Neurodevelopment

Question 1

What are key facts about the brain?

Answer 1

The brain weighs about 350g at birth, whereas in adulthood it is about 1300g. There are about 85 billion neurons and trillions of synapses in the mature brain. Brain development and maturation is not linear.

Question 2

Why should we study brain development?

Answer 2

1. For its own sake (interesting!)
2. Because many disorders can be traced back to the time of development, especially in the prenatal period - neurodevelopmental hypotheses of diseases

Question 3

What is the germinal stage?

Answer 3

1-2 weeks. The nuclei of the egg and sperm fuse to form a zygote. Membrane forms around the egg so no other sperm can enter. The zygote starts to divide at 12 hours, by a process called cleavage, to form a cluster of homogenous cells - morula. The morula continues to divide to form a blastocyst. Once implantation happens, the embryonic stage begins. This is where the nervous system begins to develop.

Question 4

What is gastrulation?

Answer 4

Initially there is an embryonic disc. There is an uneven rate of cell develop, forming 3 distinct layers: ectoderm, mesoderm, and endoderm. The ectoderm will fold itself to form the neural tube, which will eventually become the nervous system.

Question 5

What are the 6 stages of brain development?

Answer 5

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 (myelogenesis)

Question 6

What is involved in cell birth/proliferation (stage 1)?

Answer 6

Massive process - at peak, 250,000 neurons born per minute. Takes place in primitive neural tube. Involves stem cells, found in the inner surface of the neural tube - the brain’s nursery. Stem cells from progenitor (precursor) cells. They divide to from these cells. One cell remains as stem cell, the other is a precursor cell that is either a neuroblast or glioblast. Once formed, they begin to move to the outer areas of the neural tube.

Question 7

What is involved in migration (stage 2)?

Answer 7

Movement of newly formed neurons and glia to their final destination. The sub ventricular zone contains a primitive map of the cortex that predisposes cells born in a particular region to migrate to a certain location. There are temporary layers of cells that then disappear, as they are only there to guide the brain to organise the primitive neurons. Cajal-Retzius cells serve as a stop signal - when they have reached their final destination, they are stopped in their migration.

Question 8

What does migration occur with the help of (stage 2)?

Answer 8

1. Chemical signals (immunoglobulins and cytokines) - attract neurons to a particular location
2. Physical support provided by radial glia - cells climb along radial glia with help of extensions. Long extensions go from inner to outer neural tube.

Question 9

Why is migration important (stage 2)?

Answer 9

Important in the cortex (for example). Failure to migrate properly may have serious effects i.e. reeler mouse, or dyslexia and epilepsy in humans.

Question 10

What is involved in differentiation and migration (stage 3)?

Answer 10

At destination, primitive neurons begin to express particular genes that will allow them to become a particular type of cell. They start to form an axon and dendrites that will give them their distinctive shape. Depending on destination, neurons will differentiate in a particular way.

Question 11

What is dendritic development (stage 3)?

Answer 11

Growth of dendritic spines - dendritic swellings on their branches. Important because other neurons are going to synapse on this location. Can see important in Broca’s area - more branching and growth of dendritic spines in language learning.

Question 12

What is synaptogenesis (stage 4)?

Answer 12

Synaptogenesis is guided by a variety of cues and signals. Growing end of the axon is called a growth cone. Growth cones develop thin extensions called filopodia. They try to make synapses with other neurons. Growth cones are attracted to chemicals released from target sites. The neurons that want to make contact secrete chemicals to attract the neurons.

Question 13

What is synaptic pruning (stage 4)?

Answer 13

Synapses that are active are maintained and strengthened, and those that are not being used are eliminated. Due to the ability of the brain to constantly form new synapses and eliminate (prune) others, there is plasticity. Our experiences cause changes in the brain to aid what we do. “Use it or lose it”. Synaptic rearrangement occurs throughout life and is related to learning/experience.

Question 14

What is cell death (stage 5)?

Answer 14

When axons reach target, they from synapses with several cells. Inactive synapses are eliminated (neural darwinism, survival of the fittest). Apoptosis (programmed cell death, activates death code, are eliminated without damage). Necrosis (explosive death, causes damage to nearby tissue, caused by injury to the brain).

Question 15

Which neurons will live and which will die? (stage 5)

Answer 15

Rita Levi-Montalcini (1987): proteins secreted by target cells promote the survival and growth of neurons - survival signals. When secreted, it supports the neurons and enables it to be sustained. In order to avoid apoptosis neurons needs neurotrophins (growth factors), communication with neurons to strengthen connection.

Question 16

What is myelination (stage 6)?

Answer 16

Process where glia form the fatty sheath that covers the axons of neurons. Makes neurons more efficient when transporting signal. Occurs in spinal cord, then hindbrain, midbrain, and forebrain (back-to-front). Slow process, occurs for decades (in cortex is continues until adulthood).

Question 17

What are Schwann and oligodendroglia cells (stage 6)?

Answer 17

Schwann cells act in the periphery, oligodendroglia in the CNS. Schwann cells wrap itself around the entire neuron, oligodendroglia wraps itself around a particular region. Better myselination is correlated with an ability to grasp.

Question 18

Why is the developing brain vulnerable?

Answer 18

Pregnant women can’t have x-rays because they cause mutations in the developing brain. Chemical distortions i.e. glucose levels, iron level, thyroid hormone, or malnutrition, i.e. folic acid (B9) - can have a lot of neural tube defects if don’t have it. Exposure to chemicals i.e. pesticides, air pollutants. Infections in the maternal environment known as maternal immune activation (MIA).

Question 19

What are critical periods?

Answer 19

Konrad Lorenz shows we are highly sensitive (imprinting). Where brain is most sensitive to specific experience. Absence of visual stimuli can lead to blindness, or lack of exposure to language at early age may lead to inability to use language.

Question 20

What did Richard Tees say about critical periods?

Answer 20

Categorised these as a ‘train ride’ - if you miss it, you miss the opportunity to absorb that particular kind of knowledge. We need to be exposed to certain kind of stimuli to develop different senses properly.

Question 21

What did Blakemore and Cooper (1970) find about critical periods?

Answer 21

Conducted study with young kittens. Focused on early visual stimuli. Kittens were maintained in the dark, except when placed in lit vertical stripped chamber. After a couple of months, did readings from visual cortex. More firing in the cortex when shown vertical lines, and did not response to horizontal lines (as they were not exposed to this).

Question 22

What did the case of Genie show about critical periods?

Answer 22

Social and experimental deprivation and chronic malnutrition. Discovered at the age of 13. She was physically small, couldn’t walk properly, wasn’t able to speak. Initially made a lot of progress in terms of language, however she wasn’t able to use complex language. This shows the power of experience.

Question 23

What did D.O. Hebb (1947) find about experience?

Answer 23

Rats at home vs lab environment and ability to solve mazes. Environmentally complex vs social cages vs individual cages. Rats raised in an enriched environment develop a thicker cortex, have increased dendritic branching and increased dendritic spines. These changes associated with improved ability to learn.

Question 24

What are experience expectant and experience dependent opportunities?

Answer 24

Experience expectant is experiences that are common to all of us, and have a similar way of affecting our brain. Experience dependent are experience unique to us. Unique experiences are much more powerful in early experiences of our life (e.g. synaptic pruning).

Question 25

What happens to institutionalised children?

Answer 25

In 1970/80s found retarded intellectual development in Romanian Orphans - few toys, little personal interaction, poor nutrition. Massive developmental delays and attachment problems. Higher susceptibility to disorders related to impulsivity, aggression, addiction, etc.

Question 26

What happens due to exposure to drugs in utero (NIDA)?

Answer 26

Fetal Alcohol Syndrome (FAS), this is a spectrum depending on how much alcohol was consumed during gestation - well documented, but still 10% of women consume alcohol during pregnancy. 22% of all births to women under 25 in the US vs 10% in older women. 6% of women use an illicit drug at least once during their pregnancy.

Question 27

What is the Developmental Origin of Adult Health and Disease (DOHaD) hypothesis (Barker, 2004)?

Answer 27

Early conditions can program the organism for later life disease. Initially focused on nutrition but expanded later on. Experimental evidence from rodent models involving maternal separation or lack of maternal care.

Question 28

What is the impact of early experiences?

Answer 28

Early life environmental influences determine that adult health status via epigenetic mechanisms. Now appreciated there is epigenetic effects early in life, e.g. malnutrition and deprivation that can have an effect on the developing brain. Also experiences of the mother when pregnant can have an effect on the developing brain (e.g. depression and anxiety).

Question 29

What is maternal immune activation (MIA)?

Answer 29

Early reports of epidemics associated with increased prevalence of schizophrenia and ASD – may be because her immune system was activated to fight the illness, this affected the developing fetus. Neurobiological data from patients point towards deviations in early development.

Question 30

What could be happening in MIA?

Answer 30

Microglia was discovered by Del Rio Hortega (1932). Make up 5-15% of brain cells. They eliminate invaders. There from the beginning, contribute a lot. Found to invade layers of the neocortex and associate with neuronal tracts such as the CC and the DA axons.

Question 31

What states are microglia thought of as existing in?

Answer 31

Exists in one of two states - ramified states (thought to be a ‘resting state’, not activated, just waiting to see whether there is any invaders to eliminate), and activated state (see an invader, leads them to be activated, swell and secrete certain things that target invaders).

Question 32

What has been found about the ramified state?

Answer 32

However, been found that in the ramified state it is involved in neuronal function, and affect lots of processes:

• Eliminate apoptotic cell debris
• Modulate synaptic transmission
• Regulate activity-dependent synapse formation and reorganization, spine formation and elimination
• Shape embryonic and postnatal brain circuits (CC and DA)
• Linked with the regulation of neuronal numbers
• Influence neuronal migration
• Regulate the development of inhibitory interneurons.

Question 33

How are MIA models induced in the lab?

Answer 33

¥ Injections of PolyI:C (analogue of viruses) or LPS (gram-negative bacteria) to pregnant dams (rat). Trying to mimic the infection of a virus, or the infection from bacteria. This activates the immune system of the mother. Also affected by the microbiota pre- and post-natally. Associated with decreased number of precursor cells in the cerebral cortex and the hippocampus. Induce dysregulation of cortical inhibitory interneurons.

Question 34

What mental disorders are neurodevelopment relevant to?

Answer 34

Autism Spectrum Disorders, Schizophrenia, Mood disorders, and Anxiety Disorders.