NEUROGENESIS, NEUROLOGICAL MODELS, and NEUROBIOLOGY OF DRUGS,
COGNITION and DAMAGE.
Topic: development and repair.
a. Outline in a few key stages nervous system development.
Firstly, it begins with the ectoderm, which thickens. The thickened plate then
forms neural grooves these neural grooves then deepen and fuse at the top to
create the neural tube. This will then extend rostrally and caudally to create the
CNS, whilst the neural crest cells that resonate on the top of the plate during
development will travel downstream to form the peripheral nervous system.
b. What are the origins of neurons and glia in the neural tube.
The initial division of progenitor cells begin in a symmetrical fashion; the Neural
Epithelial Cells (NEC’s) are key here. First, they divide to increase number then,
due to shifting of the mitotic spindle, the division lineage becomes asymmetrical.
The NECs are now Radial Glial Cells (RGCs), these will be the progenitor cells of
the developing neurons. The primary neocortex has a long asymmetric
expansion phase.
The RGCs are one of the first structures to appear in the ventricular zone (VZ),
and span outwards, these create a pathway for developing neurons to travel
along with to their destined location. The asymmetric division results in two
different daughter cells, one that will remain a progenitor and one that will
develop into a neuron, driven by chemical gradients. Neurogenin ngn, is a pro-
neural factor, this is driving neuron development, whilst NOTCH receptors are a
neural suppressor, this will cause the cell to remain a progenitor at the VZ.
Therefore:
Notch ON cells are part of the non-neural pathway and will remain a progenitor,
and Notch OFF cells will differentiate into a neuron at the designated level,
delta signalling will cause the drive to a neuron.
The direction of neural travel is dependent on chemo attractants and repellents,
phosphatases and kinases are two key mediators to the direction of the neuron,
which ever one is more present will cause the neuron to favour a direction.
Clarification note: During development, neural stem cells divide to form a thick/
densely pack cell layer which is the ventricular zone, this extend up into an
intermediate zone and the marginal zone, the RGC’s span the full length, and
developing neurons travel up the pathways, and differentiate once in the set
location, during the differentiation is when axonal outgrowth occurs-covered
later. Neural stem cells divided in the intermediate zone will develop into
neurons, and the RGC’s are the guide wires for the neurons.
c. Cell fate and lineage.
There are many dictating factors that determine cell fate precursor cells are
neuroblasts and glioblasts. Reelin: this is a glycoprotein that guides neurons
through existing layers, the genetically mutated ‘reelin mice’, get their name
from the lacking the reelin gene, they present with a cerebellar dysfunction,
because their layers are essentially inverted. Homeobox transcription
factors: these are encoded by homeotic genes and regulate the balance
,between the RGCs to pro-neural gene. Gradients of developmental signals
control the homeobox gene expression, HOX is the term for the transcription
factors. Spatial patterns of promoter repression and activation lead to the
creation of the specialised brain regions. Homeotic in essence dictate fate of
certain facets, mutations in flies showed a displacement of limbs in facial areas.
d. Developmental changes, and subunit changes.
MUSCULAR: Acetylcholine (ACh) is a vital NT in the development of the
neuromuscular junction; and nicotinic-ACh (nACh) receptors are key in forming
these connections throughout growth. Immature nACHR synapses (or embryonic)
have long open times to facilitate maximum NT transmission and calcium influx,
however, mature neuromuscular Junction (NMJ) synapses (or adult) have a
singular subunit change that reduces the open time significantly, to a short and
strong impulse. The embryonic NMJ is determined extra junctional, this means
there is a spread of the receptors across the muscle, increasing binding efficacy,
whereas adult NMJ have junctional receptors, where they are clustered at the
synapse, because the location is set.
This localisation is brought about by competition, synapses during
development must compete to remain active, inactive synapses will be
effectively killed off (synapse elimination by activity-dependant competition).
EXCITATORY vs INHIBITORY SYNAPSE:
During initial development there is a shift in balance from excitatory to inhibitory
balances to modulate neuronal development. Initially there is a promotion of
excitatory inputs as synapses begin to develop, however this then needs to be
modulated to keep the relevant stimuli. Often in earlier development, the GABA
channels become an excitatory; this is because during early development, the
active uptake of Cl (Na-K-2Cl cotransporter) increases intracellular concentration
so much so that the equilibrium potential is driven more positive and during
GABA activation the effect is a depolarisation over hyperpolarisation, as chloride
exits the cell, making the membrane potential more positive.
e. Axonal outgrowth and pathfinding.
Axons have growth cones that guide the lamellipodia and filopodia through the
developing brain to create pathways. CAM’s or cell adhesion molecules are
glycoproteins that enable selective cell-cell adhesion via tyrosine kinase
signalling; these define the growth pathways, allows axon bundling and are key
for the two-way communications in synapse formations. The extracellular matrix
(ECM) adhesion molecules define growth paths over matrix
substrates. For axon outgrowth the occur you need:
- Actin.
- ATP.
- Microtubules.
Toxins such as cytochalasin, prevent actin polymerisation,
this prevents growth cones, and thus axonal growth. The
, activity or experience of activity of synapses determine their final placement/
function.
GROWTH FACTORS (TABLE SUMMARY).
Growth Role. Study or pathology.
factor.
NGF Neural Growth Factor is a peptide dimer, TRK channels are relevant to
binding to TRK channels, there is a greater the development of the
affinity for these to the NGF receptors. It aids in cholinergic system, KO TRKA
ONS outgrowth and projecting CNS neurons mouse had a loss in
after injury. cholinergic neurons.
Less NGF/ Trk is seen in
Alzheimer’s.
Reelin Reelin is a developing/ guidance cue, important Reelin mice, these exhibit
for cerebellar development. extreme cerebellar
dysfunction, and essentially
have an inverted layering of
the cerebellum
Notch Notch ON or OFF, dictates cell fate, whether the
RGC remains a progenitor or differentiates into
a neuron. Delta signalling causes a pro-neural
signal.
CAM’s Cell adhesion molecules, part of the two-way
communication in a synapse development, they
aid in defining the growth pathway.
Growth Axonal growth cones guide the lamellipodia and
cones. filipodia during axon development.
Kinases/ These are utilising Ca-dependency to guide the
phosphatas direction of the axon working in a balance.
es.
Neuroblast These are crucial in NS development, the Glioblastomas, or
and glioblast give rise to glia, and neuroblast to neuroblastomas, the
glioblast. neurons. developing factors turn into
cancerous cells.
f. Axon growth continued.
During the development of the pathways in the nervous system, certain neurons
will have to cross the midline of the spinal cord, creating contralateral pathways;
this is driven by chemoattractant, but once crossed, these switch to repellents to
prevent the axon from regressing backwards.
There are two terms for the spinal cord mediators, in the long range, there is
the attractants, such as netrin or repellents such as ephrin’s and semaphorin.
Then there is local range, this is the ECM and adhesion molecules, which
promote the building of axon tracts. The direct exiting of certain neurons such as
COGNITION and DAMAGE.
Topic: development and repair.
a. Outline in a few key stages nervous system development.
Firstly, it begins with the ectoderm, which thickens. The thickened plate then
forms neural grooves these neural grooves then deepen and fuse at the top to
create the neural tube. This will then extend rostrally and caudally to create the
CNS, whilst the neural crest cells that resonate on the top of the plate during
development will travel downstream to form the peripheral nervous system.
b. What are the origins of neurons and glia in the neural tube.
The initial division of progenitor cells begin in a symmetrical fashion; the Neural
Epithelial Cells (NEC’s) are key here. First, they divide to increase number then,
due to shifting of the mitotic spindle, the division lineage becomes asymmetrical.
The NECs are now Radial Glial Cells (RGCs), these will be the progenitor cells of
the developing neurons. The primary neocortex has a long asymmetric
expansion phase.
The RGCs are one of the first structures to appear in the ventricular zone (VZ),
and span outwards, these create a pathway for developing neurons to travel
along with to their destined location. The asymmetric division results in two
different daughter cells, one that will remain a progenitor and one that will
develop into a neuron, driven by chemical gradients. Neurogenin ngn, is a pro-
neural factor, this is driving neuron development, whilst NOTCH receptors are a
neural suppressor, this will cause the cell to remain a progenitor at the VZ.
Therefore:
Notch ON cells are part of the non-neural pathway and will remain a progenitor,
and Notch OFF cells will differentiate into a neuron at the designated level,
delta signalling will cause the drive to a neuron.
The direction of neural travel is dependent on chemo attractants and repellents,
phosphatases and kinases are two key mediators to the direction of the neuron,
which ever one is more present will cause the neuron to favour a direction.
Clarification note: During development, neural stem cells divide to form a thick/
densely pack cell layer which is the ventricular zone, this extend up into an
intermediate zone and the marginal zone, the RGC’s span the full length, and
developing neurons travel up the pathways, and differentiate once in the set
location, during the differentiation is when axonal outgrowth occurs-covered
later. Neural stem cells divided in the intermediate zone will develop into
neurons, and the RGC’s are the guide wires for the neurons.
c. Cell fate and lineage.
There are many dictating factors that determine cell fate precursor cells are
neuroblasts and glioblasts. Reelin: this is a glycoprotein that guides neurons
through existing layers, the genetically mutated ‘reelin mice’, get their name
from the lacking the reelin gene, they present with a cerebellar dysfunction,
because their layers are essentially inverted. Homeobox transcription
factors: these are encoded by homeotic genes and regulate the balance
,between the RGCs to pro-neural gene. Gradients of developmental signals
control the homeobox gene expression, HOX is the term for the transcription
factors. Spatial patterns of promoter repression and activation lead to the
creation of the specialised brain regions. Homeotic in essence dictate fate of
certain facets, mutations in flies showed a displacement of limbs in facial areas.
d. Developmental changes, and subunit changes.
MUSCULAR: Acetylcholine (ACh) is a vital NT in the development of the
neuromuscular junction; and nicotinic-ACh (nACh) receptors are key in forming
these connections throughout growth. Immature nACHR synapses (or embryonic)
have long open times to facilitate maximum NT transmission and calcium influx,
however, mature neuromuscular Junction (NMJ) synapses (or adult) have a
singular subunit change that reduces the open time significantly, to a short and
strong impulse. The embryonic NMJ is determined extra junctional, this means
there is a spread of the receptors across the muscle, increasing binding efficacy,
whereas adult NMJ have junctional receptors, where they are clustered at the
synapse, because the location is set.
This localisation is brought about by competition, synapses during
development must compete to remain active, inactive synapses will be
effectively killed off (synapse elimination by activity-dependant competition).
EXCITATORY vs INHIBITORY SYNAPSE:
During initial development there is a shift in balance from excitatory to inhibitory
balances to modulate neuronal development. Initially there is a promotion of
excitatory inputs as synapses begin to develop, however this then needs to be
modulated to keep the relevant stimuli. Often in earlier development, the GABA
channels become an excitatory; this is because during early development, the
active uptake of Cl (Na-K-2Cl cotransporter) increases intracellular concentration
so much so that the equilibrium potential is driven more positive and during
GABA activation the effect is a depolarisation over hyperpolarisation, as chloride
exits the cell, making the membrane potential more positive.
e. Axonal outgrowth and pathfinding.
Axons have growth cones that guide the lamellipodia and filopodia through the
developing brain to create pathways. CAM’s or cell adhesion molecules are
glycoproteins that enable selective cell-cell adhesion via tyrosine kinase
signalling; these define the growth pathways, allows axon bundling and are key
for the two-way communications in synapse formations. The extracellular matrix
(ECM) adhesion molecules define growth paths over matrix
substrates. For axon outgrowth the occur you need:
- Actin.
- ATP.
- Microtubules.
Toxins such as cytochalasin, prevent actin polymerisation,
this prevents growth cones, and thus axonal growth. The
, activity or experience of activity of synapses determine their final placement/
function.
GROWTH FACTORS (TABLE SUMMARY).
Growth Role. Study or pathology.
factor.
NGF Neural Growth Factor is a peptide dimer, TRK channels are relevant to
binding to TRK channels, there is a greater the development of the
affinity for these to the NGF receptors. It aids in cholinergic system, KO TRKA
ONS outgrowth and projecting CNS neurons mouse had a loss in
after injury. cholinergic neurons.
Less NGF/ Trk is seen in
Alzheimer’s.
Reelin Reelin is a developing/ guidance cue, important Reelin mice, these exhibit
for cerebellar development. extreme cerebellar
dysfunction, and essentially
have an inverted layering of
the cerebellum
Notch Notch ON or OFF, dictates cell fate, whether the
RGC remains a progenitor or differentiates into
a neuron. Delta signalling causes a pro-neural
signal.
CAM’s Cell adhesion molecules, part of the two-way
communication in a synapse development, they
aid in defining the growth pathway.
Growth Axonal growth cones guide the lamellipodia and
cones. filipodia during axon development.
Kinases/ These are utilising Ca-dependency to guide the
phosphatas direction of the axon working in a balance.
es.
Neuroblast These are crucial in NS development, the Glioblastomas, or
and glioblast give rise to glia, and neuroblast to neuroblastomas, the
glioblast. neurons. developing factors turn into
cancerous cells.
f. Axon growth continued.
During the development of the pathways in the nervous system, certain neurons
will have to cross the midline of the spinal cord, creating contralateral pathways;
this is driven by chemoattractant, but once crossed, these switch to repellents to
prevent the axon from regressing backwards.
There are two terms for the spinal cord mediators, in the long range, there is
the attractants, such as netrin or repellents such as ephrin’s and semaphorin.
Then there is local range, this is the ECM and adhesion molecules, which
promote the building of axon tracts. The direct exiting of certain neurons such as
