🎯 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 📈
🌱 Introduction to Neural Development
Once induction of the ectodermal layer 📋 by the mesodermal tissue 🧬 has taken place, the cells start differentiating 🔀 as their direction of growth is determined by the induction ➡️. The three cell layers would develop in different directions 🔄 after the signal has taken place 📡. The initial division of cells is differentiated into different organs 🫀 (heart 💓, kidney 🫘, brain 🧠, stomach 🍽️) - this change has been induced by the notochord which has thus determined the fates of cells/layers 🎯.
📊 Stages of Development
There are several distinct and measurable stages 📏 of development of the brain 🧠 which takes place:
🔗 Stage 1: Notochord Formation
Attachment of mesodermal tissue 🧬 to ectodermal tissue 📋 leads to the formation of the notochord ⚡. The notochord is the strip at the center of the upper surface 📍 of the ectodermal layer 🎯. This critical structure serves as the organizing center 🏗️ for neural development 🧠.
🌿 Stage 2: Neural Plate Formation
The neural plate is formed from this tissue 🧫 and this line in the center grows 📈 as the plate grows 📏. A bulb-like head end 💡 forms at one end to eventually form the forebrain 🧠 and eye field/eye cups area 👁️ around the 17th day 📅 of intrauterine life 🤰. If the bulbous end is cut ✂️, it would quickly replace itself 🔄. The cells are still rapidly dividing 🔬 at an incredible rate ⚡.
📏 Stage 3: Neural Plate Expansion
The neural plate starts becoming longer ↔️ and broader 📐 - growth in both directions ⬅️➡️ (as the cells are still dividing and multiplying 🧫 at an extremely rapid rate ⚡💨). This expansion is crucial for creating sufficient neural tissue 🧠 for the developing organism 👶.
🌊 Stage 4: Neural Groove Formation
On the 18th day 📅 there is thickening of the outside ends 📍. This leads to rising of ends ⬆️ and deepening of the center ⬇️. The sides rise ↗️ joining in the middle 🔗. Thus, the rising of the plates form a groove 🌊, this is called the neural groove 📐. The neural groove deepens ⬇️ as the sides rise higher and higher ⬆️⬆️ (remember, there is rapid cell growth 📈 and multiplication 🧫 taking place).
🔄 Neurulation
🧬 Primary Neurulation
Neural tube 🔬 (rapid cell multiplication 🧫 and division ➗), the tube folds 📏 and becomes tubular 🌀 - this is when the primary neurulation takes place 🎯. The brain 🧠 and spinal cord 🦴 are formed at this stage 🏗️.
On the 21st day 📅, the fusion of the tube takes place 🔗 and little groups of cells break away 🎯 to form bunches on both sides ⬅️➡️. These are called somites 🧫 and extend in both directions ↔️ (somites: bodies of cells in the middle/top 📍) to form the neural crest 🌊. These develop into the peripheral nervous system 🔌 and the ganglionic system ⚡. The inside of this tube 🔬, the neural canal 🌀, is empty at this stage 🕳️.
💫 The Ventricular Zone
The neural canal remains empty 🕳️ as the ventricular zone 🏠, where the next phase of development 📈 will take place. This critical area serves as the birthplace 🎂 of neurons 🧠.
🔄 Secondary Neurulation
During the process of secondary neurulation 🔬 (forming of the neural systems 🧠) the tail end part 🎯 of spinal cord 🦴 is formed. This completes the full neural architecture 🏗️ from head to tail 👶.
🔐 Closure and Internal Development
The closure of the tube is simultaneous 🔄 and inside cells starts dividing 🧫 and multiplying ✖️, growing within the tube 🌱. The cells inside increase in number rapidly 📈⚡, as cell division takes place in the ventricular zone 🏠.
Internal part of the tube consists of single layers of cells 📋 which keep multiplying 🧫 and increasing in number 📊 and as they increase in number the cells start moving out 🚶 (The interesting question ❓ is: who tells them where to go 🗺️, and where do they go 🎯? Does the region get crowded 👥?). This is the phase when Cell Migration 🚶♂️ takes place.
🚶 Cell Migration: An Inside-Out Process
Cell Migration 🚶: it is an inside-out process ↗️, cells move from the inside of the tube 🔬 towards outside 🎯. The growing cells then form three layers 📊: internal, middle, cell free:
📋 1. The Internal Layer
The innermost layer 🏠 has cells which are still dividing 🧫. This zone continues to produce new neurons 🧠 at an astonishing rate ⚡. These actively dividing cells 🔬 are the source of all future neural tissue 🧬.
🧠 2. The Middle Layer
Consists of cell bodies 🧫 which eventually form grey matter 🧠. These cells do not divide after this ⛔, these are the same cells found in the adult brain 👤. Once they finish dividing, they commit to their final neural identity 🎯.
🕳️ 3. Cell Free Zone
This contains the fiber processes 🔌 of the first two layers and as yet empty of cells 🕳️. The migration is still taking place 🚶. Once cells reach their destination 🎯, they grow dendrites 🌿 and axons 🔌 to reach out to meet other cells 🤝. Cells sprout growth cones 🌱 for the axons and dendrites, which lead the cells to grow 📈 and to develop synapse 🔗.
🌊 Neural Crests and Specialized Structures
Neural crests are forming ganglia 🧫, inputs into spinal column 🦴 and outwards 🔌. Optic stalk grows out of diencephalon 🌱 to form eye cup 👁️ - eye cups induce formation of lens 🔍 from overlapping ectodermal tissue 🧬. The frontal the eyecups: retina forms as an invagination 🌊 of the bulging optic vesicle 💡: ganglionic cells first ①, and then bipolars ②, and photoreceptors last ③: eye born directly from brain tissue 🧠👁️! Common substance in both 🔗.
🏗️ Formation of the Brain: Three Primary Vesicles
🧠 Forebrain, Midbrain, Hindbrain
On the 24th day 📅 intrauterine 🤰, the head end part of neural tube 🔬 forms three bulbs 💡💡💡. These three bulbs would form the forebrain 🧠, midbrain ⚡, hindbrain 🦴 (The question is: how do the cells know 🤔 and the areas know that they are going to be in front ⬆️ or middle ⚡ or back ⬇️?). The front most becomes the forebrain 🧠, and the end toward the tail 🎯 becomes the hindbrain 🦴. The hindbrain connects with the spinal cord 🦴🔗. At this point all three bulbs are not differentiated ❌. These are exactly the same 🔄. (How do they become different 🤔?).
🔄 Interaction and Differentiation
In the same manner as in the first stages 📋, each area depends on the other to be stimulated 📡 and through this interaction 🤝 they differentiate 🔀. At the stage also the surrounding area induces differentiation 🧬. The environmental influences 🌍 are important at every stage 🎯.
🔬 Experimental Evidence
What if the three bulbs are cut ✂️ and rotated 🔄? Always the bulb in the front forms the forebrain 🧠 and the middle, the midbrain ⚡ and the last part forms the hindbrain 🦴. The position determines direction of development 📍! The same cells develop into different regions 🔀 if their locations are changed 🗺️ (environmental change 🌍!). At this stage cell division is rapid ⚡, and the neurons 🧠 and glial cells 🧫 are forming 🏗️. The migrating cells unite to form groups of neurons 🤝. Nuclei are forming 🎯 as a result of rapid proliferation 📈 of nerve fiber tracts 🔌 and connections 🔗.
🏗️ Rapid Development Phase
- Cell division is rapid ⚡🧫
- Migrating cells unite to form groups of nuclei 🤝🎯 - nuclei form connections 🔗
- Rapid proliferation of fiber tracts 🔌 and connections 🤝
- Formation of the ganglionic systems 🧬 from the neural crests, inputs into the spinal column 🦴 and outwards 🔌
- Optic stalk grows out of the diencephalons 🌱 to form the eye cup 👁️ (the eye is formed from the same tissue as the brain 🧠👁️, eye has similarities with the brain 🔗)
- Eye cups induce formation of the lens 🔍 from overlapping ectodermal tissue 🧬
🔧 Key Concepts in Neural Development
⚙️ Regulation
If cells keep growing 📈, connections expanding 🔗, then how does it stop ⛔ - who controls the development 🎮, differentiation 🔀, and migration 🚶 etc.?
🔄 Self-Regulating
This is a process regulated by itself 🎯. A) Muscles move 💪 without the sensory input 📡 or stimulation ⚡ b) nuclei develop 🧬 even if isolated from the organs 🏥, if we denervate (cut the nerves ✂️).
Cells proliferate at more than 40 times ✖️40 the normal adult brain 🧠. What happens that cells size reduces 📉?
🧫 Critical Processes
- Cell proliferation 📈: increases in number ⬆️
- Cell migration 🚶: cells travel to their destinations form inside toward the outside ↗️
- Maturation 🌱: developing extensions 🌿
- Interconnections formed 🔗: forming connections with other cells 🤝
- Cell death 💀: cells die off ⬇️ - only the fittest survive 💪
🧫 Cell Proliferation Details
Cells are dividing 🔬, spreading 📐 and increasing in number 📈. Specific parts of the brain begin to differentiate 🧠. Small piece of ectodermal tissue removed ✂️ - defect replaced by proliferation of neighboring cells 🔄, however if surgery is done later ⏰, then it would remain as a permanent deficit ⚠️. The cell growth is in extreme density 🎯 in ventricular zone 🏠. Cell growth much more than required ⬆️ - about 1½ times more than adult brain 🧠 - then cell death takes place 💀 and has to follow some principles 📋.
Maximal cell division ⚡ is taking place at this stage and neurons are being formed at 20,000 neurons per minute ⏱️🧠!
📈 Growth Spurt
This is the time when maximal cells are being formed ⚡, connections being formed 🔗 and systems of brain areas organized 🏗️. This is between the 10-18th week of gestation 🤰📅. This is the time when the brain cells of the growing embryo 👶 are sensitive to radiation ☢️, chromosomal anomalies 🧬, viral infections 🦠 (measles 🤒 etc.). The fetus is born with defects such as mental retardation 🧠⚠️ and blindness 🙈. The sensitivity of the fetus 👶 and the newborn 🍼 to other effects are from the 30th week - 2nd year post-partum 📅. The effects of malnutrition 🍽️⚠️ on cell size 📉, brain cell connections 🔗⬇️ and myelination 🧬⚠️ are irreversible ❌.
🚶 Cell Migration: Inside-Out Principle
Cells migrate towards periphery 🎯 from the inner core of the ventricular zone 🏠. The principle of inside-out migration ↗️ is followed here. There is formation of radial glial fibers 🧬 on which cells travel 🚶 from the periventricular zone 🏠. These form the transport system 🚂 on which neurons travel 🧠! These cells move up to the different cortical regions ⬆️ which would eventually form the 6 layers of the cortex 📋, some remain 🏠.
🛤️ Radial Glial
Cells attach on both sides 🔗, neurons move up ⬆️, some slow 🐌, some fast 🐇... those which are fast 🏃 arrive earlier ⏰ and form connections with other neurons 🤝. Once they form connections they survive 💪. The sooner the connections are formed 🔗⚡, the greater chances of surviving 🎯.
🌱 Cellular Maturation
This has four stages 📊:
1️⃣ Axonal Development
The development of outgrowth 🌿 and elongation of axons 🔌.
2️⃣ Dendritic Growth
Dendritic process emerging out of the cell body 🌱.
3️⃣ Biochemical Properties
Biochemical properties appropriate to the location 🎯 and function of the location to which the cell would stay 🏠.
4️⃣ Synaptic Connection
Development of synaptic connection 🔗.
🌿 Growth Cones and NGF
The axons grow out of neurons first 🥇 and these have a growth cone 🌱 (a specialized structure with filopodia 🦵 cytoplasmic extensions - feelers needed for movement 🚶 which lie on the growing processes 🌿). This is affected by the Growth Factors 🧪, the active factors being the Nerve Growth Factor (NGF) 🧬 in the growing nervous system 🧠 and factors that maintain metabolism of neurons ⚡ (tropic factors 🔋). This is planned for a specific site 🎯 and target 🎪.
Dendrites develop after neurons/axons 🌿. Immediately upon reaching their destination 🎯 neurons attach to the site 🔗 after detaching from the transport radial glial 🚂, and send out projections 🔌. If the neurons cannot travel 🚶❌, they cannot compete ⚔️, they would not survive 💀. If they cannot form connections 🔗❌, they cannot compete ⚔️, they would die 💀. In order to survive 💪, cells sprout more extensions 🌿🌿 and form more connections 🔗🔗. This increases the cell's ability to compete for connections ⚔️🎯. If the connections not formed ❌, cells will not be able to survive 💀. Only those cells survive 💪 which have successfully formed connections 🔗 and would now be able to continue receiving the NGF 🧬.
🤝 Cell Aggregation
Cells make their way to the area 🎯 in which they will function as adults 👤 using cell adhesion molecules (CAMs) 🧬. These cell adhesion molecules are formed on the surface of neurons 🧫 and other cells 🔬. These also give the cell ability to recognize the molecules 🔍 and surfaces 📋. Cells form alignment in precision 🎯 with other cells in the region 🤝. The question is: how is it done 🤔? There is an intricate programming 🧬 which is still under study 🔬.
🗺️ Fate Mapping
Researchers such as Pasko Rakic used the fate mapping procedures 🔬📊. This involves injecting labelled substance 💉 in the growing brain 🧠 at various embryonic ages 📅 and following the migration of the neurons later 🚶 to see where they end up 🎯. These studies have shown that:
- a) Regional specialization 🎯: Regional specialization of areas and neurons appears early on 📅 in development 👶
- b) Deeper layers first 📋: The deeper cortical layers generate first ① and most superficial layers are formed last ③
- c) Inside-Out migration ↗️: The migration is at a fast pace 🏃, the cells migrate to the inner layers first ①. Neurons of the outer layers formed later ③ must migrate through the earlier formed layers ① to eventually arrive at their destination 🎯
- d) Developmental principles 📊: In the development and growth principles: i) large cells develop before small 🔵→🔴 ii) motor cells develop before sensory neurons 💪→📡 and iii) neurons develop before the glial cells 🧠→🧫
🧬 Conclusion: Genetic and Environmental Interaction
Thus, we have seen an intricate relationship 🔗 of genetic 🧬 and biological programming 🎯 with environmental stimulation 🌍. Even though the paths of development are well laid out 📋, stimulation is important 📡 for neurons to continue moving 🚶, developing 🌱 and surviving 💪.
📚 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