DEVELOPMEiT OF THE BRAIi  Maturation of the Vertebrae Brain

  • Human CNS begins to form when embryo is 2 weeks old; dorsal surface thickens, long thin lips ride, curl, form, merge, forming neural tube surrounding fluid-filled cavity
  • As tube sinks under skin surface, forward end enlarges and differentiates into hindbrain, midbrain and forebrain; rest becomes spinal cord
  • Fluid-filled cavity within neural tube becomes central canal of spinal cord and 4 ventricles of brain, containing cerebrospinal fluid (CSF). Growth and Development of ieurons
  • Proliferation: production of new cells; early in development, cells lining ventricles of brain divide; some cells remain (as stem cells) and continue to divide; others become primitive neurons and glia that start to migrate to other locations; proliferation similar across vertebrate’s, differ in number of cell divisions
  • After cells differentiated as neurons/glia  migrate; some move faster than others; some move radially from inside brain to outside; some move tangentially along surface of brain; some move in both directions

 Immunoglobins/chemokine’s: guide neuron migration

  • Deficit  impaired migration, decreased brain size, decreased axon growth, mental retardation
  • At 1st, neuron looks like any cell; gradually, neuron differentiates, form axon and dendrites; axon grows 1st; tip remains at, near or towards target; after reaching destination, dendrites grow
  • Later, slower stage is myelination (glia produce insulating fatty sheaths that accelerate transmission in vertebrate axons); myelin forms 1st in spinal cord, then in: hindbrain, midbrain, forebrain (continues gradually for years)
  • Synaptogenesis: formation of synapses; continues from before birth throughout life as neurons form new synapses and discard old ones iew ieurons Later in Life

Vertebrates’ brains formed all neurons in embryonic development or early infancy; neurons can modify shape but not develop new neurons

  • Exceptions: 1) Olfactory receptors: exposed to outside world, have short half-life; stem cells in nose remain immature, periodically they divide to replace dying receptors; it grows an axon back to appropriate site in brain. 2) Stem cells in interior of brain divide to form “daughter” cells that migrate to olfactory bulb and transform into glia cells/neurons. 3) Area of songbird brain needed for singing 4) Adult hippocampus of birds and mammals; new memory formation
  • Animals learn easily when young; with age neurons become less changeable (less able to integrate to new circuits that represent new memories); more newly formed neurons survive during times of new learning
  • Formation of new neurons in mature primate cerebral cortex is controversial; research shown in mammal’s cerebral cortex there are no/few new neurons after birth, under normal circumstances
  • After brain damage or stroke, cerebral cortex on contralateral side gradually reorganizes  new neurons form

 Pathfinding by Axons

Chemical Pathfinding by Axons

  • Early experiments: each axon doesn’t find way to exactly correct muscle in extra limb; nerves attached to muscles at random, then sent variety of messages, each one tuned to different muscles; each muscle received many signals, responded only to 1

Specificity of Axon Connections

  • Later research showed each axon has regenerated to same place where it had originally been, presumably by following a chemical trail Chemical Gradients
  • Humans have 30,000 genes, not enough to provide a specific target for each nerve; but still axons find their correct targets with precision
  • Growing axon follows path of cell-surface molecules; attracted by some chemicals, repelled by others, in process that steers axon in correct direction; eventually, axons sort themselves over surface of target area by following gradient of chemicals

Competition Among Axons as a General Principle

  • When axons initially reach targets, chemical gradients steer them to approximately their correct location, but not with perfect accuracy Rather each axon forms synapses onto many cells in approximately right location; each target cell receives synapses from many axons  over time each postsynaptic cell strengthens some synapses (most appropriate ones), eliminates others, adjustment depends on pattern of input from incoming axons
  • ieural Darwinism: in development of NS, start with more neurons and synapses than we can keep; synapses form with approximate accuracy, then selection process keeps some and rejects others; most successful axons and combinations survive

 Determinants of ieuronal Survival

  • Getting right number of neurons for each area of NS is complicated
  • Past: muscles send chemical messengers to tell ganglion how many neurons to form; now: muscles don’t determine how many axons form, rather how many survive
  • Initially, sympathetic NS forms more neurons than needs; when 1 of neurons forms a synapse onto muscle, muscle delivers protein called nerve growth factor (promotes survival and growth of axon)
  • Cell that doesn’t receive NGF degenerates, cell body dies; if axon doesn’t make contact with appropriate postsynaptic cell or by certain age, neuron kills itself through apoptosis
  • Brain’s system of overproducing neurons, then applying apoptosis enables CNS to match number of incoming axons to number of receiving cells
  • Each brain area has period of massive cell death; natural part of development, may indicate maturation of successful cells (loss of less successful ones)
  • NGF is neurotrophin (chemical that promotes survival and activity of neurons); not necessary for survival of brain neurons, essential for growth of axons/dendrites, formation of new synapses, learning (BNDF: brain-derived neurotrophic factor)
  • For immature neuron to avoid apoptosis and survive  receive neurotrophins from target cells and incoming axons; when neurons release neurotransmitters, also release neurotrophins

 The Vulnerable Developing Brain

  • If problems in early embryonic development  problems later on
  • Early stages of brain development critical; mutation in 1 gene can lead to many brain defects; developing brain sensitive to malnutrition, toxic chemicals, and infections that would produce milder effects at later age

 

Fetal alcohol syndrome: (Infant brain vulnerable to damage from alcohol) children of mothers who drink heavily during pregnancy: hyperactivity, difficulty maintaining attention, mental retardation, motor problems, heart defects; to prevent apoptosis, neuron must receive neurotrophins from incoming axons and from axon’s own target cell; alcohol suppresses release of glutamate (brain’s excitatory transmitter); neurons receive less excitation/neurotrophins, undergo apoptosis; alcohol alters migration pattern of small neurons, alter brain developing

  • Prenatal exposure to cocaine, cigarettes  increase ADHD and behavioral deficits
  • Antidepressant drugs  increased risk of heart problems
  • Immature brain responsive to influences from mother; if she is stressed, child will be too (ex: increased problems in academic and social lives) Differentiation of the Cortex
  • Neurons in different brain areas differ in shape and chemistry
  • Immature neurons moved to different part of cortex develop properties of new locations whereas neurons moved at a later stage develop some new; retain some old properties

 Fine-Tuning by Experience

 Unpredictability in life, brains have ability to remodel themselves (within limits) in response to experience

Experience and Dendritic Branching

  • In past, researchers doubted adult neurons can change their shape much
  • We know axons/dendrites continue to modify structure throughout life
  • Experiences guide neuronal changes (ex: more stimulation  thicker cortex, more dendritic branching, improved learning)
  • Neuronal changes (in rats) in an enriched environment depend on new and interesting experiences (ex: after practice, connections relevant to skills proliferate, enhancement is due to physical activity  enhances growth of axons and dendrites)
  • “far transfer”: teach one task and find improvement on similar tasks lacks proof; often improved on tasks that were trained in, but not others

To maintain intellectuality into old age, perform physical activity  enhance cognitive processes and brain anatomy

Effects of Special Experiences

Prolonged experience of certain type can enhance brain’s ability to perform same function again

Brain Adaptations in People Blind since infancy

  • Blindness doesn’t change touch/hearing receptors, rather increases attention to touch and sound, so brain adapts to that attention
  • Substantial activity in occipital cortex of blind people when reading Braille; touch info activated cortical area, ordinarily devoted to just vision; in people blind from birth, auditory stimuli produce increased responses in what are usually visual areas of brain
  • Blind people use occipital cortex to help identify what they feel
  • What happens in blind people is extreme case of what can happen to anyone Learning to Read
  • Those who learn to read have more grey mater (expanded neuron cell bodies/dendrites); in 5 gyri of cerebral cortex and greater thickness in part of corpus callosum then those that never learnt to read at young age Music Training
  • People who have experts in an area, spend much time practising
  • Musicians: 1) brain areas responding for hearing and finger control 2) numerous/easy to find
  • Area of temporal cortex in right hemisphere is larger than for normal population; enhanced responses in subcortical structures to musical and speech sounds
  • Grey matter is thicker in professional musicians; areas of hand control and vision
  • Larger than normal postcentral gyrus in right hemisphere devoted to fingers on left hand used to control strings (strongest for those who began musical study early)
  • Practicing skill reorganizes brain to maximize performance of skill or people born with brain characteristics attracting them to certain profession; studies have shown brain differences result of training in music (not cause of it)
  • Issue is whether music produces bigger effects if it begins early in life, when brain is easier to modify; those who start younger show an advantage, regardless if number of years of study is equivalent

When Brain reorganization goes too far

When people play instrument for years, representation of hand increases in somatosensory cortex; stimulation of 1 finger excites mostly same cortical areas as another finger  if can’t feel difference between fingers, hard to move independently; representation of middle finger expands (changing motor cortex); overlap and displace index/little finger

  • Focal hand dystonia: (musicians cramp  end career) fingers go into constant contraction; need to bind appropriate brain retraining; problem not in hands; give bursts of vibrations to various hand muscles, in random sequence; instructing people with cramp to attend carefully to stimuli and any changes in vibration frequency

 Brain Development and Behavioural Development Adolescence

  • Impulsive and prone to seek immediate pleasure; leads to risky driving, sex, drinking (Impulsiveness means difficulty in inhibiting an impulse)
  • Antisaccade task: look away from a powerful attention-getter; saccade

(voluntary eye movement away from normal direction); improves between 711; gradually improves during teen years, depending on areas of prefrontal cortex that mature slowly

  • Teens prefer smaller pleasure now, more than larger reward later
  • Teens not equally impulsive in all situations; make mature decisions when have time to consider options, impulsive when making quick decisions with peer pressure
  • Teen brains show stronger responses than adults when anticipating rewards; weaker responses in areas of prefrontal cortex responsible for inhibiting behaviour
  • Most research reports that teens prefrontal cortex is relatively inactive in certain situations, so doesn’t sufficiently explain behaviour Old Age
  • On average, people’s memory and reasoning fade beyond age 60
  • Neurons alter synapses slowly; thickness of temporal cortex shrinks each year; volume of hippocampus gradually declines (memory decline), frontal cortex thins

Research underestimates older people: 1) people vary in level of deterioration 2) as people age, slow in intellect, but greater base of knowledge and experience 3) older people find ways to compensate for losses; activate more brain areas to make up for less efficient activity

 

 PLASTICITY AFTER BRAIi DAMAGE

  • All survivors of brain damage show behavioural recovery to some degree; some mechanisms rely on growth of new branches of axons and dendrites Brain Damage and Short-Term Recovery
  • Causes of brain damage: tumours, infections, exposure to radiation or toxins, degenerative conditions, closed head injury (sharp blow to the head resulting from accident or assault that doesn’t puncture brain)
  • Most children sustain mild blows to the head, repeated injuries are worrisome, after severe brain injury recovery is slow and incomplete
  • Damage after closed head injury: rotational forces that drive brain tissue against inside of skull, or blood clots that interrupt blood flow to the brain Reducing the Harm from a Stroke
  • Common cause of brain damage is temporary interruption of normal blood flow to brain area during stroke (cerebrovascular incident); barely noticeable to fatal
  • Common, ischemia: result of a blood clot or other obstruction in artery; neurons deprived of blood lose much oxygen and glucose supply
  • Less common, haemorrhage: result of ruptured artery; neurons flooded with blood and excess oxygen, calcium and other chemicals
  • Both lead to: edema (accumulation of fluid) that increases pressure on brain, increases chance of future strokes, impair Na-K pump  leads to accumulation of Na inside neurons  excess release of glutamate, over stimulates neurons  Na and other ions enter neurons faster than pump can remove them  excess +ve ions block metabolism and kill neurons  microglia proliferate  remove products of dead neurons and supplying neutrophins that promote survival of neurons

Immediate Treatments

  • Ischemia: use tissue plasminogen activator: breaks up blood clots; if receive within 3 hours of a stroke, get most significant benefit, slightly useful after that time
  • Hard to determine which type of stroke patient had, use MRIs (timeconsuming); tPA can make situation worse if it’s haemorrhage, but it’s rare and most often fatal
  • Strokes kill neurons by overstimulation, objective is to decrease stimulation by blocking glutamate synapses, blocking Ca entry, or other means  helpful on animals
  • To prevent brain damage after strokes is to cool brain; slows harmful processes Exposure to cannaboids minimizes damage caused by strokes; decrease release of glutamate, exert an anti-inflammatory effects, alter brain chemistry to protect against damage  effective only within 1st few hours of stroke Later Mechanisms of Recovery
  • After 1st few days following brain damage, surviving brain areas increase in size or reorganize activity; one area may take over function of another or surviving brain areas don’t take over functions of damaged area, but compensate in other ways

Increased Brain Stimulation

  • Behavioural deficit after brain damage reflects; cells that died, other areas of brain that lose normal input (from damaged area) become less active.
  • Recovery from stroke depends on increasing activity for opposite side of brain
  • Diaschisis: decreased activity of surviving neurons after damage to other neurons; increased stimulation of brain can lead to improvements
  • Stimulant drugs promote recovery; amphetamines enhance movements and depth perception for long-term; too risky with humans, use drugs that block release of GABA (brain’s inhibitory transmitter); promote recovery after stroke Regrowth of Axons
  • Destroyed cell body can’t be replaced, damaged axons can grow back
  • Neuron in peripheral NS has its cell body in spinal cord (motor neurons), or in ganglion near spinal cord (sensory neurons); axons extend into 1 of limbs; crushed axon grows back toward periphery; following its myelin sheath to original target; if axon is cut, myelin of 2 sides of cut may not line up correctly; regenerating axon doesn’t have sure path to follow (motor nerve may attach to wrong muscle)
  • In mature mammal brain/spinal cord, damaged axons don’t regenerate, or do so slightly; in many fish, axons regenerate across cut in spinal cord
  • Limit axon regeneration in mammals: 1) cut in NS causes a scar to form, create mechanical barrier, block regrowth of axons 2) neurons on 2 sides of cut pull apart 3) glia cells that react to CNS damage release chemicals that inhibit axon growth
  • Build protein bridge  path for axons to regenerate across scar-filled gap Inject neurotrophins at appropriate locations to help axons grow and establish normal synapses

Infant axons grow under influence of mTOR; with maturity; mTOR levels decreases and axons in spinal cord lose their capacity for regrowth; deleting a gene that inhibits mTOR enables regrowth of axons in adult spinal cord Axon Sprouting

  • Usually, surface of dendrites and cell bodies covered with synapses, vacant spot doesn’t stay so for long; after cell loses input from an axon, secretes neurotrophins induce other axons to form new branches or collateral sprouts that take over vacant synapses; in area near damage, new synapses form at high rate
  • Process is helpful if sprouting axons convey info similar to those they replace; if it displays different info, sprouting interferes with behaviour and prevents recovery
  • Can be useless or even harmful

Denervation Supersensitivity

  • Neurons make adjustments to maintain a nearly constant level of arousal; after learning strengthens one set of synapses, other synapses weaken
  • Happens after brain damage (ex: if axons that transmit dopamine to some brain area die or become inactive, remaining dopamine synapses become more responsive  more easily stimulated)  denervation supersensitivity
  • Helps compensate for decreased input; allow people to have near normal behavior after losing most axons in some pathway but can lead to increased pain (mild input  enhanced responses)

Reorganized Sensory Representations and the Phantom Limb

  • If brain area loses a set of incoming axons, expect a combo of increased response by remaining axons and collateral sprouting by other axons that usually attach to another target
  • Each section of somatosensory cortex receives input from different part of body (ex: if amputate one finger of a monkey, cortical cells that usually respond to it lose input and soon become more responsive to other fingers or palm)
  • If an arm is amputated, previously assumed: arm would remain silent as axons from other areas couldn’t sprout far enough to reach area representing arm

 

However: found stretch of cortex previously responsive to limb now responsive to face; after losing sensory input from forelimb, axons representing forelimb degenerated, leaving vacant synaptic sites at several levels of CNS. Axons representing face sprouted in those sites on spinal cord, brainstem and thalamus or axons from face were present but stronger through denervation supersensitivity

  • Reorganization can also occur in other brain areas that respond to skin sensations
  • When something activates cells that used to respond to arm stimulation, but receive info from the face  it feels like stimulation from the arm
  • Phantom limb: continuing sensations of amputated body part; tingling to pain
  • Phantom limbs develop only if relevant portion of somatosensory cortex reorganizes and becomes responsive to alternative inputs (ex: axons representing face come to activate cortical area previously devoted to amputated hand; touch on face now produces a facial sensation and a sensation in phantom hand)
  • To relieve painful phantom sensation: learn to use artificial limb, attribute sensations to artificial limb; displacing abnormal connections from face Learned Readjustments in Behaviour
  • Much recovery from brain damage is based on learning
  • Someone with brain damage may lose some ability totally, or find it with enough effort; recovery from brain damage depends on learning to make better use of abilities that were spared
  • Person/animal will brain damage appears unable to perform a task, may in reality just not be trying
  • Deaffinated: lost afferent (sensory) input (ex: monkey has 1 deaffinated limb, fails to use it; when there are 2 deaffinated limbs, it uses it when there is no other option)
  • Lesion to visual cortex doesn’t destroy memory trace, just impairs ability to find it; as animal recovers, it regains access to misplaced memories

Therapy for people with brain damage focuses on practice of skills that impaired but not lost; treatment starts with observation of patient’s abilities and disabilities (evaluations conduced by neuropsychologists to pinpoint problem); after identifying problem (hearing, memory, language, muscle control), refer patient to physical or occupational therapist who helps patient improve on impaired skills; get best results if start soon after a patient’s stroke; brain has increased plasticity during the 1st few days after damage

  • Behaviour recovered after brain damage is effortful, recovery is precarious; person with brain damage who appears to function normally, works harder than usual person; recovery deteriorates after alcohol, physical exhaustion, stress or old age