Module One Flashcards
(85 cards)
1
Q
Convergent Evolution
A
Distantly related species independently evolve similar traits in response to comparable ecological pressures (e.g., tuna and dolphin body shapes for swimming).
2
Q
Homoplasy
A
Resemblance from convergent evolution (e.g., tuna vs. dolphin form).
3
Q
Homology
A
Resemblance due to common ancestry (e.g., mammalian forelimbs).
4
Q
Analogy
A
Similar function despite different structures (e.g., human hand vs. elephant trunk).
5
Q
Epigenetics
A
Environmental and experiential factors can alter gene expression without changing DNA sequence, and some of these changes can be heritable.
6
Q
Linnaean Classification and Binomial Nomenclature
A
Carolus Linnaeus (1707–1778) devised the system still used today: each species has a two‐part Latin name (binomen), italicized, with the genus capitalized and the species lowercase (e.g., Homo sapiens for modern humans).
7
Q
Hierarchical Levels of Taxonomic Classification
A
The categories—from broadest to most specific—form nested “branches” on the tree of life:
- Kingdom (e.g., Animalia: ~1 million known animal species)
- Phylum (e.g., Chordata: ~40 000 species with internal skeletons)
- Class (e.g., Mammalia: ~4 300 species with hair and mammary glands)
- Order (e.g., Carnivora: ~235 species of meat‐eaters)
- Family (e.g., Canidae: ~35 species of dogs, wolves, foxes; names end in –idae)
- Genus (e.g., Canis: 8 species including dogs, wolves, coyotes)
- Species (e.g., Canis familiaris: domestic dog; ~400 breeds but one species)
> Mnemonic: “Kindly Put Clothes On, For Goodness’ Sake.”
8
Q
Phylogeny
A
(Greek phylon “tribe” + genesis “origin”) denotes the evolutionary tree showing how species descend from common ancestors. Integrates comparisons of living species with fossil data to infer the evolution of body, brain, and behaviour.
9
Q
Fundamental Features of Vertebrate Nervous Systems
A
All vertebrates share these organizational principles inherited from a common ancestor:
- Neural Tube Development: A hollow dorsal tube forms the brain’s subdivisions; its cavity persists as the ventricular system.
- Bilateral Symmetry: Left and right halves mirror each other.
-
Segmentation: Paired spinal nerves exit at each spinal‐cord level.
Spinal cord is organized in sections. At each section (or segment) of the spinal cord, a pair of spinal nerves comes out—one going to the left side of your body and one to the right. - Hierarchical Control: Cerebral hemispheres modulate spinal‐cord activity.
- CNS vs. PNS Separation: Central (brain/spinal cord) and peripheral nerves are distinct systems.
- Localization of Function: Specific neural functions map to particular CNS regions.
10
Q
What does the equation
𝐵𝑊∝𝐵𝑀0.69
represent in brain-body allometry?
A
Back:
BW (Brain Weight) scales with BM (Body Mass) in mammals.
The relationship is proportional, meaning as body mass increases, brain weight increases at a slower rate (exponent of 0.69).
For example, if body mass increases by 10 times, brain weight increases by approximately 4.9 times.
This scaling reflects energetic constraints and neural efficiency in larger animals.
11
Q
- Encephalization Factor (k):
A
Equivalent to the vertical residual on the log–log plot. The encephalization factor (k) compares brain size to body size
- **k > 1:** Brain larger than expected (positive residual). - **k < 1:** Brain smaller than expected (negative residual). k = actualBW/predictedBW
12
Q
Social Brain Hypothesis:
A
- In primates, average clique size (groups that individuals
regularly associate with) correlates with relative cortex size (Dunbar, 1998).- Extrapolated human clique limit ≈ 150 meaningful relationships.
13
Q
Haplotypes
A
A haplotype refers to a set of genetic variations or alleles (e.g., SNPs) that are inherited together as a block. Typically, haplotypes are made up of a gene and its surrounding flanking noncoding DNA. These regions can provide important information about evolutionary history and selection pressures in a population.
14
Q
SNPs (Single-Nucleotide Polymorphisms)
A
These are variations at a single nucleotide position in the DNA sequence. SNPs are commonly used to track genetic variation between individuals or populations. They can be used to infer the selection history of certain genetic traits or regions.
15
Q
How do haplotypes and SNPs reveal recent selection?
A
A gene and nearby noncoding DNA (haplotype) are inherited together.
If a helpful variant spreads fast (recent selection), nearby SNP variation stays low because there’s little time for new mutations to appear.
16
Q
Golgi’s Reticular Theory
A
Neurons form a continuous network.
17
Q
Cajal’s Neuron Doctrine
A
Neurons are discrete cells that come close but do not fuse.
18
Q
Four Functional Zones of a Neuron
A
-
Input Zone (Dendrites):
- Tree-like branches receive synaptic inputs from many neurons.
-
Integration Zone (Cell Body/Soma):
- Contains nucleus, mitochondria, ribosomes; sums and transforms inputs.
-
Conduction Zone (Axon):
- Single, often long process conducts electrical impulses (action potentials) away from soma.
-
Output Zone (Axon Terminals/Synaptic Boutons):
- Specialized swellings that release neurotransmitter onto target cells.
19
Q
Neuronal Diversity by Shape
A
- Multipolar Neurons: Many dendrites + one axon (most common).
- Bipolar Neurons: One dendrite + one axon (e.g., retinal cells).
- Unipolar (Monopolar) Neurons: Single process branching into input and output zones (e.g., somatosensory neurons).
20
Q
Neuronal Diversity by Function
A
- Motoneurons (Motor Neurons): Long axons to muscle or gland, drive movement/secretion.
- Sensory Neurons: Detect environmental changes (light, sound, touch); diverse morphologies suited to modality.
-
Interneurons: Vast majority; connect only to other neurons, forming complex circuits.
- Typically have short axons.
21
Q
Synapse Structure
A
- Presynaptic membrane: Specialized region of the axon terminal that releases neurotransmitter.
- Synaptic cleft: Gap of ~20–40 nm separating pre- and postsynaptic membranes.
- Postsynaptic membrane: Region on dendrite or soma bearing high density of neurotransmitter receptors.
22
Q
Dendritic Spines
A
- Tiny outgrowths that increase dendritic surface area for additional synapses. Spine number and shape are highly plastic, altering over minutes to a lifetime in response to experience.
23
Q
Axon Hillock
A
- Cone-shaped origin of the axon; serves as the neuron’s integration zone, converting summed inputs into action potentials.
24
Q
- Axonal Transport:
A
-
Fast transport: 200-400 mm/day for vesicles and organelles
- Slow transport: < 8 mm/day for cytoskeletal elements and enzymes
- Carries materials bidirectionally between soma and terminals.
25
Astrocytes
- Star-shaped; regulate blood flow via end feet on capillaries to match neuronal activity.
- Monitor and modulate nearby synapses; contribute to synapse formation.
26
Microglia
- Small, highly motile; remove debris after injury.
- Participate in pain signaling and synaptic maintenance.
27
Oligodendrocytes (CNS) & Schwann Cells (PNS)
- Form myelin sheaths around axons, enabling saltatory conduction via nodes of Ranvier.
- Oligodendrocytes myelinate multiple axon segments; Schwann cells ensheath single segments.
28
Synaptic Insulation
- Glial processes envelop synapses to electrically isolate them and prevent cross-talk.
29
Ongoing Myelination
Continues 10–15 years postnatally, and possibly throughout life in some regions.
30
Saltatory Conduction in Myelinated Axons
- **Myelin Sheath Formation:**
- Glial cell processes wrap tightly around axons, layer upon layer of lipid membrane (“myelin”), providing high electrical resistance.
- **Functional Consequence:**
- Insulation **shunts passive currents farther along the axon**, reducing the number of action potentials that must be generated.
- **Nodes of Ranvier:** Gaps (~1 µm) in the myelin where voltage-gated **Na⁺ channels are concentrated.**
- **Saltatory Conduction:** Action potentials are regenerated only at nodes, “jumping” from node to node, achieving conduction velocities up to ~120 m/s (≈ length of a football field in one second).
31
Transmembrane Proteins: Pumps vs. Channels
- **Active transporters (pumps):**
- Use metabolic energy (e.g. ATP) to move ions across the membrane.
- Establish and maintain ionic concentration gradients.
- **Ion channels:**
- Provide pathways (“pores”) that allow ions to flow down their electrochemical gradients.
- Do not themselves consume energy, but contribute to membrane permeability and electrical signalling.
32
Building Blocks: Amino Acids → Peptides → Proteins
- **Amino acids:** Small molecules (e.g. leucine, lysine, tryptophan) that serve as the monomeric units.
- **Peptides:** Chains of two or more amino acids joined by peptide bonds.
- **Proteins (polypeptides):** Long chains (often hundreds of amino acids) that fold into functional three-dimensional structures.
33
Protein Structural Hierarchy
1. **Primary structure:** Linear sequence of amino acids.
2. **Secondary structure:** Local folding patterns (e.g. α-helices, β-sheets) formed by hydrogen bonds along the backbone.
3. **Tertiary structure:** Overall three-dimensional folding of a single polypeptide chain (e.g. coiling back on itself to form a globular shape).
4. **Quaternary structure:** Assembly of multiple tertiary-structure subunits into a larger complex (e.g. **an ion channel**).
34
Molecular Architecture of Ion Channels
- **Quaternary assembly:** Most ion channels are oligomers (e.g. four subunits) that together form a central pore.
- **Selectivity filter:**
- A narrow region (~12 Å wide) lined by specific amino-acid residues.
- Permits only certain ions (e.g. K⁺) to pass, excluding others (e.g. Na⁺) based on size and chemical environment.
- **Pore cavity:** Water-filled space continuous with the cytoplasm, through which ions traverse.
- **Key insight:** Crystallographic studies (e.g. MacKinnon & Doyle, 1998) revealed the inverted-V shape of the subunit assembly and detailed the filter’s structure.
35
Voltage-gated channels:
Respond to changes in transmembrane potential.
- Involved in action-potential generation (e.g. Na⁺ and K⁺ channels).
- Also exist for Cl⁻ (membrane stabilization) and Ca²⁺ (neurotransmitter release). - **Voltage-Gated Channels:**
- Exist for Na⁺, K⁺, Cl⁻, and Ca²⁺.
- Membrane depolarization alters channel conformation, opening the pore.
- **Na⁺ & K⁺ Channels:** Generate and shape the action potential.
- **Ca²⁺ Channels:** Trigger neurotransmitter release at presynaptic terminals.
- **Mechanism:** Changes in transmembrane potential induce conformational shifts in channel proteins to open or close the pore.
36
Ligand-gated (chemically gated) channels
- Open upon binding of neurotransmitters (ligands) such as glycine, dopamine, or acetylcholine.
- Found on postsynaptic membranes (e.g. dendrites, neuromuscular junction).
37
Postsynaptic Receptors: Direct vs. Indirect Coupling
1. **Directly coupled receptors:**
- The receptor **itself is** the ion channel.
- Neurotransmitter binding induces a conformational change that opens the pore, allowing immediate ion flux and rapid postsynaptic potentials.
2. **Indirectly coupled receptors:**
- Receptor binding does **not** form a pore.
- Instead, it activates intracellular G-proteins and second-messenger cascades (e.g. cAMP, cGMP, Ca²⁺, nitric oxide).
- These cascades modulate other ion channels or intracellular processes, amplifying and prolonging the signal.
38
Functional Significance of Second Messengers
- Enable **signal amplification** through enzymatic cascades.
- Regulate gene expression in response to neurotransmitters and hormones.
- Underlie more complex forms of neuronal modulation (e.g. those involved in learning and memory).
39
Sequence of Events at the Presynaptic Terminal
1. **Action-Potential Arrival:** An action potential invades the axon terminal.
2. **Voltage-Gated Ca²⁺ Channels Open:** Depolarization opens these channels.
3. **Ca²⁺ Influx:** Extracellular Ca²⁺ enters the terminal, serving as an intracellular messenger.
4. **Vesicle Fusion (“Docking”):** Ca²⁺ triggers synaptic vesicles to bind (“dock”) with the presynaptic membrane via specialized proteins—synaptotagmin, synaptobrevin, syntaxin, and SNAP-25.
5. **Exocytosis:** Vesicles fuse with the membrane and release neurotransmitter into the synaptic cleft.
6. **Diffusion:** Neurotransmitter molecules diffuse across the ~20–40 nm cleft to the postsynaptic membrane.
40
EPSP X IPSP
- **Excitatory Postsynaptic Potential (EPSP):**
- Binding opens ion channels (often Na⁺), causing depolarization.
- EPSPs from multiple synapses **sum** at the axon hillock; if threshold is reached, a new action potential is generated.
- **Inhibitory Postsynaptic Potential (IPSP):**
- Binding opens Cl⁻ channels.
- Cl⁻ influx hyperpolarizes (or shunts) the membrane, moving the potential toward the Cl⁻ equilibrium (~–60 mV), making action-potential initiation less likely.
- Even slight depolarization toward –60 mV can be inhibitory if threshold is more positive.
41
How does vesicle fusion and neurotransmitter release occur?
- **Docking Proteins:** Synaptotagmin (Ca²⁺ sensor), synaptobrevin, syntaxin, SNAP-25 act like “ropes” to tether vesicles to the presynaptic membrane.
- **Ca²⁺-Triggered Fusion:** Ca²⁺ binding to synaptotagmin induces membrane fusion and transmitter release.
42
Neurotransmitter Definition and Lifecycle
**Criteria:**
1. **Synthesis** in the presynaptic neuron.
2. **Vesicular Storage** in axon terminals.
3. **Exocytotic Release** into the synaptic cleft.
4. **Receptor Binding** on the postsynaptic cell.
5. **Removal or Degradation** by enzymatic action.
- **Diversity:** Over 100 neurotransmitters identified, varying widely in molecular structure.
43
Criteria for Neurotransmitter Identification
A candidate substance must meet all four criteria:
1. **Synthesis & Localization**
- Produced by, and localized within, the presynaptic neuron.
- Stored in synaptic vesicles in the presynaptic terminal.
2. **Activity-Dependent Release**
- Released when an action potential invades and depolarizes the terminal (via Ca²⁺ influx through voltage-gated Ca²⁺ channels).
3. **Specific Receptors**
- The postsynaptic cell expresses receptors selective for the candidate.
4. **Mimicking Synaptic Response**
- Exogenous application to the postsynaptic cell elicits the same response as presynaptic stimulation.
44
Classes of Neurotransmitters
Small-Molecule Transmitters
- **Acetylcholine (ACh)**
- **Amino Acids:** Aspartate, glutamate, GABA (γ-aminobutyric acid), glycine
- **Biogenic Amines:**
- **Catecholamines:** Dopamine, norepinephrine, epinephrine
- Serotonin (5-hydroxytryptamine)
- Histamine
45
Functional Classification by Postsynaptic Effect
- **Excitatory Transmitters** (produce EPSPs)
- ACh, catecholamines, glutamate, histamine, serotonin, certain peptides
- **Inhibitory Transmitters** (produce IPSPs)
- GABA, glycine, certain peptides
- **Conditional Transmitters**
- Require co-factors or co-transmitters to exert effects, enabling complex modulation.
46
Synthesis of Neurotransmitters
- **Large-Molecule (Peptide) Transmitters:**
- Synthesized in the **cell body**, packaged into vesicles, then fast-transported down the axon at up to 400 mm/day.
- **Small-Molecule Transmitters:**
- Synthetic **enzymes** produced in the cell body are slow-transported (~1 mm/day) to terminals, where they synthesize transmitters locally.
47
-Catecholamine Pathway (from tyrosine
1. Tyrosine ―(**tyrosine hydroxylase**)→ L-Dopa
2. L-Dopa ―(**dopa decarboxylase**)→ Dopamine
3. Dopamine ―(**dopamine β-hydroxylase**)→ Norepinephrine
4. Norepinephrine ―(phenylethanolamine N-methyltransferase)→ Epinephrine
48
Inactivation of Released Neurotransmitter
- **Reuptake:** Active transport back into the presynaptic terminal (e.g., biogenic amines).
- **Enzymatic Breakdown:** e.g., ACh broken down by **acetylcholinesterase** in the cleft.
- **Diffusion:** Passive escape of transmitter away from the synapse.
- **Autoreceptors:** Presynaptic receptors detect extracellular transmitter levels and modulate further synthesis and release.
49
Dopaminergic System
: Cell bodies in substantia nigra and ventral tegmental area project widely to cortex and basal ganglia.
50
Noradrenergic System
: Locus coeruleus neurons send norepinephrine projections throughout the cortex, mediating arousal and attention.
51
Serotonergic System
Raphe nuclei in brainstem project serotonin fibers broadly to forebrain.
52
Histaminergic System
Hypothalamic neurons release histamine to multiple brain regions.
53
Classic (Anterograde) Neurotransmission
1. **Intra-neuron:** Electrical impulses travel along an axon.
2. **Synaptic conversion:** At presynaptic terminal, electrical → chemical (neurotransmitter release).
3. **Inter-neuron:** Neurotransmitter binds postsynaptic receptors; chemical → electrical or triggers intracellular cascades (molecular/genetic changes).
4. **Scale:** ~100 billion neurons × thousands of synapses each ≈ 10^12 synaptic events.
5. **Direction:** Predominantly presynaptic → postsynaptic.
54
Retrograde Neurotransmission
- **Definition:** Postsynaptic → presynaptic signalling at the same synapse.
- **Key retrograde messengers:**
1. **Endocannabinoids (ECs):** Synthesized postsynaptically, bind presynaptic CB₁ receptors.
2. **Nitric oxide (NO):** Gaseous messenger, diffuses to presynaptic cGMP targets.
3. **Neurotrophic factors (e.g., NGF):** Released postsynaptically, taken up, transported back to the presynaptic nucleus to affect gene expression.
- **Research focus:** How retrograde signals regulate or modify synaptic communication.
55
Volume (Non-Synaptic) Neurotransmission
- **Definition:** Neurotransmitter diffuses away from its synapse (“chemical puff”) to act on receptors at distant sites—no direct synaptic contact required.
- **“Chemically addressed” system:** Analogy to cell-phone coverage: any receptor within diffusion radius can be activated.
- **Drug relevance:** Psychotropic agents act wherever receptors exist, not solely at anatomically innervated synapses.
56
Monoamine Autoreceptors
- **Somatodendritic autoreceptors** on the neuron’s cell body/dendrites detect “leaked” neurotransmitter to inhibit axonal release.
- **Clinical link:** Autoreceptor regulation is tied to antidepressant mechanisms (see Chapter 7).
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Messenger Hierarchy
1. **First messenger:** Neurotransmitter binding to a receptor.
2. **Second messenger:** Small intracellular molecule (e.g., cAMP, Ca²⁺).
3. **Third messenger:** Enzymes (kinases or phosphatases) that modify proteins.
4. **Fourth messenger:** Phosphoproteins whose activity or conformation has been altered.
5. **Downstream effects:** Gene expression, synaptogenesis, long-term neuronal changes.
58
Kinases vs. Phosphatases
- **Kinases:** Add phosphate groups to target proteins → create active phosphoproteins.
- **Phosphatases:** Remove phosphates → reverse kinase effects.
- **Balance:** Relative activation by different neurotransmitters determines net downstream signalling and biological response.
59
Temporal Profile
- **Milliseconds:** Ion-channel opening and second-messenger generation.
- **Minutes–Hours:** Activation of kinases/phosphatases and alteration of existing proteins.
- **Hours–Days (or longer):** New protein synthesis via gene activation → long-lasting synaptic modifications.
60
Four Major Signal Transduction Pathways
1. **G-protein-linked systems**
2. **Ion-channel-linked systems**
3. **Hormone-linked systems**
4. **Neurotrophin-linked systems**
61
Forming a Second Messenger
- **Overview:** Each of the four major signal transduction cascades converts an extracellular first messenger into an intracellular second messenger.
- **G-protein-linked systems:** Second messenger is a small chemical (e.g., cAMP).
- **Ion-channel-linked systems:** Second messenger can be an ion, typically Ca²⁺.
- **Hormone-linked systems:** Hormone diffuses into cytoplasm, binds its intracellular receptor to form a hormone–nuclear receptor complex.
- **Neurotrophin-linked systems:** Activate a variety of second messengers, including kinase enzymes with multiple domains.
62
G-Protein-Linked Second-Messenger System
1. **Four Key Elements:**
- First-messenger neurotransmitter.
- Seven-transmembrane-region receptor (GPCR).
- G protein that binds both receptor and enzyme.
- Effector enzyme (e.g., adenylate cyclase) that synthesizes the second messenger.
2. **Sequence of Events:**
1. Neurotransmitter docks in GPCR → receptor changes conformation.
2. Activated receptor binds G protein → G protein undergoes conformational shift.
3. G protein binds effector enzyme → enzyme becomes active.
4. Enzyme converts ATP to cyclic AMP (cAMP) → cAMP is released as the second messenger.
63
Third Messenger: Kinase Activation via cAMP
**Mechanism:**
- cAMP binds regulatory subunits of an inactive protein kinase (dimer).
- Regulatory units dissociate → kinase monomers become active.
- Active kinase phosphorylates fourth-messenger phosphoproteins (e.g., ion channels, enzymes).
---
Third Messenger: Phosphatase Activation via Ca²⁺
- **Mechanism:**
- Neurotransmitter opens ion channels → Ca²⁺ influx.
- Elevated Ca²⁺ activates calcineurin (protein phosphatase).
- Calcineurin dephosphorylates fourth-messenger phosphoproteins.
---
Kinase vs. Phosphatase Actions on Fourth Messengers
- **Kinase** adds phosphate groups
- **Phosphatase:** removes phosphate groups
- **Functional consequences:** phosphorylation or dephosphorylation may activate or inhibit phosphoproteins, altering:
- Neurotransmitter synthesis
- Neurotransmitter release
- Ion channel conductance
- Overall maintenance of the neurotransmission machinery
64
Ultimate Goal: Gene Expression
- **All four cascades** (G-protein, ion-channel, hormone, neurotrophin) culminate in modulation of gene transcription.
- **Transcription factor CREB** (cAMP response element-binding protein) is a common end-point: its phosphorylation turns on “immediate early” genes.
---
Neurotransmitter-Triggered CREB Activation
1. **G-protein pathway:**
- Neurotransmitter → GPCR → G protein → adenylate cyclase → ↑ cAMP → activates PKA → PKA translocates to nucleus → phosphorylates CREB → gene “on.”
2. **Ion-channel pathway:**
- Neurotransmitter → opens Ca²⁺ channels → ↑ intracellular Ca²⁺ → Ca²⁺-calmodulin → activates CaMK → CaMK enters nucleus → phosphorylates CREB → gene “on.”
65
Hormone-Linked Cascade
- **Steroid hormones** (e.g., estrogen) diffuse into cytoplasm → bind intracellular receptors → form hormone–receptor complex → complex translocates to nucleus → binds hormone response elements (HREs) → directly activates specific genes.
66
Neurotrophin-Linked Cascade
**Neurotrophin binding** → activates a kinase-rich cascade (Ras → Raf → MEK → ERK → RSK/MAPK/GSK-3, etc.) → successive kinases phosphorylate nuclear targets → gene expression (e.g., synaptogenesis, survival).
67
What is the molecular mechanism of gene activation?
Gene structure: Regulatory region (enhancer + promoter) + coding region.
Transcription factors: Phosphorylated → bind DNA → recruit RNA polymerase → mRNA synthesis.
mRNA → protein: mRNA translated in cytoplasm into protein.
68
What are Immediate Early Genes (IEGs) and what is their function?
Examples: cFos, cJun (leucine-zipper family).
Timing: Activated ~15 min, last ~30–60 min.
Function: Produce proteins (5th messengers) → form Fos–Jun heterodimers (6th messengers) → act as transcription factors for later gene activation.
69
Chromatin and Nucleosomes
- **Chromatin:** DNA wrapped around histone octamers (nucleosomes).
- **Open chromatin:** Accessible to transcription factors → gene expression.
- **Compact chromatin:** Inaccessible → gene silencing.
70
Chemical Modifications Governing Chromatin State
1. **Methylation**
- **Histone methyltransferases** add CH₃ to histones → chromatin compaction → gene silencing.
- **Histone demethylases** remove CH₃ → chromatin opening → gene activation.
- **DNA methyltransferases (DNMTs)** add CH₃ to DNA (via SAMe from L-methyl folate) → silencing.
- **DNA demethylases** remove CH₃ → activation.
2. **Acetylation**
- **Histone acetyltransferases** add acetyl groups → open chromatin → gene activation.
- **Histone deacetylases (HDACs)** remove acetyl groups → compaction → silencing.
3. **Phosphorylation (and others):** Additional histone marks that modulate chromatin.
71
Dynamic epigenetics in mature neurons
Life experiences—stress, diet, drugs of abuse or therapy—can trigger de novo methylation (DNMT2/3), deacetylation, demethylation, or acetylation in differentiated neurons.
- **Outcome:** Previously silenced genes can be activated, or active genes silenced, leading to adaptive (memory formation, therapeutic response) or maladaptive (addiction, anxiety disorders, chronic pain) neuronal changes.
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Early Nervous System Development
1. **Day 18 (Embryo):**
- Implantation in uterine wall
- Three germ layers form: endoderm, mesoderm, ectoderm
- Ectoderm thickens into the **neural plate**
2. **Day 20:** Neural plate folds to create the **neural groove**
3. **Day 22:** Neural groove closes, forming the **neural tube** with anterior rudiment of the brain
4. **Day 24+:** Neural tube subdivisions appear:
- **Forebrain (prosencephalon):** Telencephalon & diencephalon
- **Midbrain (mesencephalon)**
- **Hindbrain (rhombencephalon):** Metencephalon & myelencephalon
5. **Neural tube interior:**
- Becomes cerebral ventricles
- Forms central canal of spinal cord and connecting channels
73
**Embryonic Cell Cycle and Terminology**
- **Zygote:** 46 chromosomes (23 maternal + 23 paternal)
- **12 hours post-fertilization:** First cell division
- **Day 3:** ~ 200 μm cluster of homogeneous cells (“morula”)
- **Day 7:** Three distinct layers visible
- **Ectoderm** → nervous system
- **Terminology:**
- **Embryo:** Conception – 10 weeks
- **Foetus:** 10 weeks – birth
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Foetal Brain Development (Weeks 10–41)
- **Weeks 10–41:** Gradual emergence of gyri and sulci (cortical folding)
- **Postnatal maturation:** Certain brain regions continue developing into adolescence
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Six Stages of Nervous System Development
1. **Cell Division (Neurogenesis)**
- Neural tube cells undergo mitosis in the **ventricular zone**, producing all future neurons and glia.
- Each brain region has a species-characteristic “birth date” when its precursors cease dividing.
- In simple organisms (e.g., *C. elegans*), every neuron’s fate is fixed by mitotic lineage; in vertebrates, **cell–cell interactions** (“induction”) further shape cell fate.
- **Mammals** generate nearly all their neurons before birth; postnatal brain growth reflects neuron enlargement, dendritic branching, synapse elaboration, myelination, and glial proliferation.
- **Adult neurogenesis** occurs in humans (e.g., hippocampus) and in olfactory neurons throughout life.
2. **Migration**
- New neurons leave the ventricular zone and migrate along **radial glial cells**, which span from the inner to outer surfaces of the developing cortex (“glial monorail”).
- Migration can also occur perpendicular to radial glia (Tarzan-style) or via the **rostral migratory stream** to the olfactory bulb.
- **Cell adhesion molecules (CAMs)** on cell surfaces guide migrating neurons and growing axons; CAM defects disrupt migration and circuit formation.
3. **Differentiation**
- Once located, cells express specific genes to become distinct **neurons** or **glial cells**.
- Differentiation in vertebrates depends on both cell-autonomous programs and inductive signals from neighboring cells.
4. **Axon and Dendrite Growth & Synaptogenesis**
- Differentiated neurons extend **axons** and **dendrites**, establishing initial **synaptic connections** (synaptogenesis).
- In the human cortex, the six layers form in an inside-out sequence; synaptic density and neuronal differentiation increase dramatically from birth through age 2.
5. **Cell Death (Neuronal Cell Death)**
- A substantial proportion of early-born neurons undergo **programmed cell death**, refining neuronal populations to match target fields.
6. **Synapse Formation & Rearrangement**
- Initially formed synapses are pruned back, while new synapses develop later—**synapse rearrangement**—to fine-tune neural circuits for mature function.
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Migration & Cell-Adhesion
- **Cell migration** describes how newly born neurons travel from their origin to their final positions, often “riding” radial glial fibers.
- **Cell adhesion molecules (CAMs)** on cell surfaces provide the molecular “handholds” that guide migrating neurons and growing axons along correct paths.
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Differentiation & Induction
- **Cell differentiation** is the process by which a precursor cell adopts a specialized neuronal or glial identity by expressing specific genes.
- **Cell–cell interactions (induction)** occur when neighbouring cells secrete factors that influence a cell’s fate, ensuring local coordination of differentiation.
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What shapes neuronal identity during cell differentiation and induction?
Intrinsic cues: Cell-autonomous genetic programs (e.g. Purkinje cell dendrites form even in vitro).
Extrinsic cues: Inductive signals from neighboring tissues (e.g. Sonic hedgehog from notochord induces motoneuron fate).
Regulation: Embryonic cells can compensate for missing neighbors—flexible response not seen in lineage-rigid species (e.g. C. elegans).
Stem cells: Undifferentiated embryonic/reprogrammed adult cells can integrate into damaged brain tissue—potential for regenerative therapy.
79
How do neurons extend processes and form synapses?
Process outgrowth: Young neurons extend axons & dendrites with growth cones (with filopodia) exploring the environment.
Guidance cues:
CAMs provide traction.
Chemoattractants & chemorepellents (e.g. Slit) guide growth cones via gradients.
Synaptogenesis: Initial synapses form during growth; dendritic spines rapidly proliferate postnatally—experience refines connections.
80
What molecular mechanisms regulate programmed cell death (apoptosis) in neurons?
Death genes: Activated in cells destined to die.
Caspases: Proteases that dismantle proteins & DNA.
Diablo: Released from mitochondria, inhibits IAPs, freeing caspases.
Bcl-2 proteins: Block Diablo release, preventing apoptosis.
Target-based regulation: Neurons compete for limited neurotrophic factors (target-derived survival signals); those failing to obtain enough activate apoptosis.
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What are neurotrophic factors and their role in neuronal survival?
NGF (Nerve Growth Factor): First identified trophic factor; promotes outgrowth & survival of sensory and sympathetic neurons in vitro.
BDNF (Brain-Derived Neurotrophic Factor): Supports survival of specific neuron classes.
Neurotrophins: Family of survival-promoting factors; help match neuron numbers to target field size.
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How do neurotrophic factors regulate neuronal survival and connectivity? (Model stages)
1️⃣ Production: Different target cells produce different neurotrophic factors.
2️⃣ Uptake: Innervating neurons take up neurotrophic factors & transport them to their soma.
3️⃣ Gene regulation: Neurotrophic factors regulate gene expression, influencing neuronal development.
4️⃣ Survival: Neurons obtaining sufficient trophic factor survive; others undergo apoptosis.
5️⃣ Matching: Trophic factor levels help match the number of neurons to target size.
6️⃣ Synaptic competition: Later, axonal processes compete for limited neurotrophic factors—active synapses have an advantage.
7️⃣ Experience: Experience shapes synaptic connectivity by modulating activity & neurotrophic factor use.
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Cortical thinning direction
Gray matter loss proceeds caudal-to-rostral during maturation, with prefrontal cortex last—correlating with adolescents’ impulsivity and the emergence of psychiatric disorders.
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Activity-dependent competition
Active synapses capture limited neurotrophic factors more effectively than inactive ones, stabilizing them, while inactive contacts retract. Intellectual stimulation and varied experiences modulate synaptic maintenance by altering activity patterns.
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What is the role of myelination, and how does it develop?
Process: Oligodendrocytes (CNS) & Schwann cells (PNS) form myelin → faster conduction.
Multiple sclerosis: Autoimmune demyelination → impaired synchronous signaling.
Developmental timeline:
PNS: Myelination starts ~24 weeks gestation.
CNS: Postnatal peak; continues into adulthood.
Sequence: Spinal cord → hindbrain → midbrain → forebrain; sensory cortex myelinates before motor areas.
