during early development of the organism.

Testosterone impacts in two ways on behaviour. The first is called activational and typically it comes and goes in adults. Remove testosterone and the sexual behaviour decreases in adults. Give hormone back and then it returns.

Organisatonal effects are more permanent and testosterone is either present or absent at those critical periods during development.

  • The Rat Model

In lab rats it is possible to make males behave like females and females to behave like males. This is done by manipulating their early hormone environment, so the female brain becomes  masculinised or the male brain becomes feminised.

These effects are not particularly specifically related to sexual behaviour, but can be gender type differences.

One male type behaviour that can be manipulated is rough and tumble play. In male juveniles, this is a typical play with a lot of body contact and ‘playfighting’. By injecting the mother of a female foetus with testosterone the female offspring will then show more rough and tumble play behaviour. Play behaviour in infants is a good model of gender specific characteristics.

  • Early Development

Testosterone and other sex steroids are involved in development of sex organs. In humans, about week 7 of gestation the testes are active and they continue to be active until about week 20 of gestation with a rise in testosterone levels.

There is another surge in testosterone in the early postnatal period. These hormonal surges govern the development of male genitalia externally and are involved in the development of certain parts of the brain such as the SGN.

Then the gonads become quiescent until adolescence when they become active again. So play behaviour is not influenced by the amounts of testosterone being produced in infancy as it is turned off.

  • Gender Type Behaviour

Some of the typical gender type characteristics seem to be at least partially under the influence of testosterone levels in the foetus. These include gender identity, sexual preference (most men and women have heterosexual choice preferences), and height and toy preferences. The scale of this influence seems to be higher in terms of gender identity and toy preferences, whereas it seems to be lower in terms of height and sexual preference. So testosterone levels alone will not determine sexual preference, which is likely to be influenced only in some small part by sex hormonal influences during early development.

There are other reported behavioural differences between males and females including aggression, empathy, and specific cognitive abilities including mental orientations and verbal fluency.

The Y Factor

The influence of the early human environment on these gender differences may include genetic factors (such as the presence or absence of the Y-chromosome), but some of the differences may be social determined by learning (eg parents may reinforce certain sex type behaviours), cognitive development (eg the child develops an increased understanding of being a male or female).

The Y chromosome is involved in sex determinism. It tells the gonads to become testes. If it is absent, then they become ovaries.

After that the products of the testis determine the physical phenotype beyond the gonads including the external genitalia and also probably to a certain extent the behavioural phenotype. So there seems to be a role for direct genetic effects, but the vast majority of effects are exerted by the products of the gonads

Value to Rare Disorders

It is not ethical to manipulate hormones in the developing human so other methods need to be used. One approach is to look at rare genetic disorders and a hormonal abnormality called congenital adrenal hyperplasia provides an opportunity to look at the influence of hormones in gender differentiation. Similarly it is possible to look at the offspring of women who required medical treatment with androgens such as testosterone during pregnancy. Amniotic fluid samples can be taken to look at the normal early hormone environment and to investigate variability within the norm.

CAH is a rare disease that causes increased levels of testosterone and other androgens. In girls, the internal reproductive structures are female and they are able to reproduce. They are usually undergo surgical feminisation and live as girls.

Sex and Toy Play

Play shows very large sex differences giving scope for detecting hormone effects and gender specific play also predicts adult behaviours that are of interest such as sexual orientation.

Childhood is a period of gonadal acquiescence so it is possible to separate out the effects that are hormone organisational effects and those that are effects of adult hormones.

In many cases, questionnaires and interviews are used to gather data on play behaviours. But it is often complicated by the fact that mothers of CAH girls may either perceive them as different and more male and the girls themselves may have this perception. In these studies, the environment is important so it is best to choose comparators that are siblings. From these studies it does seem that girls with CAH exhibit more male type play behaviour.

Also women with CAH are less likely to be exclusively heterosexual and this varies with the severity of the disease. Similarly they have more male type aggression and empathy behaviours whereas dominant behaviour does not seem to be affected.

From these studies of CAH, it seems that child play is affected by a 60% move from more female type to male type, gender identity and sex orientation are only affected by a 10% move from female type to male type behaviours

So other factors are involved in all of these behaviours other than genders specific toy choices including environmental, genetic, and sociocultural.

Females and Testosterone

The testosterone levels in CAH girls correlates with the level in the mother. So there is a correlation between girls and their mothers but not boys and their mothers. If carrying a male foetus, testosterone levels in the mother do not go up.

In the studies with toys, it was found that cars are more commonly favoured by boys and dolls by girls. If toy choices are to some extent socially determined, then what properties of these cars, a relatively modern invention in evolutionary terms, make them more popular with boys and the female with a testosterone exposed brain.

Learning from Play Choices

Elucidation of the properties of the cars revealed that it was not necessarily colour; as pink or blue are, despite the stereotype, not favoured by girls and boys respectively. Most infants prefer the colour red.

Similarly, shape was not implicated when comparing rounded and angular toys, as most very young kids prefer more rounded toys. One property of the cars that is being investigated is related to their ability for motion.

It seems that there is some genetic component to sex-type behaviours and this may be mediated in some way through hormone levels during development.

The challenge to identifying the hardwiring that results in gender specific behaviours through putative inherited, perhaps hormonal, effects is brain plasticity.

This involves the realm of the science of epigenetics. The switching on and off of parts of genes in the uterus during the development of male and female sex differences, particularly in the brain, is likely to be key. This may involve another generation of research to elucidate the precise mechanisms that have the most profound effects.

Conor Caffrey is a medical and science writer. This article was written after attending the Wiring the Brain Conference at Powerscourt in County Wicklow, Ireland.



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