🎯 Objectives
To familiarize the students with:
- Various stages of neuronal development 🧬🔬
- Development of the brain 🧠: from the fertilization 🥚 to the various developmental stages in-utero 🤰, and postnatally 👶
- Cell differentiation 🧫, determination, migration 🚶, (inside-out) ↗️, cell competition ⚔️, cell death 💀, growth cones 🌱, Nerve Growth Factor and its role 🧪, influences in growth and development of the brain 📈
⚔️ Cell Competition and Survival
If all cells keep growing 📈, connections expanding 🔗, how does it stop ⛔ - who controls development 🎮, differentiation 🔀, migration 🚶? Research has shown this is a self-regulatory process 🔄 and the cell number in early development is 40 times ✖️40 more than the normal adult brain 🧠. What happens - how do cells reduce in size 📉?
⚔️ Cell Competition
Cells compete for limited resources 🎯; some have to die 💀 so others can live 💪. There is a fight for:
- a) Life preserving factors 🧬: NGF and Tropic factors from the target site are limited ⚠️
- b) Limited sites 📍: There are few sites available 🎯 for the millions of neurons 🧠
💀 Cell Death
Some cells will die off 💀 and only the fittest would survive 💪. Cells would die off:
- a) If connections were not formed 🔗❌: No synaptic connections = no survival
- b) If neurons reach sites but fail to send out projections 🌿❌: Neurons that arrive but don't project die 💀
- c) Unable to compete for post synaptic space 📍⚔️: Competition failure leads to death 💀
- d) If NGF is more or less than required ⚖️: Imbalance in growth factors causes cell death 💀
🔄 Synaptic Rearrangement
Cells sprout 🌱 and make a large number of connections 🔗🔗🔗 - eventually these are refined 🎯 and made more precise ✨. Is cell rearrangement possible 🤔? Yes! Weaker ⚠️ or incorrectly placed connections 🔗❌ or cells die 💀 and leave space for others 🎯. Synaptic rearrangement makes for more efficient systems ⚡. This ensures that a specific and selective system 🎯 for transmission remains functional 💪.
🧬 Important Factors for Migration and Growth
Important for the migration 🚶 and growth 📈 of the developing neurons are:
- a) Radial Glials 🛤️: Form the transport system 🚂 to take the neurons from the inner ventricular zone 🏠 where they are born to the sites 🎯 where they would eventually form the brain 🧠
- b) Nerve Growth Factor (NGF) 🌱: Important for Axonal Growth cones 🌿 and for cells to locate themselves 📍 and connect 🔗
Since there are a huge number of cells 🧫🧫🧫 and limited resources 🎯 and locations 📍, cells compete for these (Cell Competition ⚔️) and those who cannot do so die (Cell Death 💀). Therefore, forming of connections is important for survival 💪 and each cell forms more synapses than needed 🔗🔗 (to compete with others ⚔️). These connections are reformed later 🔄 to make the system more efficient ⚡, also depending on the stimulation received 📡.
🗺️ Destinations for Migration
The question of how do the newborn cells know where to go 🤔, how are their destinations for migration "decided" 🎯 is an interesting and complex one 🧩. Several hypotheses have been developed to explain this phenomenon 📊.
🧪 The Chemoaffinity Hypothesis
This theory is based on the work of Sperry and his colleagues 👨🔬 on the regeneration of ganglionic neurons of retina 👁️. They cut the optic nerves ✂️🔌 and rotated the eyeballs of frogs 🐸 by 180 degrees 🔄. They report that after regeneration 🔄 when tested it was found that visual world rotates at same angles 🌀. Sperry then hypothesized that chemicals 🧪 to attract axons are released by the growing postsynaptic surface 📡, and axons attracted to the "label" 🏷️ during neurulation and migration 🚶 as well as during regeneration 🔄 (if these are damaged during early period ⚠️).
✅ Evidence Supporting Chemoaffinity
There is strong evidence that:
- a) In vitro experiments 🔬: When growing axons are laid with tissue in the Petri dish 🧫, axons move to connect to their targets 🎯 (there is no signaling from the other parts of the brain in the Petri dish 🧪!)
- b) Chemical signals 🧪📡: There are chemical signals which attract ➡️ or repel ⬅️ growth cones from the extracellular tissue
❌ Limitations of Chemoaffinity Hypothesis
However, this hypothesis cannot explain:
- Extra growth with transplanted organs 🏥: Experiments by Whitelaw and Hollyday (1983) where they added an extra thigh 🦵 to the two normal chick legs 🐔 (where the chick's legs had two thighs instead of one 🦵🦵!). Where did the 2nd thigh get its nerves from 🤔 (from the calf, or from the 1st thigh 🦵?)
- Roundabout routes 🔄: Why and how do some axons find their way to same targets 🎯 in every species using a roundabout route 🌀, not go by the shortest routes directly ➡️(!)
- Genetic impossibility 🧬❌: If this is genetically programmed then there should be genes in each body cell 🧫 to produce and release its own chemicals 🧪, this is not possible ⚠️!
Therefore, we go for the next possible hypothesis 📊 and see if that one is tenable 🤔.
🗺️ The Blueprint Hypothesis
This hypothesis states that the undeveloped Nervous system has a blueprint 📋 in the form of specific chemical 🧪, biological/mechanical pathways 🛤️ which the growing axons would follow 🚶 to get to their destination 🎯. These pathways are laid out by the Pioneer Growth Cones 🌱⭐, which are the first growth cones to travel 🏃 on the specific radial glial 🛤️ and the route 🗺️. These pioneer growth cones do so through their interaction with the CAMs 🧬 (it's like the blind feeling the walls along the way 🤚🧱). Interestingly, the axons are also growing while traveling 🌿📈. This is called fasciculation 🔗.
🌟 Pioneer Axons
If these pioneer axons are destroyed 💥, the following axons get lost 😵 and go to different destinations 🎯❌!
❌ Limitations of Blueprint Hypothesis
However, this hypothesis cannot explain:
- In vitro travels 🧫: No radials or pioneer axons there, yet neurons still reach correct destinations 🎯
- Inverted spinal cord experiments 🔄: In experiments on transected and then inverted spinal cord of chicks 🐔, the axons were able to reach their correct target muscles 💪, in spite of starting from an inverted location 🔄!
Since this hypothesis also has not been able to explain the migratory programming 🧬 of the neurons, we move to the next hypothesis 📊.
📊 Topographic Gradient Hypothesis
This hypothesis proposes that cells follow their topographic gradients 📍 or locations 🗺️. Though neurons develop in topographic layers 📋, they maintain their relationships 🔗 with topographically different groups of neurons 🧠. For example, the relationship of the optic tectum 👁️ in the brain with retina 🔍: cells growing out of an original sheet of cell bodies 🧫 retain their relationships 🤝 as they grow in different locations 📍 even if they have migrated 🚶. There are in the same point to point relationship 🔗 (held previously on the sheet 📋: whether up-down ⬆️⬇️ or left-right ⬅️➡️ gradient).
✅ Evidence from Retina and Tectum
Evidence from retina 👁️ and tectum 🧠 cells connections, when mapped 🗺️ show that cells are maintaining their earlier relationships 🤝. There is evidence that this hypothesis has more strong evidence in favor of it 💪✅.
🧩 The Ongoing Mystery
This is an interesting piece of the puzzle 🧩 that we in the developmental neurosciences 🧬 are still trying to unravel 🔓. There are other mysteries such as what is the role of the environment 🌍 if the cells are preprogrammed 🧬🤔? We would discuss it in the next lecture 📚.
📚 References
- Kalat, J.W. (1998). Biological Psychology. Brooks/Cole Publishing Company.
- Carlson, N. R. (2005). Foundations of physiological psychology. Pearson Education New Zealand.
- Pinel, J. P. (2003). Biopsychology. (5th ed). Allyn & Bacon Singapore.
- Bloom, F., Nelson., & Lazerson. (2001), Behavioral Neuroscience: Brain, Mind and Behaviors. (3rd ed). Worth Publishers New York
- Bridgeman, B. (1988). The Biology of Behavior and Mind. John Wiley & Sons, New York
- Brown, T.S. & Wallace, P.S. (1980). Physiological Psychology. Academic Press, New York