CNS development Flashcards
Describe who Paul Ehrlich was and what he did
• Paul Ehrlich was a bacteriologist who was more interested in staining tissues
o Paul Ehrlich introduced salvarsan (syphilis) and noticed the blood brain barrier
• Paul Ehrlich was a bacteriologist who was more interested in staining tissues
o Paul Ehrlich introduced salvarsan (syphilis) and noticed the blood brain barrier
Describe who Edwin Goldman was and what he did
• It was one of his students (Edwin Goldman) who showed that the brain can be stained if the dyes are injected directly into the cerebrospinal fluid
Describe who Shtern was and what he did?
- It is sometimes claimed that the concept of BBB was formulated by Shtern in 1921
- Shtern was more neurologically oriented and, perhaps, the credit should go to her
What is the role of the blood brain barrier
- The role of the blood brain barrier is to protect the brain from neuroactive and neurotoxic substances
- Desirable substances (such as oxygen, glucose) must be allowed to enter and leave
What are neuroactive compounds and what can they do?
o Neuroactive compounds (amino acids, bioamines, neuropeptides, drugs…) have to be kept out of the brain
Neuroactive compounds interact with receptors and could activate/inhibit neurons haphazardly- this is why they need to be kept out
What are neurotoxic compounds and what can they do?
o Neurotoxic compounds have to be kept out of the brain
Neurotoxic compounds can overexcite cells and can trigger process that leads to death of neurons, or can be toxic to neurons specifically
When can compounds cross the blood brain barrier and what compounds do so?
• Compounds can only cross the blood brain barrier if:
o They can dissolve in the lipid component of BBB (Such as caffeine, nicotine or ethanol)
More lipophilic compounds pass more easily across the blood brain barrier (BBB)
Some lipid soluble undesirables can get through
Large molecules (proteins) do not normally get through but sometimes they do (like viruses)
Molecules that have a high oil-water partition coefficient (dissolve more readily in oil than water (lipophilic vs hydrophilic) dissolve more easily through the Blood Brain Barrier
o They are actively transported
Phenylalanine, D-Glucose, L-DOPA and essential amino acids (which contain aromatic groups not synthesised naturally by mammals) are actively transported across the blood brain barrier
Fast process
Different transporter used for each molecule
o If via cerebrospinal fluid which is taken up by brain
Hormones and vitamins
Route via CSG is slower than the active transport
What is the structure of the blood brain barrier
o Non-fenestrated capillaries with tight junctions surrounded by basement membrane formed by an insoluble protein secreted by pericyte, whose structural and functional character is maintained by surrounding adjacent astrocyte foot processes
Astrocytes secrete molecules which maintains non-fenestrated morphology
What transporters does the blood brain barrier contain
o It contains:
GLUT1 transporters and amino acid transporters
Essential fatty acid transporters
ABC transporters (able to expel neurotoxic compounds)
What happens if there is deficient expression or damage of transporters in the blood brain barrier?
• Deficient expression and/or genetic variations of the blood brain barrier-located transporters or damage they may sustain during the lifetime (environment or life-style) could very well contribute to the neurodegeneration seen in
o Alzheimer’s disease
o Amyotrophic lateral sclerosis
o Brain ischaemia (stroke or head injury)
o Other neurodegenerative conditions
How can the blood brain barrier be damaged or altered?
• The blood brain barrier can be damaged or altered by:
o High blood pressure for a very long time
o Infections (thought that inflammatory response can accidently change and damage the blood brain barrier)
o Specific compounds (N-Acetyl-aspartyl-glutamate, quinolinic acid, hormones, vascular endothelial growth factor)
o In brain tumours
o In multiple sclerosis
o Brain oedema (stroke, head injury)
Is the blood brain barrier uniform throughout the entire brain? Elaborate
• Even in healthy organisms, some parts of the brain have a naturally low blood brain barrier (circumventricular organs: organum vasculosum of lamina terminalis, area posterema)
o These areas are permeable to certain compounds as they monitor blood content
What is de vivo disease?
• De Vivo disease: glucose transport (via GLUT1) is compromised, patients tend to have serious problems such as mental retardation
How do chemists help get drugs across the blood brain barrier? What are the implications of these options?
o Making them more lipophilic (e.g. by adding an aromatic component (lipophilic moiety to the molecule to make it less charged)
Such treatment may change chemical or pharmacological characteristics of the compounds- increases specificity
o Synthesizing prodrug compounds with little or no pharmalogical activity but readily crossing the blood brain barrier, then converting to active compounds
E.g. heroin which, when reaching the blood brain barrier, is converted into morphine which can have a dramatic effect
o High intensity focused ultrasound (except it opens blood brain barrier for everything)
But if it can be focused, then can introduce drug into small part of the brain
How many brain cells are produced, on average, during each second throughout most of gestation?
at least 50,000
How much of our genome is involved in producing the brain?
• At least ½ of our entire genome is involved producing the brain
Up until what age does brain development occur?
• Grossly measurable brain development occurs up to the mid 20s (25-27)
Up until what age does synaptic development occur?
• Synaptic development is known to occur throughout life
How many excess neurons do we produce?
• Produce more than a 100 billion neurons as produce more neurons than needed
o Many die
What are the major processes involved in establishing nervous system organisation during brain development?
- Induction of the neural plate and closure of the neural tube
- Establishment of brain vesicles and overall plan of the nervous system
- Proliferation and migration of neuronal progenitors
- Outgrowth and targeting of fibre pathways
- Neuronal cell death and pruning of connections
- Remodelling of input and output
- Expansion and remodelling of synapses
- Myelination
Describe the timeframes of the major processes that occur during brain development
• These major processes overlap during development
o Neurulation: from conception to 4 weeks gestation
Happens first
If it fails, embryo is usually not viable
o Neuronal proliferation: from 4 weeks gestation to 12 weeks gestation
Happens seconds
o Neural migration: from 12 weeks gestation to birth
Starts third
o Myelination: from 28 weeks gestation to adulthood
Starts 6th
o Synaptogenesis: from 20 weeks gestation to adulthood
Starts 5th
o Apoptosis: from 16 weeks gestation to about 6 months after birth
Starts 4th
Describe the summary of the plan of brain development
- Ectoderm thickens to form
- Neural plate which folds and fuses to form
- Neural tube which forms
a. Prosencephalon which forms
i. Telencephalon which forms cerebral cortex and basal ganglia
ii. Diencephalon which forms retina, thalamus and hypothalamus
b. Mesencephalon which forms
i. Mesencephalon which forms midbrain
c. Rhombencephalon which forms
i. Melencephalon which forms pons and cerebellum
ii. Myelencephalon which forms medulla
d. Spinal cord which forms
i. Alar plate which forms the dorsal horn
ii. Basal plate which forms the ventral horn - Neural crest cells migrate away from nervous system and form:
a. Dorsal root ganglia
b. Schwann cells
c. Melanocytes
d. Enteric ganglia
e. Sympathetic ganglia
What are the three primitive cell layers of the embryo and what do they develop into?
• Three primitive cell layers of the embryo
o Ectoderm
Skin, hair, nails and nervous system
o Mesoderm
Great muscle masses (voluntary and involuntary), bones
o Endoderm
Cell systems that line organs and vessels
What is the notochord and what is its role?
o Notochord induces formation of the neural plate in ectoderm
Highly specific organising influence on overlying primitive ectoderm
How is a neural tube formed and when is it formed?
o Overlying ectoderm is induced to divide rapidly and forms a thickened cell mass
o A fold in the neural plate deepens to form the neural groove that runs rostral to caudal
The entire embryo is also lengthening as this happens
Walls of the groove are called neural folds
o Neurulation- The neural groove closes to form the neural tube (early week 4- 22 to 23 days)
Fusion of the neural folds to form neural tube occurs first in the middle, then anteriorly and posteriorly
How is the neural crest formed?
As the neural folds come together, some neural ectoderm is pinched off and comes to lie lateral to the neural tube- this tissue at either side of the tube is called the neural crest
What do neural crest cells become and how so?
• Neural crest cells- migrate to form peripheral nervous system components o Cranial o Dorsal root and autonomic ganglia o Schwann cells o Meninges o Bones and muscles of the head
How are somites formed and what do they in turn form?
• Neural crest develops in close association with the underlying mesoderm
o The mesoderm at this stage in development forms prominent bulges on either side of the neural tube called somites
From these somites, the 33 individual vertebrae of the spinal column and related skeletal muscles will develop
What are neuropores and what happens to them eventually during brain development and when?
o Neuropores- residual openings remain temporarily at either end of the neural tube
o The rostral neuropore closes around day 25 and caudal neuropore around day 27
Rostral neuropore will be the brain
Caudal neuropore will be the spinal cord
What happens if neural tubes fail to close?
o Neural tube closure failure- anencephaly (rostral) or spinabifida (caudal)
Describe which 3 primary brain vesicles form at the rostral neural tube and when
• Formation of 3 primary brain vesicles from top to bottom at the rostral neural tube at about week 4
o Prosencephalon or forebrain (rostral-most)
o Mesencephalon or midbrain
o Rhombencephalon or hindbrain (caudal)
Describe the divergence of the 3 primary brain vesicles into the secondary vesicles and when this happens. What will these secondary vesicles become afterwards?
o The vesicles will become the ventricles of the brain, cells around the vesicles will become the brain and spinal cord about week 5
o 5 secondary vesicles
Developing from prosoncephalon
• Telencephalon (cortex and basal ganglia)-from side of prosoncephalon
• Diencephalon (thalamus, retina, hypothalamus)-from middle of prosoncephalon
• Optic vesicles- from side of prosoncephalon which eventually fold to become the optic nerves and retinas
Developing from the mesencephalon
• Mesencephalon (midbrain)
Developing from the rhombencephalon
• Metencephalon (pons and cerebellum)-rostral half
• Myelencephalon (medulla)-caudal half
Describe the development of the telencephalon
• Telencephalon (cortex and basal ganglia)-from side of prosoncephalon
o Lateral ventricles develop
o Telencephalic vesicles grow posterior so that they lie over and lateral to the diencephalon
o Another pair of vesicles sprout off the ventral surfaces of the cerebral hemispheres, giving rise to the olfactory bulbs and related structures that participate in the sense of smell
o The cells of the walls of the telencephalon divide and differentiate into various structures
o White matter systems develop, carrying axons to and from the neurons of the telencephalon
Describe the development of the mesencephalon
• Mesencephalon (midbrain)
o Dorsal surface of the mesencephalic vesicle becomes a structure called the tectum
o The floor of the midbrain becomes the tegmentum
o Cerebral aqueduct is formed
Describe the development of the metencephalon
• Metencephalon (pons and cerebellum)-rostral half
o Rhombic lip on dorsal-lateral tube wall grows dorsally and medially until it fuses with its twin on the other side- results in cerebellum
o Ventral wall of the tube differentiates and swells to become the pons
Describe the development of the myelencephalon
• Myelencephalon (medulla)-caudal half
o Ventral and lateral walls of this region swell, leaving the roof covered only with a thin layer of non-neuronal ependymal cells
Which ventricle is the rhombencephalon associated with
4th ventricle
When does full development of gyri and sulci occur?
• At the end of gestation, gyri and sulci still not fully developed- most of this development happens after birth
Describe spinal cord development from the neural tube, include which ventricle forms, and how the dorsal and ventral sides of the spinal cord form
• Spinal canal forms
• Dorsal plate of neural tube is alar plate
o Becomes somatosensory
o Afferent growing of axons
• Ventral plate of neural tube is basal plate
o Becomes somatomotor
o Efferent growing of axons
Where are the proliferative zones during brain development and what are they called?
• Proliferative zones
o Around the neural tube vesicles (these vesicles will become the future ventricular system)
o Two types of proliferative zones around the neural tube
Ventricular zone
Subventricular zone
Where is the ventricular proliferative zone during brain development and what does it do?
Ventricular zone
• Older, produces cells of deep grey structures such as thalamus
• Cells divide and bulge out (form deep grey structures)
• Around the ventricles
Where is the subventricular proliferative zone during brain development and what does it do?
Subventricular zone
• Around the ventricular zone
• More recent, produces cells of brain structures such as the neocortex
How does cortical layer formation occur? What is used in this process?
• Form cortical layers, has more active radial migration along glial tracks
o Radial glia span between the outer part of the embryo and their origins in the sub-ventricular zone (radial glia tracks)
o Neurons drag themselves on radial glia spokes to migrate to their final destination
o Cortical neuron migration: inside out lamination
Newer neurons migrate past previously generated cells to create an inside-out gradient
Layer VI formed 1st, layer I is formed last
Each successive migration travels superficially- beyond the layer already set
The sub-plate and radial glial template is then eliminated (cell death)
What is the definition of neuronal birth and what happens after it?
- Neuronal birth is defined at completion of final division (mitosis) of the neuron
- After neuronal birth- migration occurs
Is neuronal migration the same between the ventricular and subventricular zones?
o Migration differs between the ventricular and subventricular zones
Why could there be an overproduction of neurons during brain development?
• More cells are formed than needed
• Approximately ½ neurons will die soon after their birth
• Fewer neurons as adult than baby
• There could be an overproduction because:
o Some neurons are just templates- just there to help other neurons migrate and once those neurons migrate, since they are not needed anymore, they die
o Make more neurons than needed- if there is any injury, there are back s
o Genetic efficiency- more effective to make lots of neurons then refine them
When does the process of synapse formation occur? What is its rate throughhout life?
- The process of synapse formation probably starts in the second trimester and continues throughout life
- Synapse formation proceeds at its highest rate during the first 6-8 years of postnatal life, then plateaus and rate begins to decrease with the onset of puberty, but synapses continue to form throughout life
What happens to all the connections formed during brain development? Do all connections survive? What is the mechanism behind this?
• Many more connections are formed than survive
o Transient connections- exuberant growth
One neuron (or groups of neurons) innervates more cells than in adult
Neurons compete for trophic factors, with the losers dying
Functional connections (synaptic firing) must occur to maintain connection during development
• Neuron needs activity to live
Therefore, an important part of development is loss of excess connections
What occurs if there is neural stimulation deprivation during critical period of brain development and why
- Post-natal refinement of input and output is dependent on experience
- Competition of input and output molds defined connection
- Deprivation during critical period results in permanent difficulties
How are the connections of the visual pathway refined, what is the result of this and when does this occur?
o Conscious binocular vision requires specific carefully mapped input to the visual cortex
o Excessive connections established between thalamus (LGN) and cortex during formation of the optic radiations
o Experience (light input) after birth results in loss of overlapping input
o Result: segregation of input to yield high specificity of input
o For vision, this occurs within 3-8 months after birth (the critical period)
How is layer IV of the visual cortex and lateral geniculate nucleus organised in terms of input from the visual pathway and how did this occur? What is the result of this?
o Lateral geniculate nucleus of the thalamus receives input from both eyes , synapses and inputs to visual cortex
o The nasal and temporal pathways remain separate to the visual cortex
o This input to the cortex is segregated by cortical columns
Ocular dominance columns in the human primary visual cortex
• Axons from the two eyes are mixed in the optic tract, but in the lateral geniculate nucleus, they are sorted out again by
o Ganglion cell type
o Eye of origin
o Retinotopic vision
• Alternating columns get alternating input from different parts of the lateral geniculate nucleus
• In infant, this input from lateral geniculate nucleus is overlapping- signals are mixed and unspecific
• In adult, input is pruned back through stimulation so that columns of visual cortex receive alternating, non-overlapping lateral geniculate nucleus input in the adult
o According to cell type and retinotopic position
o Stray retinal inputs in the inappropriate LGN layer die as their activity does not consistently correlate with the strongest postsynaptic response
• Helps binocular vision and enable detection of contrast borders
What happens if one eye does not receive stimulation and what is this known as?
If one eye does not receive stimulation (monocular deprivation), other eye would map on more cortical territory- known as ocular dominance shift
Describe the myelination process throughout development/ when the myelination order of specific neurons occur
- Axons serving the primary sensory (touch, vision, audition etc.) and motor areas are myelinated shortly after birth
- Axons involved with more complex associative and cognitive functions are myelinated later
- Fiber systems of the prefrontal lobes myelinate last, a process that may go into young adulthood up to about 25 years
- White/grey matter ratio change with age
What is binocular vision and how is it established?
Binocular vision- convergence of inputs from layer IV cells serving the right and left eyes onto cells in layer III
Establishment of binocular receptive fields depends on correlated patterns of activity that arise from the two eyes as a consequence of vision
What is a critical period?
Critical period- specific times when developmental fate is influenced by the environment
How are visual pathway connections developed?
• First axons to reach LGN are contralateral nuclei, and then ipsilateral projections arrive
• Then, the axons from the two eyes segregate into eye-specific domains
o Ganglion cells fire in waves independently in the two retinas, so that the activity patterns arising in the two eyes are not correlated with respect to each other
Action potentials in retinal axons allows retina and LGN neuron synapse to be stabilised
What is binocular competition?
• Binocular competition- the inputs from the two eyes actively compete for synaptic control at the post-synaptic neuron
o If the activity of the two eyes is correlated and equal in strength, the two inputs will be retained on the same cortical cell
How does neural tube differentiation and connections establish themselves?
o Differentiation of brain cell types- neurons and glia
o Cell migration: Patterning of the brain
o Axon pathfinding
o Cell-cell interactions: initiation of synaptic connections
o Refinement of synaptic connections- synaptic competition, homeostasis and plasticity
o Continuing refinement and brain plasticity in the adult
What are the stages and timeframes of neuronal development?
- Stage 1- Lamellipodia- 6 hours
- Stage 2- Immature neurites- 12 hours
- Stage 3- Axon formation- 36 hours
- Stage 4- Dendrite formation- 4 days
- Stage 5- Further maturation- 7 days
How is cell differentiation regulated?
Cell differentiation regulated by differences in gene expression during development
1. If transcription factors are unevenly distributed within a cell, then the cleavage plane during asymmetrical cell division can determine which factors are passed on to the daughter cells and this can determine their fate
Ultimate fate of the migrating daughter cell is determined by combination of factors, including:
1. Age of precursor cell
2. Position within ventricular zone
3. Environment at time of division
Describe how neuronal destination for anterior or posterior parts of the cortex is determined
o Neurons destined for the anterior region of the neocortex express higher levels of Pax6, and neurons destined for the posterior cortex express higher levels of Emx2
Which brain cells differentiate first and last?
Neuronal differentiation occurs first, followed by astrocyte differentiation. Oligodendrocyte differentiation is last
When does cell differentiation occur?
Differentiation is programmed before the cell arrives at its final resting place
How does neurite growth occur?
o Growth of the neurite occurs when a filopodium takes hold of the substrate and pulls advancing growth cone forward
Growth occurs only if the extracellular matrix contains the appropriate proteins
o Fasciculation- mechanism that causes axons growing together to stick together
Due to expression of cell-adhesion molecules
What is an example of a permissive substrate for neurite growth?
Example of permissive substrate is glycoprotein laminin
• Growing axons express integrins that bind laminin, and this interaction promotes axonal elongation
What does axonal pathfinding involve?
o Pathway selection- axons travel to specific region
o Target selection- axons recognise and bind to set of cells and form stable connections
o Refinement of connections- axons ends up binding to just a subset of original targets (dependent on neural activity)
Involves interactions between several active neurons and converts the overlapping projections into a finely tuned pattern of connections
Selective pruning occurs during development through use of neurons- neurons that are not used are discarded
Describe how axonal pathway selection occurs
Responds to specific intermediate guidance cues through projections at the end of axonal growth cone (growing tip of a neurite) which responds to environmental cues
What are potential environmental cues for axonal pathway selection?
- Chemoattractants
- Chemorepellants
- Pioneering axons
What is a chemoattractant?
o Chemoattractants- molecules in the environment that are attracting of the growth cone
What is a chemorepellant?
o Chemorepellants- molecules in the environment that are repelling of the growth cone.
How do chemoattractants/chemorepellants allow for axonal pathway selection to occur?
o These chemoattractant/chemorepellant molecules will bind to receptors on surface of the filapodia
o Intracellular signalling cascade will result
o This will modulate actin dynamics
o Mostly involves diffusible ligands in a complementary gradient which allows fine tuning
o Long range cue
What is the chemoaffinity hypothesis and who was it developed by?
o Chemoaffinity hypothesis- molecular tags on projecting axons and their target cells determine the specificity of axonal connections within a neural map. These molecular tags might be distributed in complementary gradients marking corresponding points in the sensory and target structures (Sperry 1963)
Describe how pioneering axons can aid in axonal pathway selection
o Pioneering axons can aid guidance of subsequent axons that move across the axonal tract
o Pioneering axons stretch as the nervous system expands and guide their later developing neighbour axons to the same targets
o Contact-mediated attraction and contact-mediated repulsion through bound ligands
Bound ligands can be found on membranes of pioneering axons
o Short-range cues
What controls the movement and directionality of the growth cone?
As growth cone moves in brain, there is alteration of underlying cytoskeleton within that growth cone- the polymerisation and depolymerisation of actin filaments controls the movement and directionality of the growth cone
What is the cytoskeleton of a neuron composed of and what is the role of each part?
• Cytoskeleton is composed of: o Microtubules Tracks for axonal transport Vesicle and organelle trafficking o Neurofilaments Intermediate filaments Provide tensile strength to axonal processes o Actin filaments Microfilaments Cell shape, motility Propel neurite outgrowth from the axonal growth cone Synaptic structure and function
What is the role of actin filaments in neurite outgrowth?
• Actin filaments are responsible for sensing, motility and direction steering of axonal growth cone
What is the composition of actin filaments and their respective roles in neurite outgrowth?
o Actin bundles called filapodia are responsible for sensing the environment
Extension from the lamellipodia which are constantly moving in and out of lamellipodia
o Actin gels called lamellipodia are branched actin filaments
Leading edge of growth cone
Are flat sheets of membrane that undulate in rhythmic waves
• Microtubules push the growth cone forward
What is SLIT, its role and receptors?
• SLIT- secreted proteins, control midline repulsion, dual role, signalling through roundabout receptors (Robo)
What are ephrins, their roles and receptors?
• Ephrins- (A+B) membrane anchored, repellent and attractive functions, receptors: EphA, EphB
What are netrins, their roles and their receptors?
• Netrins and their receptors- secreted molecules which act to attract or repel axons by binding to their receptors (e.g. DCC receptor)
What are semaphorins, their roles and their receptors?
• Semaphorins- 5 different subfamilies characterised by a 500 aa semaphoring domain, secreted and anchored. Primarily axonal repellent and activate complexes of surface receptors called plexins and neurofilaments.
Describe the semantics of comissural axon guidance in the spinal cord
- Cross midline of spinal cord
a. Axon growth cone is attracted by a gradient of netrin from ventral to dorsal side of spinal cord expressed on the foreplate
i. Enables axon to be attracted to this gradient and cross the foreplate
ii. Netrin is produced by ventral midline of spinal cord
iii. Binding of netrin to netrin receptors spurs growth toward source of netrins - Go towards brain
a. SLIT repellent after foreplate prevents axon from crossing back
i. SLIT produced by midline cells
ii. For SLIT to be effective, axon must express on its surface robo (the slit receptor)
- –. Growth cones that are attracted to the midline by netrin express little robo and are therefore insensitive to repulsion by slit
- –. However, once they cross the midline, they encounter a signal that causes robo to be up-regulated, allowing slit to repel axons away from the midline
b. Repellent semaphoring also prevents axon from growing towards other side of spinal cord and directs it towards the brain - Forms a tight vesicle that can move up towards brain
Describe how collosal axons go across the corpus callosum
- SLIT2 ligand expressed by the glial wedge and contributes to repulsion of the growth cone axon
Describe how retinal ganglion cell projections in the visual system project to different parts of the optic tectum and why
- Projections from nasal retinal ganglion cell will be projecting more posteriorly within the optic tectum
- Temporal ganglion cells will project to anterior part of tectum as are repelled from posterior part of tectum
- This is because anterior and posterior tectal neurons differentially express factors that allow the growth of nasal and temporal retinal axons
a. Nasal axons grow well on the substrate provided by both anterior and posterior tectal membranes
b. However, temporal axons grow only on anterior tectal membranes- posterior membranes are repulsive as they contain ephrins
What is the synaptic capacity of a neuron and when does it peak?
• Synaptic capacity of a neuron
1. Synaptic capacity- number of synapses a neuron can have on its dendrites
Synaptic capacity peaks early in development then declines as neurons mature
What are the processes involved in synaptogenesis?
- Synaptic pre-patterning
- Coordinated morphological and structural changes
- Contact stabilisation
- Synaptic refinement
What is synaptic pre-patterning?
Cell intrinsic processes that contribute to pre-establishment of synaptic components
• Along axonal shaft, there will be nascent presynaptic machinery being assembled
How do coordinated morphological and structural changes for synaptogenesis occur?
Dendritic filopodia motility
• Glial guideposts at regions near the axon primed for synaptogenesis may secrete chemotractant-like molecules that cause initiation of dendritic filopodia in that region
• Likewise, cues can also be inhibitory that can inhibit formation of synapse along neurite stretch
• Postynaptic dendritic filopodia approach presynaptic specalizations to form synapses
Occurs once sensory structure makes connection with dendritic spine at target structure
How does contact stabilisation for synaptogenesis occur?
Triggered by cell-to-cell ligand-receptor interactions and intra-cellular signalling cascades that will leave to assembly and maturation of both post and pre-synaptic connections
How does synaptic refinement for synaptogenesis occur?
Activity-mediated strengthening or weakening of connections. Activity-mediated refinement of topography. Could include:
• Growth of boutons and spines
• Recruitment of neurotransmitter receptors to spine
• Growth of synapses
• Pruning of other synapses
Synaptic rearrangement
• Synaptic rearrangement occurs as a consequence of neural activity and synaptic transmission
What are the two types of mechanisms for synaptic initiation?
- Mechanism 1
The axon contains pre-assembled apparatus that is primed for the connection of a dendritic spine when contact is made. Other areas of the axon shaft contact is inhibitory - Mechanism 2
A transient axo-dendritic contact matures into a functional synapse
Requires stabilisation of the cell-cell interaction and transport of synaptic components to the nacent adhesion site
Are glial cells important for synaptic initiation?
• Glial cells are essential for this process of synaptic initiation for both pre and post-synaptic side to occur
Are glial cells important for neuronal development? Why/why not?
- In cell cultures, survival beyond dendrite formation (stage 4 of neuronal development) requires glial-cell factors, specifically diffusible factors from astrocytes
Why does neuronal death during development occur?
- After axons have reached their targets and synapse formation has begun, there is a progressive decline in the number of presynaptic axons and neurons
- Cell death reflects competition for trophic factors, life-sustaining substances that are provided in limited quantities by target cells
What is the impact of neurotrophins on apoptosis? Give an example
• Nerve growth factor- a type of neurotrophin
o Produced by targets of axons in sympathetic division
o NGF is taken up by sympathetic axons and transported retrogradely, where it acts to promote neuronal survival
• Neurotrophins act at specific cell surface receptors
o Most of the receptors are neurotrophin-activated protein kinases (trk receptors) that phosphorylate tyrosine residues on their substrate proteins
o This phosphorylation reaction stimulates a second messenger cascade that ultimately alters gene expression in the cell’s nucleus and switches off apoptosis (cell induced death by genetics) mechanisms
What is synaptic plasticity?
- Synaptic plasticity is the ability of synapses to change their strength over time in response to increases or decreases in their activity
- After the initial synaptic contact is made, the future of the relationship depends upon effective communication
What is Hebb’s theorem on how synaptic plasticity occurs?
• Hebb’s idea
o If a nerve terminal or group of nerve terminals can make a cell to which they are connected fire repeatedly, the coordinated firing of pre-and post-synaptic cell will lead to selective strengthening of their synaptic connections
Will involve strengthening of synaptic structure such as transport of more post-synaptic receptors
Structural and molecular changes in synapse itself
o Synapses on a target neuron that do not fire in synchrony with the postsynaptic cell will be weakened
What does synaptic plasticity in the cortex require?
• Synaptic plasticity in the cortex requires the release of enabling factors that are linked to behavioural state
How does synaptic modification occur?
o When the presynaptic axon is active and, at the same time, the postsynaptic neuron is strongly activated under the influence of other inputs, then the synapse formed by the presynaptic axon is strengthened
o When the presynaptic axon is active and, at the same time, the post-synaptic neuron is weakly activated by other inputs, then the synapse formed by the presynaptic axon is weakened
o NMDA receptors detect simultaneous presynaptic and postsynaptic activity
Calcium entry through NMDA receptor channel triggers the biochemical mechanism that modify synaptic effectiveness
Strong NMDA receptor activation cause long-term potentiation
• Causes new AMPA receptors to be inserted in synaptic membrane which makes transmission stronger
Weak NMDA receptor activation causes long-term depression of activity synapses
• Causes loss of AMPA receptors
Describe how glia regulate synaptic connectivity
• Astrocytes and microglia
o Astrocytes can sense activity across a synapse- sense whether a neuron is firing an action potential robustly or weakly and use microglia to regulate this
Astrocytes will secrete molecules that then lead to upregulation of other proteins within the neuronal presynaptic and postsynaptic compartment
• One of these molecules is C1q
C1q tags weakly active synapses
Proteins are secreted, including C3 and C4
C3 and C4 further tags synapse
Microglial cells express Cr3 receptors on their surface and can recognise weak synapses
Phagocytoses synapse
What are the layers that walls of vesicles contain?
• Walls of vesicles consist of 2 layers
o Ventricular zone- lines the inside of each vesicle
o Marginal zone- faces overlying pia
How does cell proliferation occur in general in the developing vesicle walls?
o A cell in ventricular zone extends a process that reaches upward toward the pia
o The nucleus of the cell migrates upward from the ventricular surface towards the pial surface: the cell’s DNA is copied
o The nucleus, containing two complete copies of the genetic instructions, settles back to the ventricular surface
o The cell retracts its arm from the pial surface
o The cell divides in two
What are radial glial cells?
• Radial glial cells
o Neural progenitors that give rise to all the neurons and astrocytes of the cerebral cortex
What is symmetrical cell division and when does it occur?
Symmetrical cell division
• Early in development
• Both daughter cells remain in ventricular zone to divide again
What is asymmetrical cell division and when does it occur?
Asymmetrical cell division
• Late in development
• One daughter cell migrates away to take up its position in the cortex, where it will never divide again
• The other daughter remains in the ventricular zone to undergo more divisions
Where do cortical pyramidal neurons, astrocytes, interneurons and oligodendroglia derive from?
• Cortical pyramidal neurons and astrocytes derive from the dorsal ventricular zone, whereas inhibitory interneurons and oligodendroglia derive from ventral telencephalon
What is the thalamus important for in development of cotical areas?
• Thalamus is important for specifying the pattern of cortical areas
o Area-specific thalamic axons initially innervate distinct populations of subplate cells
o Subplate layer of earliest born neurons seems to contain instructions for assembly of cortex
What is another word for memory traces?
Engrams
Where are memory traces stored?
• Memory traces (engram) most likely exists in connections between neurons
o But not all cortical areas contribute equally to all memories
o Hebb- engrams are widely distributed among the connections that link the cells of the assembly and involve the same neurons that are involved in sensation and perception
• Memory is enhanced connections between networks: recall is the activation of that network through activation of one neuron in that network
o The more neurons you have connected to a memory, the easier it is to recall
What does consolidation of memory depend on?
• Consolidation of memory depends on coordinated enhancement of distributed neural networks and recall depends on coordinated firing of these networks
What is long term potentiation and what does it require?
Long term potentiation (LTP)-
• Decreased firing threshold resulting (easier firing) from paired firing- candidate mechanism for increased synaptic efficiency
o When neurons fire together, they are wired together
• Requires time, gene transcription, protein synthesis, cytoskeletal reorganisation, adhesion molecule production and receptor expression
o Long term memory takes a few days
• Enduring long term potentiation requires structural changes in the neuron
What structural changes occur in neurons during long term potentiation
o Some structural changes include increased number/stability of synapses, dendritic spines, outgrowth/pruning of connections
Dendritic spines changes with LTP and membrane-
• Increased receptors
• Increased vesicle docking
• Spine growth (actin filaments, membrane expansion, intracellular adhesion molecule expression)
o Intracellular adhesion molecule sticks synapses together -> when synapse is stuck together it is smaller
What does memory require?
o Coordinated strengthening of network connections during consolidation
o Coordinated activation of multiple cortical regions o Coordinated activation of multiple cortical regions
Describe Hebb’s cell assembly hypothesis for memory
Hebb and cell assembly
• Internal representation of an object consists of all the cortical cells that are activated by the external stimulus (cell assembly)
• Internal representation of object held in working memory as long as activity reverberated through the connections of the cell assembly
• If activation of the cell assembly persisted long enough, consolidation would occur by growth process that made these reciprocal connections more effective- neurons that fired together would be wired together
• If only a fraction of the cells of the assembly were activated by a later stimulus, the reciprocal connections would cause the whole assembly to become active again, thus recalling the entire internal representation of the external stimulus
What is the standard model of memory consolidation and problems with this model?
• Standard model of memory consolidation
o Information comes through neocortex areas associated with sensory systems and is then sent to the medial temporal lobe for processing
o Changes in synapses create a memory trace via a process sometimes called synaptic consolidation
o After synaptic consolidation, systems consolidation occurs in which engrams are moved gradually over time into distributed areas of the neocortex
o Before systems consolidation, memory retrieval requires the hippocampus, but after systems consolidation is complete, the hippocampus is no longer needed.
But consolidation process would have to takes years to account for extended retrograde amnesia- is this feasible in a species with short life span like humans?
When we recall a memory, it becomes susceptible to change and reconsolidation
What is the multiple trace model of consolidation?
• Multiple trace model of consolidation
o Fixes consolidation problem
o Engrams involve neocortex, but even old memories also involve hippocampus
o Each time an episodic memory is retrieved, it occurs in a context different from the initial experience and the recalled information combines with new sensory input to form a new memory trace involving both the hippocampus and neocortex
What is electrophysiological recording during neurosurgery, and what were findings stemming from it?
Electrophysiological recording during neurosurgery
• Person undergoes memory task- recall
• Recorded activation
• Finding- consistent, highly reproduceable but not exact distributed network activated during successful memory recall task
• First real detection of a human memory trace
What is the current paradigm for memory consolidation, storage and retrieval in terms of anatomy
• Memory formation is both localised and distributed
o Memory formation is distributed across multiple modality-specific areas and association areas
o Particular localised brain regions direct storage and consolidation
Medial temporal lobe structures (hippocampus, entorhinal cortex) direct memory consolidation
Once memory is consolidated, hippocampus and other such structures are not needed anymore as memory is now stored in distributed areas
o Areas such as dorsolateral prefrontal cortex direct strategies for storing and retrieval
What are the components of the multistore model from Attkinson and Shiffrin
o Sensory memory
o Short term memories
o Long term storage
Describe the sensory memory store
- Components
- Time frame
- Anatomy
- How it is lost
o Sensory memory Homologous terms • Iconic • Echoic • Transient: 0.25-2 seconds Signals active in the thalamo-cortico, cortico-cortico circuits • Sensory input to thalamus and cortex Is lost through competition, lack of attention and prior learning
Describe the short term memory store
- Capacity
- Anatomy
- How it can be lost
Limited capacity store (e.g. 7 digits), short duration (seconds to minutes)
The active stage requires hippocampal and entorhinal cortex activity
Vulnerable to neurophysiological disruption (loss of consciousness), interference, low attention, low emotional importance, drugs
Describe the long term storage
- Capacity
- Anatomy
- Stability
Spread over modality-specific cortical areas and association areas
Not in hippocampus/entorhinal area
• Exception- posterior hippocampus: may store places and smells
Large capacity, enduring store
Dynamic and not static- not faithful
Becomes increasingly stable (consolidated) over time
Describe working memory in terms of
- Anatomy
- Mechanism
- Role
- Discrepancy between left and right
- Capacity
Dependent on prefrontal areas (area 46/9)
• Lesions results in people remembering memories in disorganised way
Using long term memory for short term memory
Association of active new stuff with old stored stuff
• Every time you recall old information, the trace is changed
Directs active filling of information, strategic recall
Strategic decisions about storage
Left is better for storage whilst right is better for retrieval
Shortly limited in capacity and require rehearsal
Working memory is distinguished from short-term memory by the very limited capacity, the need for repetition and the very short duration
• Capacity: 7+-2
Describe the neurotransmitters in the hippocampus and their effect on memory consolidation
o Glutamate
Excitatory
• Increases long term potentiation
• Antagonise (block) receptors reduces memory consolidation
o GABA
Inhibitory
• Activation of these receptors reduces memory consolidation
Where is the hippocampus?
• Location:
o Sits underneath the inferior horn of the lateral ventricle
What is the name of the 3 layer archicortex of the hippocampus?
• 3 layer archicortex
o Cornu ammonis (CA) CA1-3
What is the major input and output to and from the hippocampus?
• Major input to the hippocampus and output from the hippocampus is the entorhinal cortex
Describe how the hippocampus keeps a memory trace alive long enough for LTP to happen
o Unimodal and polymodal areas, especially prefrontal and cingulate areas –>parahippocampal and perirhinal cortex –> entorhinal cortex –> hippocampus (dentate, CA3, CA1 and subiculum) –> entorhinal cortex –> Parahippocampal and perirhinal cortex –> unimodal and polymodal areas
Projections to and from all over the cortex are funnelled through hippocampus and entorhinal area
Entorhinal area has massive projection to cortex and receives massive projections from cortex
This circuit is what keeps the trace alive long enough for LTP to happen
Hippocampus is a rehearsal system- stalls until it has time to be consolidated
• Hippocampal activity (via entorhinal cortex) maintains activity in network of distributed brain areas
o Binds sensory information for the purpose of memory consolidation
o Important for spatial memory
o Builds and enhances memories by connecting new sensory input with existing knowledge
• Efficiency of network enhanced
• Recall reactivates enhanced network
Where is the entorhinal area found?
• Located in the medial bank of the rhinal sulcus
Where is the parahippocampal cortex located?
Parahippocampal cortex is located lateral to the rhinal sulcus
Where is the perirhinal cortex located?
Perirhinal cortex occupies the lateral bank
Describe the memory limbic connection for emotion
o CA1 –> fornix to mammillary body –> anterior nucleus of thalamus –> cingulate cortex
This is the limbic connection
Which part of the hippocampus is specialised for place memory?
Posterior
Which part of the fusiform gyrus is specialised for face recognition?
• Fusiform gyrus (occipitotemporal) specialised for face recognition
Who was Scoville?
• Scoville- 1950s pioneered surgery for epilepsy and schizophrenia
Describe what surgery HM went through and why
- Medial Temporal lobe/hippocampus areas- frequent sites of seizure foci
- Temporal lobectomy to remove damaged brain tissue and successfully eliminate seizures
- Patient HM underwent a bilateral temporal lobectomy for his epilepsy
What was the result of HM’s surgery?
o Resulted in permanent anterograde amnesia (no new consolidation of memories)
o Did not recognise his examiners despite being tested repeatedly for more than 40 years
• Some temporal neocortex removal
o Minor retrograde amnesia (previously consolidated memory lost) but more past memories intact
• No basal ganglia or cerebellum removal
o No loss of procedural memory (could learn new skills)
• Working memory was intact
• Had a passive demeanour, possibly due to removal of amygdala
What did HM’s amnesia demonstrate?
• HM’s amnesia demonstrated:
o The existence of multiple memory systems
o Localisation of different memory systems to different brain regions
o Localisation of declarative memory to medial temporal lobe (MTL)
o Medial temporal lobe is critical for memory consolidation but not for retrieval of memories
Medial temporal lobe does not store all memories
What is anterograde amnesia and how specific can it be? What anatomical parts are affected
o No new memory
o Declarative: damage to medial temporal lobes
o Can be global (all modalities affected)
o Can be hemisphere-specific
o Can be material specific
What retrograde amnesia and what anatomical parts are affected?
o Forgetting things that occurred in the past
o Loss of consolidated memories- damage to cortex
o Impaired retrieval-damage to prefrontal cortex; mediodorsal thalamus
