Neuronal Development Flashcards
Define sex-limited genes
- Present in both sexes but active mainly in one
- Different than sex-linked genes
- Ex. Chest hair in men, breast size in women
What is heritability and how is it determined?
- Ranges from 0 (no genetic contribution to variation) to 1 (complete genetic control)
Determined using
- Twins
- Adopted Children
- Genetic approachesHow are twin studies used to determine heritability?
- Stronger resemblance between monozygotic vs dizygotic twins indicates a greater genetic contribution
Virtual twins: same age, adopted at the same time into the same family
- Any similarity implies an environmental influence- There is potential bias for social workers putting adopted twins to similar families, so they may have similar environment
How are adopted children used to determine heritability?
- Resemblance to biological parents suggests a hereditary influence or an epigenetic influence from the mothers prenatal environment
What is the candidate gene approach
Used to determine heritability
Identifies 1 gene with a significant influence
What is the genome wide association study
Used to determine heritability
Examines all the genes while comparing 2 groups
Has a risk of seeing apparent effect by accident since thousands of hypotheses are studies at once (1 for each gene)
What is epigenetics?
- Changes in gene expression that can be inherited
- Result of an experience alters the chemical environment within a cell
Describe the Dutch Hunger Winter study
Dutch born/conceived in the winter of 1944-45 during the Nazi embargo that resulted in the starvation (500-750 kcal) in cities but not in self-served rural areas
- Men examined at 19 when entering the army for mental check
- Grouped by occupation of their fathers (manuals vs. non manual)
- Manual labour = increased probability of mental retardation
- No change in retardation in cities (famine) vs. rural areas
- Weaknesses:
- There are other differences between cities and rural areas, not just starvation
- Only men examined
- Short term stress on mothers
- Selective survival — only look at men at 19 but some may have died before then
- Basic testing
- Only tested at one age
Follow up to the original Dutch Hunger Winter study
- Looked at same people at older ages, men and women
- Schizophrenia and bipolar disorder risk increased if conceived during the famine in men and women
Compare methyl and acetyl additions to DNA
Acetyl:
- Addition/removal to histone tail close to gene
- Addition causes the histone to loosen grip on DNA, facilitating expression of that gene
- Removal causes the gene to turn of by histones tightening their grip
Methyl:
- Addition/removal at a promotor
- Addition turns off a gene
- Removal turns gene on
What is Phenylketonuria
- Inability to metabolize phenylalanine leading to toxic levels that impairs brain development leading to mental retardation, restlessness and irritability in a child
- Environmental interventions can modify it (ie. low phenylalanine diet)
Describe coefficient of relatedness (r)
- Represents the average percentage of genes two individuals share
- r = 0.5 to your parent or siblings
- r = 1 in monozygotic twins, r = 0.5 in dizygotic twins
When does the CNS begin to develop
When the embryo is 2 weeks old
Steps to neuronal development
- Proliferation
- Migration
- Differentiation
- Myelination
- Synaptogenesis
Describe Proliferation
The cells lining the ventricles divide, 1 remains a stem cell (radial glial), and the other becomes a primitive neuron/glia that migrates
- Mammalian cerebral cortex forms few/no new neurons after brith
- Nearly all neurons form within the first 28 weeks
Describe Migration
Immunoglobulins and chemokines are chemicals released to guide cells to their destinations
- Most migration occurs before birth
Describe differentiation
- Formation of axon and dendrites
- Axon grows first, either during migration or once cell reaches its target - New neurons are small interneurons
Describe myelination
- Process of glia producing myelin sheaths
- Occurs gradually for decades
- Spinal cord → Hindbrain → Midbrain → Forebrain in order
Describe synaptogenesis
Formation of synapses that begins before birth but continues throughout life
- Axon seeks target for synaptogenesis lead by immature axon tip (growth cone)
- Filopodia (on growth cone) sample the environment
- Molecules produced by target cells that attract filopodia
- Each axons forms synapses onto many cells in the approximate correct location
- Postsynaptic cells strengthen the most appropriate synapses and weakens others
What are determinants of neuron survival?
- Must form a synapse with the target cell and receive growth factor from that cell
- Must be stimulated to release neurotransmitters into the synapse
- Apoptosis occurs when the conditions are not met
- Must be stimulated to release neurotransmitters into the synapse
How can neuronal development be studied?
- Use immunohistochemistry to bind antibodies to proteins present during division
- Can radiolable proliferating DNA
What are homeobox genes?
regulate the expression of other genes and control the start of anatomic developments
How is the hippocampus involved in neuron development?
- Replacement of neurons in the hippocampus and striatum (basal ganglia) is important for new learning
- Blocking the formation of new neurons the hippocampus impairs new memory formation
Describe Neuron Darwinism
Start with more neurons and synapses than we can keep and a selection process keeps some and rejects other
What does nerve growth factor do?
Sympathetic nervous systems forms more neurons than needed
- When a neurons forms a synapse onto a muscle, the muscle delivers a protein called nerve growth factor (NGF) that promotes the survival and growth of an axon
- An axon not receiving NGF dies
What is apoptosis?
- Programmed mechanism of cell death
- NGF cancels the program for apoptosis
What is a neurotrophin?
- Chemical promoting the survival and activity of neuron
- ex. NGF, brain-derived neurotrophic factor (BDNF)
- Do not control the survival of neurons within the brain, only in the periphery
Compare near and far transfer
Near transfer:
Training in one task produces improvements on a similar task
Far transfer:
Training in one task produces improvements in other dissimilar tasks
Symptoms and characteristics of Autism Spectrum Disorder
- 4x more common in boys, but more severe in girls
- Deficits in social and emotional exchange
- Deficits in non verbal communication
- Stereotyped behaviors (ie. repetitive movements)
- Resistance to change in routine
- Unusually weak or strong responses to stimuli
Treatments for ASD
- Pregnant women taking Follic acid (B9) pill have half the probability to have a child with autism
- Risperidone sometimes reduces stereotyped behaviors, but comes with serious side effects
- CBT has benefits according to therapists and parents but not according to people with autism
What are possible causes and risks of ASD?
- Mutation in a gene in the mitochondria has been identified
- Most mutations are inherited from the father
- Increased risk if the mother is exposed to pesticides, solvents, perfumes, and air pollutants in pregnancy
- Some mothers have antibodies attacking brain proteins
Effects of being blind from infancy
- Blind people improve their attention to touch and sound based on practrice
- Reading Braille shows activity in occipital cortex
Effects of musicality
- Auditory cortex in musicians responded 2 times more strongly to sounds
- Temporal cortex on right hemisphere is 30% larger in musicians
- Some have focal hand dystonia
What is focal hand dystonia?
- Not being able to move 1 finger without moving another
- Happens in individuals who repetitively practice precise hand movement
Characteristics of Alzheimer’s disease
- Most common cause of memory loss
- Individuals with it learn procedural skills better than facts
- Gene linked on chromosome 21 connected to early-onset Alzheimers (<60) so those with Down syndrome invariably get it. Causes amyloid-beta to accumulate inside and outside of the cells, damaging axons and dendrites which cluster into plaques, decreasing synaptic input and plasticity and damage the cortex and hippocampus.
- Hippocampus among the first areas affected
- 2015: 750,000 Canadians, 2035: 1.5 million
- 1 in 10 Canadians >65
- Affects more women then men (but women also live longer)
Symptoms of Alzheimer’s
- Memory loss
- Challenges in planning and executive functions
- New problems with speaking or writing
- Changes in mood and reduced arousal (acetylcholine transmission affected from basal forebrain)
- Delusions
Common Alzheimer’s myths
- Largely result of genetics (93% have late onset which is not related to genetics)
- Only affects elderly
- There is a cure
- Memory loss = AD
Alzheimer’s risk factors
- Age (>65)
- Genetics (ApoE gene with 4 types. If 4 type on both chromosomes, 50% chance of developing AD)
- Female gender - estradiol is protective so menopause has effects
- Obesity
- Type 2 Diabetes
- CD (cardiovascular disease)
Possible causes of Alzheimer’s
- Extracellular plaques made of beta-amyloid
- Intracellular neurofibrillary tangles made of phosphorylated tau proteins
- Increased levels of amyloid-beta increases the phosphate groups attached to tau proteins. Cannot bind to usual targets and spreads to the cell body and dendrites
Physical exercise and Alzheimer’s mouse study
- Transgenic (3xTf-AD) female mouse model (both amyloid plaques and neurofibrillary tangles)
- At 4 months: Sham surgery or Ovariectomy (Ov)
- At 6 months: no running wheel or running wheel (Ex)
- 8 groups in total
- At 9 months, use Morris water maze
- 3 days after behaviour testing, the hippocampus and cortex was collected for western blot to test amyloid, tau, and actin (control group since actin is found in all cells)
What is a western blot?
Take out tissue, homogenize in buffer, isolate proteins and put in gel to separate by size, apply antibody to bind to protein to quantify amount of proteins by the darkness of the band
Results of physical exercise study
Western Blot:
- Stained for APP, C99 and pan actin
- Tg and TgOv has more C99 and APP that NTg, Tg+Ex, TgOv+Ex
2. Stained p-tau and pan actin
- No difference if p-tau levels
Morris Water Maze (Probe Trial):
- NTg, Tg + Ex, NTgOv + Ex, TgOv + Ex spend more time in PQ - Tg, NTgOv, and TgOv spend no difference time in quadrants
Study: Amyloid is an antimicrobial peptide
- Temporal lobe and cerebellum from AD and age matched non AD subjects homogenized in culture broth
1.- Homogenates incubated with Candita abicans (yeast), and microbial growth determined by alamar blue viability assays
- split the AD and non AD subjects into 2:
- Incubated with IgG (general antibiotic) or anti-amyloid antibiotic
- Homogenates incubated with Candita abicans (yeast), and microbial growth determined by alamar blue viability assays
Results of amyloid is an antimicrobial peptide study
- Less yeast in temporal lobe in AD (which contains more amyloid), no difference in the cerebellum (little amyloid)
- Growth showed no difference in anti-amyloid antibodies between AD and non-AD
Describe Infant amnesia
- Older children and adults remember little from infancy
- Due to hippocampus forming new neuronal connections and replacing old ones, weakening the older connections
