1&2. introduction and neurodevelopment

what influences behaviour

what influences behaviour

evolutionary and genetic influences

environmental and social influences

previous experience

current motivational state

hierarchy of organisation means that: (2)

1. levels are connected

2. any manipulation at any level can change the function at other and at all levels of the hierarchy

building blocks of the brain

neurodevelopment, genetics →

neurophysiology (neurotransmission and neuromodulation, pain etc) →

behaviour (social behaviour, sleep and circadian rhythms, typical and atypical functioning)

brain weight at birth

350g

brain weight in adulthood

1300g

prenatal development - germinal stage

• 1-2 weeks

• nuclei of the egg and sperm fuse to form a zygote

• zygote begins to divide at 12h, by a process called cleavage, to form a cluster of homogenous cells (morula)

• morula continues to divide to form a blastocyst (200-300 cells)

• once implantation in the uterus begins, the embryonic stage takes place

zygote

fusion of egg and sperm nuclei

morula

cluster of homogenous cells resulting from cleavage of a zygote

embryonic stage - gastrulation

1. initially - embryonic disc

2. uneven rate of cell development forms 3 distinct layers

   • ectoderm

   • mesoderm

   • endoderm

3. the ectoderm will fold in on itself to form the neural tube which will eventually become the nervous system

formation of the neural tube

day 18: ectoderm outer layer thickens and form a plate - edges form ridges and curl towards each other in a longitudinal line

day 21: ridges touch each other and fuse together, forming neural tube (brain and spinal cord)

day 28: neural tube is closed - rostal end has developed 3 interconnected chambers (will become ventricles, with the tissue around them becoming the forebrain, midbrain, and hindbrain)

neural tube defects

spinal bifida - failure of the closure of the neural fold at the level of the spinal cord

• 1 in 1000 live births

• small opening can often be surgically corrected

• larger openings can lead to paralysis and limb deform

• can be prevented by folic acid supplements

anencephaly - brain fails to develop - generally results in stillborn

stages of brain development

1. cell birth/proliferation (neurogenesis and gliogenesis)

2. cell migration

3. cell differentiation and maturation

4. synaptogenesis and synaptic pruning

5. cell death

6. myelination (myelongenesis)

impact of experience on synapse formation

experience expectant

• development will not happen unless an experience happens during its critical period (the result of evolution and genes) and is species-specific

experience dependent

• not predetermined but are generated in response to the environment

• vary between individuals eg rats in complex environments have more synapses and more neurons than the ones in standard conditions

stage 1 of brain development - cell birth/proliferation

• at peak, 250,000 neurons are born per minute

• initially, neural tube is 1-cell thick touching on both ends

• as neural tube widens, the extensions of the cells elongate still holding on to the outer wall

• neurogenesis does not take place with neuronal division - neurons do not divide

• immature cells called stem cells divide to form progenitor (precursor) cells

• each progenitor cell can be a neuroblast or a glioblast

• cells undergoing mitosis were always closer to the inner surface of the neural tube - the ventricular tube (brain nursery)

• the neural tube gives rise to the ventricular system in a mature brain

• in adulthood, the lining of the ventricles still contain stem cells

• an abundance of neurons will be created during early development - more than you will have as adults

stage 2 of brain development - cell migration

• movement of the newly formed cells towards the outer layers (marginal zone)

• the cortex develops in an inside-out manner

• there is a primitive map of the cortex that predisposes cells born in a certain region to migrate to a certain cortical location (aka where cells are born dictates where they go)

• occurs with the help of:

  • chemical signals (immunoglobulins and cytokines - secreted by target cells to guide stem cells to that direction)

  • physical support (provided by radial glia - cells ‘climb’ up the radial glia with the help of extensions

• some cells migrate tangentially (sideways) to form areas such as basal ganglia and amygdala

what helps cell migration

chemical signals and physical support

what chemical signals help cell migration

immunoglobulins and cytokines

secreted by target cells to guide stems cells to that direction

what physical support helps cell migration

radial glia - cells climbs along them with the help of extensions

radial glia exist only during time of neurodevelopment

migration of young neurons into the infant frontal lobe

• a large wave of neurons are still migrating into the frontal cortex after birth

• most prominent in the first few months of life (up to 3-7 months)

• most will become inhibitory GABAergic interneurons - important in modulating excitation

step 3 of brain development - differentiation and maturation

• once they arrive at their destination, immature neurons begin to express particular genes that will allow them to become a particular type of cell

• they start to form an axon (grow in mm/day) and dendrites (grow in µm/day)

• dendritic development:

  • dendritic arborization (branching)

  • growth of dendritic spines (swelling on neurons - providing space for other neurons to synapse onto them)

broca’s area

• associated with expression of language eg being able to articulate and produce speech

• (compared to Wernicke’s area associated with ability to piece together meaning of words)

• branching continues to develop in Broca’s area to 24 months - cells are differentiating during this time

differentiation and maturation

• there are ongoing cell-cell interactions via the secretion of chemicals, where cells influence the fate of neighbouring cells - a process known as induction

• if immature cells are removed from a given region, they will be replaced by subsequent neurons that will acquire the same characteristics - pluripotency

• because of this pluripotency of immature cells or stem cells, they can be used therapeutically to help neurodegenerative conditions eg Parkinson’s

• once the cells mature and differentiate they lose that property

what is induction

cells influence the fate of neighbouring cells through the secretion of chemicals

what is pluripotency

stem cells can give rise to any of the cells in the body

stage 4 of brain development - synaptogenesis and synaptic pruning

• growing end of axon = growth cone

  • axons extend by additing microtubules to the tip of the axon

• growth cones develop thin extensions - filopodia

• growth cones are attracted (or repelled) to chemicals released from target sites:

  • cell adhesion molecules (CAMs)

  • tropic molecules

synaptogenesis

• once a successful contact has been made, axon and target induce each other to construct machinery to help them attach to one another (neurexins and neuroligins) and to form a synapse (post synaptic density proteins, PSDs)

• once synapses are formed, they are sluggish and slow in their firing compared to those in adults or more mature brains, but they get faster with time

• the majority of our synapses take place after birth and continue to rearrange themselves throughout life

filopodia advance by …

… adhering to other cells or by sensing their way around

• they can make physical contact with other cells (contact guidance)

• or they can be chemically guided (chemotropism)

• they have proteins on their membrane which serve as receptors that ‘recognise’ various molecules to which they will adhere or not

• so growth cones detect and select among a wide range of guidance cues

• both contact guidance and chemotropism can be either attractive or repulsive to the growth cone

synaptic pruning

• successful synapses are those who are active and thus maintained and strengthened

• those that are not successful are eliminated - synaptic pruning

• due to the ability of the brain to constantly form new synapses and eliminate (prune) others there is plasticity

• the determining factor is experience - “use it or lose it” principle

synaptic rearrangement

• occurs throughout life and is related to learning or experience

• branches are being redirected / redacted throughout life

• branches look different at different time - dynamic process that changes depending on what is going on in the brain

adolescence - period of increased synaptic pruning

• prefrontal cortex still immature, while other areas are better developed eg limbic system

• brain scans of 4-25 year olds every 2 years: grey matter thickens in childhood but then begins to thin out gradually

  • synaptic pruning starting from the back to the front by early adulthood

  • increase in white matter (myelination) which peaks in adulthood - adults faster in responses compared to adolescents

  • “use it or lose it” again

  • process is completed earlier in girls than boys

• environmental influences important

stage 5 of brain development - cell death - apoptosis

• type of cell death in development - apoptosis - Programmed Cell Death (PCD)

• useful in the shaping of organisms

• eg separation of our fingers occurs through apoptosis of the cells of the webbing whereas in ducks the webbed feet remain

• when axons initially reach their targets, they form synapses with several cells - there is overabundance

  • there are more neurons and more connections than we will eventually need, so some have to go

  • many will not form active synapses and will be eliminated → neural darwinism (survival of the fittest idea)

apoptosis vs necrosis

• apopsis is an active process - cells that undergo apoptosis are expressing genes that enable them to die → death genes (caspases)

  • eliminates itself quietly - doesn’t disturb vicinity

• necrosis = kind of death that happens with disease or injury

  • cell swells, plasma, organelles, and nucleus break down, leakage of contents

  • cause a lot of inflammation and hurt the other neurons in the area

  • very disturbing to area

which neurons will live and which will die?

• proteins secreted by target cells promote the survival and growth of neurons - survival signals

• these proteins are neurotrophic factors - eg nerve growth factor (NGF)

• in order to avoid apoptosis and survive a neuron will need:

  • neurotrophins (growth factors) from its target cells AND

  • active communication with other neurons which leads to the strengthening of the synapses

stage 6 of brain development - myelination

• process by which glia form the fatty sheath that covers the axon of neurons

• myelin speeds up the transmission of neural impulses

• first occurs in the spinal cord and then in the hindbrain, midbrain and forebrain (back-to-front)

• slow process - it occurs gradually for decades, depending on the region eg in the cortex it continues until adulthood

myelination in peripheral nervous system (PNS)

shwann cells (glial cells that provide the myelin sheath)

• wrap themselves around the axon of a neuron - monogamous

• creates a pathway after injury - can trace which glial cells are damaged

myelination in central nervous system (CNS)

oligodendroglia

• more poly - wrap themselves around as many axons as they can

motor behaviour

• correlation between myelination and ability to grasp

• eg 2 months, infant orients hand towards object and gropes to hold it

• 4 months, grasps object with entire hand

• 10 months, uses pincer grip

summary of brain development

• immature neurons are created, migrate, differentiate and mature, form synapses and compete for survival

• synapses and dendritic branches of a neuron are not fixed - they extend, retract, or even disappear

• myelination is a job for glia and is a slow process

• some processes extend beyond prenatal life and continue to shape our brains

new neurons - in songbirds

• in songbirds, there is a steady replacement (seasonal) of neurons in the ‘singing’ area

• generated in the lining of the ventricles, migrated to their final destination, differentiated, and then responded to auditory stimuli

• songbirds need to learn a song every mating season

neurogenic regions in the adult human brain

• olfactory epithelium - contains cells that continuously divide to provide new olfactory sensory neurons, and replaced damaged ones → we are exposed to a lot of new chemicals / smells so this is useful

• also cells produced in the subventricular zone (SVZ) of the lateral ventricles migrate to replace interneurons in the adult olfactory bulb

• this path of migration to the olfactory bulb is called the Rostral Migratory Stream (RMS)

rostral migratory stream (RMS)

• newborn cells from the subventricular zone (SVZ) migrate to the olfactory bulb and become interneurons

• astrocytes (another type of glial cell) wrap around the migrating neurons to create a ‘pipeline’ and keep them on the right path

• this occurs throughout life

neurogenesis in the hippocampus

the granular layer of the dentate gyrus in the hippocampus was the first neurogenic area to be discovered

• new neurons are created and added to the dentate gyrus throughout life

• hippocampus - learning and memory → supported by neurogenesis

neurogenesis in the cerebral cortex

• there seems to be very few adult-born neurons in the cortex, which are created in the SVZ

  • neurogenesis can be induced by injury but depends on the extent of the injury

recovery following injury

• recovery is better in younger brains than older brains and is better in the periphery than in the brain

• mechanisms of recovery mainly involve new branching of axons and dendrites - process = collateral sprouting

  • new branches formed by non-damaged axons attach to vacant spots of dendrites and cell bodies

  • the cells secrete neurotrophins that allow collateral sprouting to occur

• especially in the first 2 weeks after damage, the rate of new synapses forming is very fast

brain adaptations throughout life

• in people blind since infancy there is enhanced tactile (finger sensitivity) and auditory ability

• people who are deaf have a better sense of touch and vision

• in cases of amblyopia or lazy eye we can intervene (ie wear eye patch on good eye) and reinstate good vision - usually for children

• so the brain adapts according to environmental stimuli → neuroplasticity (synaptic plasticity)

reorganisation in the monkey brain

• monkey amputation study - one finger cut off

• somatosensory cortex - mapped out areas in the cortex that responded to stimulation of the fingers

• looked at brain again some time after finger was cut off

• area of brain that corresponded to missing finger was taken over by areas related to fingers on either side

• shows rearrangement of brain depending on environment

blindness - brain adaptations

researchers asked sighted and blind people to feel Braille letters or other items and say if they were the same or different

• blind people performed better

• PET and fMRI scans indicated substantial activity in the occipital cortex [visual] of blind people while they performed these tasks

• auditory stimuli also produced increased responses in visual areas of the cortex

• aka brain areas not being used are taken over by areas that are being used

music training - brain adaptations

musicians have larger brain areas responsible for hearing and finger control

MRI scans reveal:

• the temporal cortex of professional musicians in the right hemisphere is 30% larger than in non-musicians

• thicker grey matter in the part of the brain responsible for hand control and vision of professional keyboard players

• larger than normal area of the postcentral gyrus in the right hemisphere for the movements of the left hand (string control)

enriched environments

• rats raised in enriched environments developed a thicker cortex and have increased dendritic branching

• much of the enhancement was due to physical activity

• increased dendritic branching was correlated with improved ability to learn

broca’s area and language development

increased dendritic branching also as a result of increased experience of language - lots of people talking to others

critical periods

• a period in which the brain is most sensitive to a specific experience

• absence of visual stimuli can lead to blindness, or lack of exposure to language at an early age may lead to the inability to use language

  • sensitive periods could be conceived as a brief opening of a window of vulnerability, of need, and of opportunity

richard tees - ‘train ride’

3 waves of critical periods:

1. senses (infancy)

2. language

3. higher cognition (childhood)

critical periods - evidence

cats and stripes

• cats in enclosures of stripes with just one orientation for 3 hours (rest of time was dark)

• neurons in visual cortex only fired for same orientation of line

• shows critical period

the case of genie

• social and experiential deprivation and chronic malnutrition

• kept from birth to 13 years in the dark in a room - not allowed to leave

• learned words after being discovered but never learnt language the way normal developed children would

many conditions can be traced back to early development

• epidemiological studies show evidence for environmental factors that lead to pathology later in life such as epilepsy, autism, schizophrenia etc

  • activation of the mother’s immune system (MIA) - season of birth, viral epidemics, population density

  • prenatal malnutrition (folic acid, thiamine deficiency etc)

  • substance abuse

  • complications during pregnancy and delivery particularly anoxia or hypoxia

summary

• brain development begins prenatally but extends beyond birth and continues throughout life

• because of this constant interaction between our genetic blueprint and our environment, each one of us shapes a unique brain

• neuroplasticity allows for great potential and susceptibility to environment influences throughout life, but especially during the critical periods of development

• our brains are more adaptive than we previously thought