Lecture 6 - Neurodevelopment Flashcards
What does development refer to?
The change in a specific property over time (e.g., brain size)
What does a developmental trajectory refer to?
The normal rate of change in a group (e.g., brain size in humans)
Abnormal trajectories are often associated with ______
Impairments
Five parts of prenatal neurodevelopment
- Induction of neural plate
- Neuronal proliferation
- Neuronal migration + aggregation
- Axonal growth + synapse formation
- Neuronal death + synapse elimination
(0) Development begins when the sperm fertilizes the egg, making a ______
Zygote
(0) _______ implants around 7-10d, continues to develop
Blastocyst
(1) ~18d after conception, ______ has three layers: ectoderm, mesoderm, endoderm
embryo
(1) ________ is on the ectoderm
Neural plate
(1) How is the neural plate induced?
Induced by chemicals from mesoderm
(1) Neural plate will become the ________
Nervous system
(1) In the neural plate cells are ________
Stem cells
(1) Important properties of stem cells
- Nearly unlimited capacity for self-renewal (in artificial conditions; i.e. culture)
- pluripotent (can develop into many cell types)
(1) Stem cells can both ______ and _______
replicate themselves and differentiate into another cell type
(1) Over time the neural plate forms the _______
neural groove
(1) Sides of the neural groove fuse to form the _______
neural tube
(1) What will the center of the neural tube become?
The ventricular system + spinal canal (for CSF)
(1) What do growths on the anterior of the tube (~40d) become?
midbrain, hindbrain, and forebrain
(2) Progenitor cells divide, how does the thickness of the tube increase?
Increases with more cells
(2) Most division occurs in the __________
Ventricular zone (tube interior)
(3) What is migration?
Movement of cells to their target location
(3) _________ process (outside layers migrate last)
Inside-out
(3) Migration may be _______ or ________
tangential (moving in diff. way), radial (moving outward)
(3) Methods of migration: Somal translocation (works for both cell types)
Extension is directed by ‘attractive’ and ‘repellant’ chemical cues
(3) Methods of migration: Glia-mediated migration (radial only)
Migration guided by networks of radial glial cells
(3) What is aggregation
Neurons align with other neurons in the same area
(3) ________ vital here for aggregation
Cell adhesion molecules (CAMs)
(3) Where are CAMs present?
On the surface of cells
(3) What do CAMs recognize and do?
They recognize other cells and adhere to them
(3) ________ prevalent during period of aggregation
Gap junctions
(4) What is axonal growth?
Axons grow outward to their targets, this is a very precise process
(4) At the end of each axon is a _______
Growth cone
(4) Each cone has _______ (finger-like extensions: ‘search’, extend + retract)
filopodia
(4) Sperry’s experiments provided us with important insights into _________
Axonal development
(4) Key points of Sperry’s experiment
Found that even with the optic nerve cut + regenerated, the axons of the optic nerve grow back to their original synaptic sites (A-A, B-B, etc.)
(4) Small group of ________ move first
Pioneer axons
(4) Growth cones responds to various chem. signals _________ + _________. Released by ________ + _________
attractants, repellants; neurons, other cells in the matrix
(4) Other axons will follow the pioneer axons later, forming axonal bundles (e.g.,_______)
Tracts
(4) Theories of axonal development: chemoaffinity hypothesis
The axon is guided toward its target cell (post-synaptic) because that cell releases special chemicals:
- Cell A releases chem. X
- Axon B is sensitive to chem. X but axon C is not
- Axon B grows toward cell A, but axon C does not
*evidence suggest that signalling is not simply point-to-point, but more complex
(4) Theories of axonal development: Lesion studies
- Retina or tectum lesioned
- If an area loses its normal axonal input, it will receive input from other axons instead (1)
- If axons have ‘lost’ their normal target, they will project to another target instead (2)
(4) Theories of axonal development: topographic gradient hypothesis
Axons are sensitive to the same factors but in different amounts.
Exposure to factors is determined by the relative position of the axons in the tissue (e.g., retina):
- Cell A releases chem. X
- Axon B and axon C are both sensitive to chem. X
- However, axon B is exposed to more chem. X
- Axon B grows toward Cell A but axon C does not
(4) topogrpahic gradient hypothesis depends on _______ + ________
What chemical, amount of chemical
(4) Synapse Formation: __________ (making of new synapses) occurs next, but is less well understood
synaptogenesis
(4) Do you form more or less synapses than you need originally?
More
(4) What cells are important in synapse formation?
glial cells
(4) The inputs of a mature neuron are ________ but more elaborate and more effective (i.e. stronger)
fewer
(4) What happens if synapses aren’t formed?
When two cells are connected via a synapse, they exchange chemical signals. This signal is vital to cell survival. Cells that do not form synapses will often die.
(5) Cell death is normal. How many more neurons do you generate than you need?
~50% more than needed
(5) Removing what in the SC increases rate of neuronal death?
limb buds
(5) Apoptosis vs. Necrosis
Apoptosis is a form of ‘programmed cell death’:
- cleaner process, wherein the cell’s contents are packaged for convenient disposal
- less inflammation
In necrosis, another form of cell death (e.g., via nutritional insufficiency) the results are different:
- cells ‘break apart’ + spill their contents
- more risk for inflammation
(5) ________ play an important role in mitigating inflammation and ‘cleaning up the mess’
Microglia
(5) What are the survival signals for cells?
Neurotrophins - transmitted via retrograde signalling (from Cell B > Cell A)
Limited amount of NTs released, which leads to a competition among terminals (NT hypothesis)
(5) Examples of Neurotrophins: Four main factors
Nerve growth factor (NGF), brain-derived neurotrophic growth factor (BDNF) and neurotrophin-3 and neurotrophin-4 (NT-3, NT-4)
(5) Neurotrophins can act on _______ receptors (high affinity) or ________ receptors (low affinity)
Tyrosine kinase (Trk) receptors, p75 receptors
(5) Cell signalling determines ________
Neurotrophin? Neurotransmitter? phenotype
3 main parts of postnatal neurodevelopment
synaptic density, developmental periods, neurogenesis
From birth to adulthood volume of brain ________
quadruples (x4)
Brain growth is not due to gain in neurons, but other processes such as…
- synaptogenesis (more synapses)
- dendritic arborization (growth of dendrites)
- myelination of axons
What brain area develops faster than others?
Primary sensory cortices (e.g., visual, auditory) - associated w/ vital survival functions for infants
What brain area develops last?
Prefrontal cortex (PFC)
Consequences of the PFC developing last
- The PFC is involved in planning, initiation and inhibition of behaviour (thereby impulse control)
- These functions are most developed at age 25 (and are often poorly developed beforehand)
- Development of the PFC w/ time + experience may explain the striking behaviour differences between adolescents and adults
- alterations in the PFC developmental trajectory may delay - or impair - executive function
What cells play an important role in synapse formation, elimination, and maintenance?
Glial cells
________ is affected by life experiences (e.g., learning)
Synaptic density
Critical period for development
Time interval where an experience must occur for proper development (if you do not get it at a specific time, you don’t get normal growth)
Sensitive period for development
Time interval where an experience has a relatively greater effect on development. Thought to be periods of high neuroplasticity.
We can identify potential developmental periods with ________ and _________ studies in animals
deprivation, enrichment
Critical period example
In animals, early visual deprivation disrupts the development of visual pathways (e.g., lateral geniculate axons)
Effects of early visual deprivation cannot be reversed by later experiences (even if you remove the blindfold)
Later visual deprivation is much less consequential (as it is outside the critical period)
CNS changes w/ Enrichment
Changes in vascular tissue, and astrocytes may also contribute
Why do critical periods end?
Many theories; several focus on axons:
- myelination of axons occurs after critical period close
- myelination of axons occurs after critical periods close
- myelination of existing neurons creates a physical barrier to growth and sprouting of other axons
- myelination can also release certain factors which inhibit axonal growth, such as NOGO
Adult neurogenesis
The process whereby new neurons are generated in adulthood
Two main areas of adult neurogenesis in mammals
Hippocampus + lateral ventricles
Why does neurogenesis matter?
- when young, new adult-born neurons have enhanced excitability and plasticity relative to older, developmentally-generated cells
- enhanced hippocampal neurogenesis is correlated with improved memory and reduced anxiety
- young neurons may play a role in stress resiliency, allowing for greater resistance to stress-induced depression
Neurodevelopmental disorders (NDDs)
Disorders wherein there is abnormal development of the nervous system, leading to abnormal cognition and behaviour
NDD’s are often considered distinct from what? and why?
From acquired disorders, which normally emerge in adulthood and are the result of brain changes (e.g. injuries) in adulthood (e.g., traumatic brain injury, alzheimer’s disease, multiple sclerosis, etc.)
Schizophrenia (SZ)
Has positive, negative, and cognitive symptoms
Neural features of SZ
- cortical atrophy/ gray matter loss (temporal cortex, hippocampus, and prefrontal cortex)
- abnormal cell organization (in the HPC)
- hypofrontality
- alterations in DA transmission
Causes of SZ
Prenatal + postnatal risk factors; some are choices (e.g., drugs) whereas others are “random accidents” (e.g., illness). A major factor worth discussing is cannabis.
Cannabis during development
- Heavy cannabis use during adolescence is a concern as it may impede brain development during a vital sensitive period
- Cannabis use is associated with an increased risk for schizophrenia (~2x) and an earlier onset
- Earlier onset of cannabis use is associated with more significant impairments in cognitive functioning
Adolescent cannabis + the brain
- White matter integrity reduced
- Gray matter reduced in the HPC + OFC (like SZ)
SZ and the DISC-1 gene
- DISC-1 disrupted in SZ, produces protein involved in neuronal proliferation, differentiation and migration (consistent with the idea of NDD)
- Variants associated with SZ-like symptoms in humans and animals (these symptoms can be reversed by antipsychotic treatment)
- Risk variants of DISC-1 likely arose through a translocation between chromosomes 1 and 11
Convergent model for SZ
Many hits (risk factors) - genetic and environmental - create risk for neurodevelopmental disorders
Autism - Symptoms
Poor social interaction:
- Fails to respond to name, poor eye contact, resists cuddling, prefers playing/being alone, may not recognize/respond to social cues
Repetitive behaviours:
- Arranging objects, making sounds, hand flapping, head rolling and body rocking, inability to switch between behaviours easily
Slow language development:
- >2 years, repeat with words/phrases, abnormal tone/rhythm
Autism - Spectrum
Heterogeneous group of disorders, defined by a set of symptoms
Autism - Epidemiology
- ~1% of the population, more common in boys (~3:1)
- Increase in diagnosis is associated w/ increased awareness, increased parental age + more sensitive diagnostic procedures
ASD + synaptic pruning
- In ASD, synapse number is higher in childhood and remains higher throughout adulthood
- ASD risk is associated with cortical expansion in certain areas
ADHD - Symptoms (two main ones)
Inattention:
- lack of attention to details or careless mistakes
- does not seem to listen when spoken to directly
Hyperactivity:
- excessive fidgeting
- running, climbing, restlessness in inappropriate situations
ADHD - Epidemiology
- 6-10% of the population
- Recent data suggests rates are increasing over the past few decades
Neural features of ADHD
- reduced total cerebral volume as well as PFC, BG, dACC, + cerebellum volume
- delay in cortical maturation (late gray matter peak, 3 years) that is most prominent in PFC regions
- lower white matter volumes (corpus callosum in particular)
Co-morbidity of NDDs
Two or more conditions at the same time:
- people with one NDD are at much higher risk for having another
- odds of people with ASD and ADHD together (~20/10,000) are much higher than expected by chance (~1/10,000)
Co-morbidities may be due to similarities in _______ or ________
Genetic factors, environmental factors
Shared basis of NDDs
A common set of genetic variation may underlie many NDDs (intellectual disability, ASD, SZ and epilepsy)
DA hypothesis of SZ
- Higher levels of DA metabolites (HVA)
- More D2 receptors
- Positive symptoms are similar to the effects of drugs that increase DA signalling (e.g. amphetamine, L-DOPA)
- Positive symptoms reduced by drugs that block DA signalling (DA antagonists; antipsychotic drugs such as haloperidol)
Dopamine hypothesis of SZ
Higher DA activity in the mesolimbic pathway.
Lower DA activity in the mesocortical pathway
How do we get two different effects on DA pathways?
Might start in the PFC:
- PFC neurons regulate mesolimbic and mesocortical pathways in different ways
- PFC neurons are less active in SZ (hypofrontality)
Reduced activity of PFC neurons has downstream effects:
- Increased mesolimbic (higher DA)
- Decreased mesocortical (lower DA)
*hypoglutamate hypothesis
Antipsychotic drugs
- Most antipsychotic drugs block D2 recpetors
- Conventional antipsychotics are relatively selective in this action, atypical antipsychotics (clozapine, risperidone) block other targets (e.g., 5-HT2 receptors)
Which symptoms are best treated with antipsychotics?
Positive symptoms
ADHD treatment - Psychostimulants
Most of these drugs work by increasing dopaminergic or noradrenergic transmission in different ways
Amphetamine actions
- dopamine and noradrenaline transporter inhibiton
- monoamine oxidase activity inhibiton (altered metabolism)
- VMAT2 inhibiton (not tested)
Methylphenidate actions
- dopamine and noradrenaline transporter inhibiton
- agonist activity at the serotonin type 1A receptor (not tested)
- redistribution of the VMAT-2 (not tested)
Shared mechanism
- Cocaine, for example, can block dopamine transport, leading to increased dopamine levels at the synapse
- Effects of 5-HT and NA transporters are also evident
Non-stimulant use for ADHD
- 30% of people may not respond to stimulants
- Other people might be at risk for certain drug interactions with classical stimulants
- Non-stimulants for ADHD are also available: atomoxetine (targets noradrenaline re-uptake), guanfacine and clonidine (which target alpha-2 recpetors, activated by noradrenaline)
- Different side effects for these particular drugs
Degeneration
- Active process requiring signalling pathways be active
- Degeneration can be inhibited by blocking certain signalling pathways
- Degeneration is less dramatic/slower in certain cases (Wlds - Wallerian degeneration slow - mice, SARM1 KO mice)
- Findings suggest degeneration can be prevented; therapeutic relevance of this information still unclear (no good strategy for doing this in humans)
Why is regeneration poor in the CNS
Once damage in the CNS there is macrophage infiltration and astrocyte invasion. Myelination inhibits regeneration.
How does myelination inhibit regeneration?
- Myelin contains multiple elements, including Nogo-A
- Nogo-A is released when myelin breaks down
- Nogo-A can, via various signalling pathways, act to inhibit axon growth
Potential options for recovery after degeneration in the CNS: Peripheral nerve grafts
Putting CNS nerves in a peripheral environment encourages limited growth
Potential options for recovery after degeneration in the CNS: Transplantation
Add new cells to replace those lost (e.g. adding DA neurons in someone with Parkinson’s Disease)
Potential options for recovery after degeneration in the CNS: Transplantation Issues
- Immunological incompatibility
- Lack of viable cells for the procedure
- Transplanted cells too developed to integrate into pre-existing circuits
- Outcome has not been impressive (this is the case for many experimental therapies shown today)
Stem cell transplants
- Stem cells can generate any cell type and could theoretically be used to replace any cell lost to injury
Potential options for recovery after degeneration in the CNS: Other options
- Transplantation of non-neuronal cells (i.e. glia; oligodendroglia, astroglia)
- Pharmacologically inhibiting degenerative processes and/or encouraging regenerative processes in axons
- Encouraging neurogenesis
- Various psychological, physical and cognitive therapies
- Emphasis on recovery of function, not recovery of cells
