Week 5 (Neural and Behavioral Development) Flashcards
Mental disorders where developmental abnormalities are likely to be involved
Autism Spectrum Disorders (ASD)
Attention deficit hyperactivity disorder (ADHD)
Schizophrenia
Fetal Alcohol Syndrome (FAS)
Note: may be due to genetic associations, exposure of toxins
When is the “risk period” for exposure of CNS to toxins?
All throughout pregnancy and even through childhood and adolescence (brain weight increases 3 fold from birth to young adulthood!)
Significant develomental changes occur in cerebral cortex and in myelination until end of 2nd decade
Note: different from other developmental problems where toxin exposure during first trimester is worst
Embryonic regions of neural tube and the parts of the brain they give rise to
Forebain (prosencephalon) –> telencephalon –> cerebral hemispheres
Forebrain (prosencephalon) –> diencephalon –> thalamus and hypothalamus
Midbrain (mesencephalon) –> Mesencephalon –> midbrain
Hindbrain (rhombencephalon) –> metencephalon –> pons and cerebellum
Hindbrain (rhombencephalon) –> myelencephalon –> medulla
Spina bifida
Abnormal closure of neural tube during weeks 3 and 4
1/1000 births in US
Lack of folic acid intake before conception and during pregnancy
Spina bifida occulta: vertebrae do not fuse across the top; dura intact and no structural hermiation; hairs or dimple at level of defect; usually seen at lower vertebral levels
Meningocele: vertebrae do not fuse across the top; meningial coverings of spinal cord enlarged and bulge out under skin but spinal cord itself still in place
Meningomyelocele: vertebrae do not fuse across the top; cord itself is bulging out into skin area (serious vulnerability for permanent damage to spinal cord)
How/where does massive cell proliferation occur during embryogenesis?
Massive cell proliferation occurrs primarily in periventricular germinal zones (on one side of the neural tube)
Periventricular regions contain neural stem cells (NSC) that generate neural progenitors (embryonic stem cells, transition “stem” cells, multipotent neural stem cells, committed neural progenitors)
Cellular differentiation during development
NSCs in a particular region initially generate neurons then astrocytes then oligodendrocytes
Cellular differentiation is regulated by molecular signals that include protein growth factors (FGF, EGF, IGF, BMP, NGF, etc), retinoic acid (accelerates maturation of stem cells too early which is bad!), transmitters
Environmental toxins that interfere with or mimic these signaling mechanisms can disturb cell division/differentiation and cause developmental abnormalities
Different processes going on simultaneously in diff regions so toxins or ischemia may affect one region and not another, or may affect different regions at different times
Periventricular Leukomalacia (PVL)
Failure to develop white matter secondary to periventricular ischemia during gestation
Highest vulnerability during 26-36 weeks gestation
Premature infants at particular risk
Periventricular ischemia leads to loss of oligodendrocyte progenitor cells in periventricular tissue (and other things)
Juvenile and adult neurogenesis
Multipotent neural stem cells in periventricular regions of juvenile and adult CNS can be propagated in tissue culture and give rise to neurons, astrocytes and oligodendrocytes
Function in vivo not yet well established: give rise to certain neurons and glia, replace cells after injury or disease, tumor stem cell hypothesis (are adult NSC a source of cancer stem cells for glioma?)
NSCs in hippocampal dentate gyrus
NSCs persist throughout life in hippocampal dentate gyrus
New neurons are born and incorporated there throughout life (total number of neurons stays stable though because neurons die)
Neurons may be important in: formation of certain types of new memories, certain types of seizure disorders
Behavioral effects of chemotherapy
“Chemobrain” when you get cognitive disturbances after chemotherapy
May be due to toxic effects on adult NSCs and reductions in adult hippocampal neurogenesis
Cell migration in the brain
Spatial organization in CNS is achieved by cell migration
Periventricular regions contain NSCs that generate neural progenitors that then migrate away
Cell migration guided by molecular cues (integrins, NCAMs, laminin, fibronectin, ephrins, semaphorins)
Neuroblasts and neurons migrate along processes of radial glia
Cell migration proceeds from inside (ventricular zone) to outside (surface of brain/pia) and occurs over a long period of time during gestation
Deeper layers of cortex (zone VI) form first, then V, then IV, then III, etc
When does generation of cortical neurons occur during gestation?
Cortical neurogenesis is from 2 months to at least 8 months of gestation
Radial glia
Guide neurons during development, then turn into astrocytes
Note: Alcohol causes premature transformation of radial glia into astrocytes, which disrupts migration of cortical neurons and disturbs cortical development
Growth of connections
Neural connections are formed by axonal migration
Axonal growth and migration are achieved by growth cones (contains machinery in it, and new membrane is added immediately behind the growth cone)
Direction of axonal migration controlled by positive and negative guidance cues that attract or repulse growth cones, in particular the filopodia
Guidance cues can be contact-mediated or diffusion-mediated
Synapse formation (synaptogenesis)
Mature synapses are complex structures with high densities of many different kinds of molecules (adhesion, structural, receptors, ion channels, second messengers)
Formation of individual synapses can occur quickly (minutes to hours) and begins with spine formation and interaction of adhesion molecules followed by accumulation of vesicles and other structural elements
Synaptogenesis begins during first trimester, continues throughout gestation and juvenile development, is ongoing to some degree throughout adult life (and aging) where it is an essential part of synaptic plasticity
Synapse density in cerebral cortex
Increases rapidly during 3rd trimester of gestation and first postnatal year
Peaks in visual and auditory cortices at 1 year postnatal
Peaks in frontal cortex at 4-5 years postnatal
Is subject to “pruning” after peaking
Myelination
In CNS, myelination achieved by oligodendrocytes
Oligodendrocytes derive from periventricular progenitors and migrate to where they are active
Very few axon tracts myelinated at birth, most occurs after birth and proceeds until end of teenage years
Many developmental milestones (walking, talking) correlate with myelination
Disturbances in myelination result in functional defects
Myelination can be assessed in vivo during childhood development using MRI
What happens to white and grey matter throughout childhood and adolescence
White matter increases and grey matter decreases
Not losing neurons, but losing synapses, which accounts for decrease in grey matter
Obesogens
Environmental toxins that may cause fetus to grow up to be obese
Pesticides (fungicides), phthalates (shampoos, cosmetics), BPA (in plastic), about 20 substances total
Developmental age groups
Infancy: 0-12 months
Toddlers: 12-36 months
Preschool: 3-5 years
School-age: 6-12 years
Adolescence: 13-18 years
Behaviorism
John Watson said “give me a dozen healthy infants…I can train them to become anything I want–doctor, lawyer, artist, thief, etc”
Emphasis on nurture over nature
Jean Piaget
Nature and nurture are interactive and inseparable
Cognitive development occurs in stages and each stage contingent on the one before
Each stage represents qualitative change in cognitive conceptual structures, not just an increase in knowledge
Schemas: building blocks of knowledge (dog is four legged and furry –> later on…that barks and slobbers)
Piaget’s cognitive stages
Sensorimotor (0-2 years): infant explores world through direct sensory and motor contact; object permanence and separation anxiety develop during this stage
Preoperational (2-6 years): child uses symbols (words and images) to represent objects but does not reason logically; has ability to pretend; is egocentric
Concrete operational (7-12 years): child can think logically about concrete objects and can add and subtract; understands conservation
Formal operational (12-adult): adolescent can reason abstractly and think in hypothetical terms
Erik Erikson’s stages of psychological development
Basic trust vs. mistrust (0-1 years): children develop sense of trust when caregivers provide reliable care; success leads to trust
Autonomy vs. shame and doubt (1-3 years): children need to develop a sense of personal control over skills; success leads to autonomy
Initiative vs. guilt (3-5 years): children need to begin to assert power and control over their environment; success leads to sense of purpose
Industry vs. inferiority (5-11 years): children need to cope with new social and academic demands; success leads to sense of competence
Ego identity vs. role diffusion (11-21 years): teens need to develop sense of self and personal identity; success leads to ability to stay true to oneself
Temperament in infancy
Way in which child interacts and responds to his/her environment
Can change over time with environment
Easy, slow-to-warm-up, difficult = 40%, 15%, 10%
Gross motor developmental milestones
Infancy:
6 weeks: controls head when held upright
4 months: rolls front to back
6 months: rolls back to front and sits unattended
9 months: pulls to stand
12 months: starts to walk unattended
Toddlers:
15 months: crawl up stairs, walk backwards
18 months: walk stairs with help and run
24 months: ball skills and walk on tip-toes
30 months: jump
36 months: alternate feet up stairs
Preschool:
3 years: use of utensils, broad jump, gallop (most show hand preference by age 3)
4 years: alternate feet down stairs, hop and skip
5 years: balance 10 seconds on one foot and print letters
School age: refined coordination for sports/fine arts
Fine motor developmental milestones
Infancy:
6 weeks: reaches for objects
4 months: grasps objects
6 months: transfers objects across midline and puts objects in mouth
9 months: plays pat-a-cake and uses refined pincer grasp
12 months: tower of 3 blocks
Toddlers:
18 months: scribble
24 months: put on garments
36 months: 9 blocks; bridge of blocks; R/L preference
School age: cursive, typing
Language developmental milestones
Infancy:
1 month: responds to directed call
3 month: coos
6 months: babbles (mama, dada) inappropriately
9 months: mama and dada appropriately
12 months: follows simple commands, at least 1 word
Toddlers:
2 years: 2 words; 50% intelligible; follow 2-step commands
3 years: 3 words (phrases); 75% intelligible; follow multi-step commands
4 years: 4 words (sentences); 100% intelligible
Preschool: conversation, feelings, talk about past
School age: inferences, jokes, sarcasm, reading
Adolescence: comprehend double meanings, make inferences
Social-emotional developmental milestones
Infancy:
3 months: responsive smile
6 months: sense of self and attachment with caregiver
9 months: separation and stranger anxiety
12 months: beginning of empathy
Toddler: increasing anxiety over separation and seek extra support when returning, but as comfort level with separation increases, length of separation increases
Preschool:
3 years: toilet trained, know own age and gender, play imaginative, take turns, share
4 years: interactive play in small groups, pretend social scenarios and role playing
4-5 years: simple board games, follow rules
School age: accomplishment, best friend, segregate by gender, sportsmanship
Adolescence: peer group sets standard, individuality from parents, romantic relationships, hobbies, etc
Cognition developmental milestones
Infancy:
0-4 months: modify/regulate primitive reflexes
4-8 months: manipulate objects meaningfully
7 months: attention span is 5 minutes
9 months: object permanence
8-12 months: goal-directed behavior
Toddlers:
12-18 months: cause and effect
15 months: functional play (push the car) and early representational play (toy phone)
18-24 months: symbolic representation and body parts
24 months: start of simple concepts (size, color, number)
Preschool:
3-4 years: identify colors
4-5 years: identify complex body parts
5-6 years: understand abstract symbols (letters, numbers)
School age: conservation, reasoning, organization (HW), active working memory, attn span 1 hour
Adolescence: abstract thinking, hypotheses, deductive reasoning, speculate and consider alternative possibilities (can lead to idealism)
Assessment tools
Parent questionnaires and examiner based assessments
Early development: Denver Developmental Assessment and Mullen scales of Early Learning (ages 0-5)
Cognitive assessments: WPPSI (ages 3-7), WISC-IV (ages 6-16)
How do neural circuits develop?
Incorporates mechanisms that are able to deal with targeting errors and with influences that derive from interactions with the environment
Regressive events
Prominent features of neural development
Naturally occurring cell death
Pruning exuberant connections and synapses (reduction in grey matter during childhood and adolescence)
Combinations of synaptic plasticity and regressive events during juvenile development allow interactions with the environment to “sculpt” neural systems in permanent or long lasting ways: “critical periods,” language, ocular dominance, colonization of “unused” cortex
Naturally occurring cell death
Plays central role in the formation of neural circuits
More neurons are born than are needed
Only those neurons survive that make connections to appropriate target neurons
Survival is determined by retrograde transport of trophic factor produced by target cells!
Neurotrophic growth factors (NTF) produced by target neurons
Neuronal survival is supported by neurotrophic growth factors (NTF) that are produced by target neurons and are retrogradely transported by input neurons
Afferent (signaler) neuron must be active in order to cause target neuron to secrete NTF though!
External (environmental) factors that influence target neural activity can alter trophic factor production and influence circuit development!
Pruning exuberant axonal connections
Pruning of connections plays a central role in the formation of neural circuits
More connections are made than are needed
Only appropriate connections are maintained
Maintenance of connections is determined by neural activity and by trophic factors produced by target cells
Axons can overshoot their normal targets by long distances and send out many exuberant branches that are either pruned or in some cases persist on the basis of activity dependent interactions.
How can environment affect neuronal survival?
Environmental factors that influence target cell activity and trophic factor production can sculpt circuit development by influencing afferent neuronal survival and the maintenance of connections
Environmental factors that influence target cell activity by the afferent neuron can regulate trophic factor production by the target neuron, which in turn can sculpt circuit development by influencing afferent neuronal survival and synaptic connections
If no activity, whole connection pruned
If weak activity, synapses may be pruned
If highly active, synapse strengthened
NGF
Founding member of the neurotrophin family
Can activate multiple signaling pathways that influence different cellular processes (PI3 kinase for cell survival and ras and PLC pathways for neurite outgrowth and neuronal differentiation)
Other molecules that act as developmental growth factors
BDNF, NT3, NT4/5
These are structurally related to NGF but also have other functions in mature animals (other than developmental growth factors)
Neurotrophins
NGF, BDNF, NT3, NT4/5, CNTF, FGFs, IGF, EGF, thrombospondin (produced by astrocytes)
Capable of complex signalling interactions that can influence many different cellular activities during development and after maturity (cell survival, neurite outgrowth and neuronal differentiation, activity-dependent plasticity, cell cycle arrest, cell death)
Different neurotrophins, alone or in combination, help to determine final pattern of connectivity of sensory neurons in the peripheral nervous system by mediating target effects on regressive effects that determine which neurons and terminals survive pruning
Molecules other than neurotrophic factors that have effects on developing nervous system
Steroids (sex and adrenal)
Thyroxin
Transmitters
Etc
Synapse plasticity and synapse formation
New growth in the form of terminal sprouting, dendritic branching and synapse formation are important aspects of juvenile neural development that add substantially to tissue volume
Synapse formation also “sculpted” by environmental interactions or influenced by exposure to hormones, toxins and other molecules
Note: neuropil fills space between neurons with dendritic branches and synapses, which is a lot of space, so changes in neuropil volume (which correlates with synapse density) can be measured in MRI scans
Synaptic pruning in adolescents with schizophrenia
Adolescents with schizophrenia have decreased grey matter in cortex
This loss may correlate with increased synaptic pruning and decreased synaptic density
Critical periods in development
Developmental windows in which anatomical connections and functional properties of neural cells and circuits can be modified by experience (AKA environmental interactions during juvenile development can have permanent effects on CNS structure)
Changes (increases or decreases) in activity during the brief developmental “critical periods” can cause permanent changes in CNS structure
Critical periods are windows of opportunity–activity that occurs after a critical period has passed will not be able to establish the normal adult pattern of structure
Loss of activity in adults does not alter the established structural pattern in adults in the same way as loss of activity during the critical period
The time of critical period varies with systems
Examples at the behavioral level: parent imprinting in birds, language in humans (learn language with no accent if 3-7yo)
Example at the cellular level: visual system
Critical period for primary visual cortex
Evidence for environmental regulation (pruning) of afferent axon terminals in ocular dominance columns in the primary visual cortex
During development, projections from both eyes initially overlap, followed by progressive segregation of projections into separated domains for each eye by pruning of exuberant collateral branches (this segregation requires stimulation in the form of light activation of the retina)
If light activation of retina and pathways is blocked in one eye during critical period of development (2-3 months), then the pathways of the activated eye survive, while those of the un-activated eye are pruned
Clinical therapy for amblyopia based on recognition of critical period importance
Amblyopia is abnormal development of visual cortex due to deprivation of vision in one or both eyes during childhood due to strabismus, congenital cataract or other causes
Untreated strabismus can lead to domination of visual cortex development by one eye, with consequent failure of development of binocular vision
Treatment consists of achieving binocular stimulation of the visual cortices by use of eye patches (over dominant eye) or glasses (or surgery to adjust extra-ocular muscles)
Treatment is most effective when initiated before 5 years of age, and is somewhat effective in teenagers and less so in adults
Colonization of “unused” cortex
In sighted people, V1 is the primary visual cortex
In the blind (from birth), V1 can be used for verbal memory
Mental disorders where developmental abnormalities are known or suspected
Autism Spectrum Disorders (ASD)
Attention deficit hyperactivity disorder (ADHD)
Schizophrenia
Fetal alcohol syndrome (FAS)
(Drugs of abuse)
Potential causes include genetic associations and exposure to toxins, the timing during development of which determines symptoms
Variety of developmental abnormalities in autism spectrum disorders (ASD)
Neuropathological evidence for multiregional dysregulation of neurogenesis (increased brain mass, increased regional cell densities, reduced neuronal size), neuronal migration (heterotopia (abnormal neuronal groups), dysplasia of cortical architecture (dyslamination)), synapse development (abnormal signaling in post-synaptic spines and dysregulation of glutamate signaling in Fragile X)
Imaging evidence for increased brain mass, abnormal myelination
Etiologies are not certain: evidence for complex genetic influences, but also ASD symptoms from single gene mutations (Fragile X syndrome with FMR1 and Rett syndrome with MECP2)
Similarities between ADHD and FAS
ADHD and FAS exhibit abnormalities of cerebral cortex development that result in certain cortical regions having either increased or decreased cortical thickness relative to controls
This suggests it may be possible to identify cortical changes associated with behavioral phenotypes and eventually may help with diagnosis or therapy
Environmental factors that may be essential to development during critical periods
Social interactions
Training and learning
Exposure to toxins
Essential nutrients
Hormones
The attachment relationship
Emotional or affective bond between infant and caregiver
Nature of attachment relationship is thought to reflect the quality of interaction between infant and caregiver, not to be reflective of attributes of either the infant or caregiver alone
Thus, each attachment relationship is unique to a particular dyad
Caregiver functions (ideally) as a secure base and as a safe haven
Secure base and safe haven
Caregiver functions (ideally) as both of these
Secure base: when a child trusts that (s)he has a sensitive, responsive, dependable caregiver, (s)he is able to venture out and explore the world around him/her
Safe haven: when a child trusts that (s)he has a sensitive, responsive, dependable caregiver, (s)he will seek comfort or reassurance from that caregiver when (s)he feels distressed or threatened
Attachment behavior
Organized system of behaviors (not just single behavior) that infant uses to maintain interaction, proximity, connection with caregiver
Activated under conditions of threat
Serves a protective function, evolutionarily adaptive
Attachment figures
Can be primary and secondary
Historically, mothers were considered a priori to be primary attachment figure, but now is increased recognition that other caregivers can be primary attachment figures (fathers, grandparents, child care providers)
As childcare duties are dispersed across more caregivers, child may develop more than one primary attachment figure
Attachment theory
John Bowlby’s assumptions
Early infant-caregiver interactions are viewed as a foundation for other social relationships established in childhood, adolescence, and adulthood
Patterns of dyadic regulation between infant and caregiver give rise to the child’s ability to self-regulate
Quality of attachment relationship (secure vs. insecure) reflects differences in these patterns of dyadic regulation
Quality of child’s early attachment relationships will have implications for patterns of adaptation throughout the life span, with regards to behavioral, social, emotional, cognitive functioning
Development as a relational process
Early development is inextricably embedded in the infant-caregiver relationship
The human infant relies on caregiver not just for sustenance but for external regulation of physiological states
Over time we learn to regulate ourselves, but this ability to self-regulate originates in large part in the context of earliest relationships with caregivers
Capacities of newborn infants
Just a few hours after birth, infants will show preference for mother’s face over a female stranger’s and that preference will occur even with relatively little viewing of the mother
By 1-2 days of life, infants can recognize mother’s smell
As early as 3rd day, infants can discriminate mother’s voice
Development of attachment relationship between mother and newborn infant
Mutual regulation: mothers and newborn infants help regulate physiological responses of one another
Ideally a synchrony develops between infant and caregiver: the “dance” that occurs between parent and child during brief, but emotionally intense, playful interactions
Notably, much of infant-caregiver interaction involves mismatched states: the key is not whether infant and caregiver are always in sync, but whether there are attempts to repair interactions
Strange situation
Lab procedure to develop methodology for assessing patterns of infant-caregiver interaction in order to provide empirical validation for attachment theory
