PSY290 - Lecture 5: Neurodevelopment

development

development

change in a specific property over time

developmental trajectory

refers to the normal rate of change in a group

prenatal neurodevelopment steps

1. induction of neural plate

2. neuronal proliferation

3. neuronal migration + aggregation

4. axonal growth + synapse formation

5. neuronal death + synapse elimination

the beginning

• begins when the sperm fertilizes the egg, making a zygote

• blastocyst implants around 7-10 days, continues to develop

neural plate

• ~18 days after conception, embryo has 3 layers

• neural plate is on the ectoderm

• formation of the neural plate is induced by chemicals from the mesoderm

• neural plate will become the nervous system

embryo layers

• ectoderm (outside)

• mesoderm (middle)

• endoderm (inside)

in the neural plate…

• cells are stem cells

• important properties

  • nearly unlimited capacity for self-renewal

  • pluripotent (can develop into many cell types)

• division produces a new stem cell + another cell

• stem cells can give rise to other cells at a very high rate

over time, the neural plate…

• folds to form neural groove

• sides of neural groove fuse to form neural tube (~24 days)

• tube center will become the ventricular system + spinal canal

• growths on the anterior of the tube (~40 days) later become midbrain, hindbrain + forebrain

neuronal proliferation

• progenitor cells divide thickness of tube increases with more cells

• most division occurs in the ventricular zone (tube interior)

• proliferation affected by chemical signals from the dorsal surface (roof plate) + ventral surface (floor plate) of tube

• some cells along the ventricular zone may retain this capacity

migration

• movement of cells to their target locations

• inside-out process (outside layers migrate last)

• at this stage, cells lack processes (no dendrite/axons)

• migration may be tangential or radial

• mechanisms of each may be distinct

radial

migration of the cells outward

tangential

migration of the cells across

migration and cortical layers

deeper layers are migrated to first

aggregation

• neurons align with other neurons in the same area

• cell adhesion molecules (CAMs) vital here

  • CAMs are present on the surface of cells

  • CAMs recognize other cells and adhere to them

• Gap junctions prevalent during this period

axonal growth basics

• axons grow outward to their target

• very precise process

• at the end of each axon is a growth cone

• each cone has filopodia

  • ‘search’, extend + retract

growth cone

as you move forward, your growing this tract outwards

how does the axon “know where to go”?

chemical sensitivity

Sperry’s Exp - Healthy Frog

• well developed visual processing pathway

• sever the optic nerve and it will regrow

• when an insect is dangled in front of a normal frog, the frog strikes at it accurately with its tongue

Sperry’s Exp - with eye rotation

• rotate the eye and the frog misdirects its tongue

• mismatch in the projection

• when the eye is rotated 180 degrees, the frog misdirects its strikes by 180 degrees

Sperry’s Exp - with cut nerve

• unalike regions are close together

• when the optic nerve is cut and the eye is rotated by 180 degrees, at first the frog is blind

  • but once the optic nerve has regenerated the frog misdirects its strikes by 180 degrees

  • this is because the axons of the optic nerve, although rotated, grow back to their original synaptic sites

axonal growth pathway

• small group of pioneer axons moves first

• growth cones responds to various chemical signals

  • attractants + repellants

  • released by neurons + other cells in the matrix

• other axons will follow the pioneer axons later, forming axonal bundles (eg. tracts)

• eg. thick snow on the ground, first person to walk through the snow will have a horrible time but they will leave tracks for other people to follow

fasciculation

bundles of tracts

chemoaffinity hypothesis

• the axon (pre-synaptic) is guided toward its target cell (post-synaptic) because that cell releases special chemicals

  • cell A releases chemical X

  • axon B is sensitive to chemical X, but axon C is not

  • axon B grows toward cell A, but axon C does not

• however evidence suggests that this signaling is not simply point-to-point (eg. A to B) but more complex

chemoaffinity in reality

• the retina or tectum were lesioned

• if an area loses its normal axonal input, it will recieve input from other axons instead (1)

• if axons have ‘lost’ their normal target, they will project to another target instead (2)

• cells can receive new projections that they otherwise wouldnt in specific circumstances

• chemoaffinity theory is proven false

topographic gradient hypothesis

• variation of chemoaffinity theory

• 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

  • Cell A releases Chemical X

  • Axon B and Axon C are both sensitive to Chemical X

  • however, Axon B is more exposed to Chemical X

  • Axon B grows toward Cell A but Axon C does not

• it is not just the chemical that matters but the concentration of that chemical

• high concentrations of one chemical may result in growth that are very different than those patterns that would be observed in low concentration

synaptogenesis

• synapse formation occurs after axonal growth

• astrocytes (and other glial cells) are important here

  • important for synaptic development

  • associated with more synapses

• form more synapses than necessary

• many synapses created are later removed

• this is a method of the axon communicating chemically with a compartment of another cell

• select for the best and eliminate the rest

  • many synapses we make are not useful and need to be eliminated

at the neuromuscular junction

• an axon may “lose” at some synapses, but “win” at others

• the inputs of a mature neuron are fewer but more elaborate and more effective

• keep the strongest

what does synaptogenesis mean?

synapse formation

what if synapses aren’t formed?

• when two cells are connected via a synapse, they exchange chemical signals

• this form of signaling is vital to cell survival

• cells that do not form synapses will often die

• when a cell forms connections with another, the cell receives survival signal from the partner

• Cell A connects with Cell B, Cell B releases important factors keeping Cell A alive

what are the survival signals?

• neurotrophins are transmitted via retrograde signaling (from Cell B —> Cell A)

• there is a limited amount of NTs released, which leads to a competition among terminals (NT hypothesis)

• you keep about 50% of the cells you make

• very competitive process

apoptosis

• form of programmed cell death

• cleaner process, wherein the cell’s contents are packaged for convenient disposal

• less inflammation

• preferred, safer process

necrosis

• form of cell death (eg. via nutritional insufficiency)

• cells ‘break apart’ + spill their contents (leave behind trash)

• more risk for inflammation

• only used in extreme situations

• very problematic

• microglia play an important role in mitigating inflammation and ‘cleaning up the mess’

cell death

• is normal and a good thing

• you generate about 50% more neurons than needed

• many neurons are lost during development

• the neurons that survive, you keep for a long time

• in most of the CNS, new neurons are not generated

in the mouse brain

similar order of events as the human brain, myelinate an axon after its found its home not before

from birth to adulthood…

• volume of brain quadruples (x4)

• growth not due to a gain in neurons (in fact many neurons are lost), but other processes

  • synaptogenesis (more synapses)

  • dendritic arborization (growth of dendrites)

  • myelination of axons

• some brain areas develop faster than others

  • primary sensory cortices develop early (associated with vital survival functions for infants

  • prefrontal cortex develops last

synaptic density with age

• the density of synapses declines after the first year of life

• synapses develop rapidly then pruning happens later on

consequences of pruning

• the prefrontal cortex is involved in planning, initiating and inhibition of behavior (and thereby impulse control)

• these functions are most developed at age 25 (and often poorly developed beforehand)

  • if we were to take synaptic pruning as an indicator of maturity, the 25 years old thing is true (cognitive peak)

• development of the prefrontal cortex with time + experience explain the striking behavior differences between adolescents and adults

  • develop maturity over time w/experience is the evolutionary argument

• alterations in PFC developmental trajectory may delay or impair executive function

  • people with a delay in PFC will have poor impulse control

synapse elimination

• glial cells play an important role in synapse formation, elimination and maintenance

• increasingly, we are considering the role that glial cells might play in disorders of the nervous system

• disorders can be from too much cortex

synaptic properties are…

• modifiable with experiences!

• get rid of the synapses that are not needed

• it is not quantity of the synapses, but the quality

  • what they do and how strong they are

developmental periods

• critical and sensitive period

• thought to be periods of high neuroplasticity

• we can identify potential developmental periods with deprivation and enrichment studies in animals

  • periods in humans suggested by correlational data

• periods of time where our nervous system has a lot of change or adjustment

critical period

time interval where an experience MUST occur for proper development

sensitive period

time interval where an experience has a relatively greater effect on development

critical period example

• in animals, early visual deprivation (eg via blindfolding when young) disrupts the development of visual pathways

• effects of early visual deprivation cannot be reversed by later experiences (even if you remove the blindfold)

  • will never get normal visual system

• later visual deprivation is much less consequential (as it is outside the critical period)

why do critical periods end?

• many theories; several are focused on axons

• myelination of axons occur 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

• a developing nervous system is easier to change than a mature one

• need the input during the critical because that is when it is easy

sensitive periods for language

• input is more meaningful for development

• language is much easier to learn when you are young vs trying to learn a language when you are an adult

• language acquisition is easiest between 3-7 years old

• much harder to acquire after 18 years

why is learning a language when you are older harder?

• difficult to test

• motivation for second language learning is different than first

• context in which second language is learned varies

  • for kids its to communicate

  • for adults its mainly for interest or a job

• language acquisition may involve different mechanisms in different ages

• when you are younger you are immersed in that language and there is no backup language

• when you are older you spend an hr a week but you have a native language to fall back on if you are struggling

adult neurogenesis

• means generation of new cells in adulthood

• for the most part, the CNS has limited regenerative capacity

• neurons, once lost, are lost forever (and were losing them all the time)

• you can only really make new neurons in large amounts during development - we are thus continuously running out of cells

• there may be exceptions

where does adult neurogenesis occur?

• either in hippocampus or lateral ventricles

  • not a lot of new cells

• humans have had a handful of cases

  • requires post mortem tissue

• takes about 48 weeks to develop a new cell

the neurogenesis debate

• neurogenesis occurs in most mammalian species studied - but it is currently unclear whether the extent is significant enough to be meaningful in adult humans

• assuming it does occur in humans, why does it matter?

  • learning and mood regulation

• not super meaningful if youre just making a handful of cells

why does neurogenesis matter?

• when young, new adultborn 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 behavior

• NDDs often emerge early in life (eg autism, adhd, intellectual disabilities and language disabilities)

  • high heritability, strong role of genetic factors

• NDDs are considered distinct from aquired disorders, which usually emerge in adult hood and are the result of brain changes (eg injuries) in adult hood

• abnormal development —> abnormal cognition and behavior

• result of processes that have been ongoing for a long time

comorbidity

• two or more conditions at the same time

• people with one NDD are at much higher risk for having another

• odds of autism and ADHD (~20/10,000) are much higher than expected by chance

• comorbidity may be due to similarities in genetic factors or environmental factors

  • eg gene X contributes to ASD and ADHD

  • if you have the variation of it, you could get both disorders

schizophrenia

• SZ

• cluster of symptoms both

• positive (add something) and

  • most commonly hallucinations

• negative (absence or reduction of something that is usually present)

  • reduction in speech or motivation

  • flat emotional face

• it is unlikely to have every single symptom, but most of the time you have a few positive and a few negative

neural features of schizophrenia

• cortical atrophy (temporal cortex, HPC and PFC)

  • less gray matter

• abnormal cell organization (HPC)

• hypofrontality

  • reduced ability frontal lobe to process info

  • less active during tasks

• tends to appear later in life

  • males is earlier, females is later

• soft signs

  • impairments that predict later emergence of a disorder

  • not remarkable or strong

• alterations in DA transmission

major risk factor of schizophrenia

• prenatal + postnatal risk factors; some are “choices” (eg drugs) whereas others are “random accidents” (eg illness)

• major factor is cannabis

• family history has the greatest correlation

• born in the winter

• maternal depression

cannabis during development

• correlation

• 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 HPC and OFC just like schizophrenia)

DA hypothesis of schizophrenia

• higher levels of DA metabolites (HVA)

• more D2 receptors

• positive symptoms are similar to the effects of drugs that increase DA signalling

• positive symptoms reduced by drugs that block DA signalling

• schizophrenia is NOT a disorder of too much dopamine

• higher DA activity in mesolimbic pathway

• lower DA activity in mesocortical pathway

antipsychotic drugs

• most antipsychotics block D2 receptors

• conventional antipyschotics are relatively selective in this action, atypical antipsychotics block other targets

• if you inhibit dopamine a side effect is developing Parkinson’s like symptoms

  • fix one dopamine imbalance but create another in its place

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 behaviors

  • arranging objects, making sounds, hand flapping, head rolling and body rocking

  • inability to switch between behaviors easily

• slow language development

  • >2 years, repeat with words/phrases, abnormal tone/rhythm

• can be evident early on in childhood

autism spectrum

heterogeneous group of disorders defined by a set of symptoms, varying degrees of symptoms + cognitive ability

autism epidemiology

• ~1% of population

• more common in boys (3:1)

• increase in diagnosis is associated w/increased awareness, increased parental age + more sensitive diagnostic procedures

• conspiracy theories are associated with the increase including microplastics and vaccines but no evidence has proven these to contribute with higher rates

ASD + synaptic density

• synapse number is higher in childhood and remains higher throughout adulthood

• greater cortical expansion in specific areas may predict ASD risk

• when we see more cortex it isnt healthy, and we see this in ASD

ADHD symptoms

• two main symptoms which may manifest differently

• inattention

  • lack of attention to details or careless mistakes

  • does not seem to listen when spoken to directly

• hyperactivity/impulsivity

  • excessive fidgeting

  • running, climbing, restlessness in appropriate situations

• three forms (combined + 2 predominant forms)

ADHD

• 6-10% of the population

• recent data suggests rates are increasing over the past few decades (this is mysterious)

• conspiracy theory: big pharma, drugs are needed for ADHD so the increased diagnosis is financially motivated

neural features of ADHD

• reduced total cerebral volume as well as PFC, BG, dACC + cerebellum volume

• delay in cortical maturation, prominent in the PFC

• lower white matter volumes

• lower DA levels (reward deficiency theory)

• changes in the PFC are thought to be central to the disorder and its treatment with drugs

psychostimulants for ADHD

• most of these drugs work by increasing dopaminergic or noradrenergic transmission in different ways

  • people with ADHD normally have less dopamine, so the drugs increase the dopamine levels

• amphetamine actions

  • dopamine and noradrenaline transporter inhibition

  • monoamine oxidase activity inhibition (altered metabolism)

• methylphenidate actions

  • dopamine and noradrenaline transporter inhibition

non-stimulant use for ADHD

• 30% of people may not respond to stimulants

• other people might be at risk for certain drug interactions with classic stimulants

• non-stimulants for ADHD are also available (targets noradrenaline reuptake), guanfacine and clonidine (which target alpha2 receptors, activated by noradrenaline)

• different side effects for these particular drugs

• these target receptors not transporters

normalizing DA levels

• when you look at the healthy nervous system where everything is present, with the addition of the same drug does not correct anything, if anything it creates an imbalance

• take a brain with too little dopamine and you inhibit dopamine transport, that is a good thing

• if you take a brain that already has enough dopamine and you inhibit dopamine transport that is not necessarily useful and can be harmful