Development view markdown

notes from Purves et al. "Neuroscience", 5th edition (chapter numbers in headers) + Intro to neurobiology course at UVA

22 early development

  • ways to study
    1. top-down: rosy retrospection
    2. bottom-up: e.g. LTP/LTD
    3. human disease: stroke-by-stroke
    4. development=ontogeny
  • timeframe
    • month 1 - gastrulation
      • most sensitive time for mom
    • month 2-5 - cells being born
    • up to year 2 - axon guidance / synapse formation
  1. gastrulation - process by which early embryo undergoes folds = shapes of NS
    • diseases
      • spina bifida - neural tube fails to seal
        • vitamin B12 can fix this
      • anencephaly - neural tube fails to close higher up
    • parts
      1. roofplate at top (back)
      2. floorplate on bottom (stomach)
      3. neural crest - pinches off top of roofplate
  2. neuroblasts = classic stem cells
    • assymetric division - cells generate themselves and differentiated progeny
    • ultimate stem cell - fertilized eggs
  3. differentiation
    • cells made by neuroblasts decide what they are going to become
    • morphogens
      • BMP - roofplate
        • cyclopia - fatal defect in BMP
      • Hedge hogs - at floor plate
      • Retinoids - axial, affect skin
        • affected by thalidomide - helps morning sickness but causes missing limb segments
        • also affected by accutane
      • FGFs - axial symmetry
      • Wnts - skin, gut, hair
        • loss of wnts is loss of hair
    • floor plate loses function after embryogenesis except glioblastoma
    • measure BMP and HH gradient to figure out where you are
      • treat ALS by adding HH to make more alpha motor neurons
    1. dorsal direction
      • roofplate makes BMP
      • low HH - interneurons, sensory neurons (ex. nociceptors)
      • even BMP/HH - sympathetic
      • high HH - more motor neurons
      • floorplate makes HH (hedge hog)
    2. axial specification (anterior/posterior)
      • tube swells into bulbs that become cerebellum, superior colliculus, cortex
    • homeotic genes = hox genes - set of genes (transcription factors) in order on chromosome
      • order corresponds to order of your body parts
      • rhombomeres - segments in brainstem made by hox gene patterns
  4. lineages
    • when neuroblast is born, starts producing progeny (family tree of neuron types)
    • very often, cells are produced in certain order
    • timing: cell-cell interations and tyrosine kinases determine order
    • first alpha neurons, then GABAergic to control those, last is glia
    • neural crest function
      • migratory - moves out and divides:
      • neuroblastoma - developed early - severe problem because missing parts of NS
      • makes DRG and associated glial cells (schwann cells)
      • makes sympathetic NS and target ganglia, enteric NS, parasympathetic NS targets
      • makes melanocytes - know how to migrate and divide but can make melanoma (cancer)
    • cortex is made inside out (6->1)
      • starts with stem cells called radial glia
      • cortical dysplasia - missing a layer / duplicating a layer
        • small part with 2 layer 3s - severe epilepsy
  5. cell death
    • 1/2 of cells die in development
  6. axon guidance (ch 23)
    • each cell born and axon grows and are guided to a target
    • dendrite basically follows same rules
  7. synapse formation (ch 23, 24)
    • pruning and plasticity
    • NMDA receptor type
    • form synapses and if they don’t look right - get rid of them
    • K1/K-1 synapses breaking and forming
    • after age 21, K-1 starts increasing and net loss of synapses

23 circuit formation

  • growth cone - motile tip of axon
    • actin tip
      1. lamellipodium - sheet (hand)
      2. filopodium - huge curves (fingers)
        • chemo attraction (actin assembly) and chemo repulsion (actin disassembly)
    • microtubule shaft - tubulin is much more cemented in
    • mauthner cell of tadpole - first recorded growth cone
    • can’t regrow (that’s why we can’t regrow spinal cord)
  • signals in growing axons
    1. pioneer axons (Betz cells) are first - often die
    2. follower axons (other Betz cells) can jump onto these and connect before pioneer dies
      • trophic support - neuron survives on contact
  • frog tectum (has superior colliculus) with map of retina:
    • ephrin (EPH) repulses axon
      • retinal NT -> tectum AP
      • axons have different amount of EPH receptors (in retina temporal has more than nasal)
      • gradient of EPH (in tectum anterior has less than posterior)
      • if we flip eye upside down (on nasal-temporal axis), image will be upside down
  • 3 classes of axon guidance molecules:
    1. ECM/integrins
    2. NCAM (homophilic—binds to another neuron that is NCAM),
      • follower neurons bind to pioneer through NCAM-NCAM interactions
    3. Cadherin (homophilic)
      • involved in recognition of being some place
  • 4 important ligands/receptors
    1. ephrins/eph
      • gradient of eph receptor
    2. netrin/dcc = guidance moleculereceptor = DCC
      • attracts axons to floorplate (midline)
      • cells without DCC don’t cross midline
    3. slit/robo - receptor is slit
      • chases axons off (away from midline)
      • axons not destined to cross midline are born expressing robo
      • axons destined to cross the midline only express robo after crossing
      • if DCC (-) and robo (-) will continue wandering around
      • robo 4 is associated with Tourette’s
    4. semaphorins/plexins
      • combinatorial code - use combinations of these to guide axons
      • these are the same genes that move cancer around
  • synaptic formation
    • neuroexins - further recognition
      • turn up in autism and schizophrenia
    • DSCAM
      • associated with Down’s syndrome
      • doesn’t use gradients
      • makes different kinds of proteins by differential slicing
  • competition
    • neurotrophins are secreted by muscle
      • in early development, a muscle fiber has many alpha motor neurons innervating it
      • all innervating neurons suck up neurotrophin and whichever sucks up most, kills all the others
      • eventually, each muscle fiber is innervated by one alpha motor neuron
      • only enough neurotrophin in target cells for a certain number of synapses
    • happens everywhere
      • ex. sympathetic ganglia
      • ex. sensory neurons in skin get axons to correct cell types based on neurotrophin
        • merkel - BDNF
        • proprioceptor - NT3
        • nociceptor - NGF
      • ex. muscles - produce NGF
        • treating ALS with NGF hyperactivates sensory neurons with trkA -> causes chicken pox
    • signals/receptors
      1. NGF - trk a (Trk receptor - survival signaling pathways)
      2. BDNF - trk b
      3. NT3 - trk b and c
      4. NT4/5 - trk b
        • all bind p75 (death receptor)
        • want to keep neurotrophins local, because there aren’t that many of them

24 plasticity in systems

  • experience-dependent plasticity - critical periods and molecular regulators for some neural systems (table 24.1)

    system species critical period (postnatal) confirmed molecular regulators
    neuromuscular junction mouse prior to day 12 ACh
    cerebellum mouse day 15–16 NMDA, mGluR1, Gq, PLCβ, PKCγ
    lateral geniculate nucleus layers mouse, ferret, cat prior to day 10 ACh, cAMP, MAOA, NO, MHC1, CREB
    ocular dominance cat, rat, mouse, ferret 3 weeks–months GABA, NMDA, PKA, ERK, CaMKII, CREB, BDNF, tPA, protein synthesis, NE, ACh
    orientation bias cat, mouse prior to day 28 NR1, NR2A, PSD95
    somatosensory map mouse, rat prior to day 7–16 NR1, MAOA, 5HT1B, cAMP, mGluR5, PLCβ, FGF8
    tonotopic map (cortex) rat days 16–50 ACh
    absolute pitch human before 7 years unknown
    taste, olfaction mouse none GABA, mGluR2, NO, neurogenesis
    imprinting chick 14–42 hours catecholamines
    stress, anxiety rat, mouse prior to day 21 hormones, 5HT1A
    slow-wave sleep cat, mouse day 40–60 NMDA
    sound localization barn owl prior to day 200 GABA, NMDA
    birdsong zebra finch prior to day 100 GABA, hormones, neurogenesis
    language human 0–12 years unknown
    • ex. ducks imprinting is non-reversable
    • learning is crystallized during critical period
      • CREB and protein synthesis
      • NMDA receptors
      • epigenetics - histones control transcription and other things
    • follow Hebb’s postulate - fire together, wire together
      • different eyes firing together will sync up (NMDA receptors to strengthen synapses)
  • systems
    1. ocular dominance
      • left/right neurons terminate in adjacent zones
      • LGN in cortex uses efferents just like superior colliculus
      • label injected into retina can make it into cortex
      • cat experiments
        • some cells see only one eye, some see both
        • cats need to form visual map in short critical period (<6 days)
        • this is why you need cochlear implant early
        • both eyes open - equal OD columns
          • one eye closed - unequal OD columns
          • branches coming out of LGN neurons grow more branches based on relative light exposure (they compete for eye’s real estate)
      • strabismus = lazy eye - poor coordination with one of the muscles
        • one eye is not quite seeing
        • treat with patch on good eye -> allows bad eye to catch up since eyes compete for ocular dominance columns
        • more stimulus = more branches
      • dye from retina goes through thalamus into cortex
        • rabies virus does same thing: cell->ganglion->brain
    2. tonotopic map
      • connection between MSO and inferior/superior colliculus
      • playing one tone increases representation
      • playing white noise disorganizes map
      • birdsong
        • hear song 10-20 times when young - crystallized
        • afterwards can’t learn new skills
    3. stress
      • early stress sets stress points later in life
      • uses serotonin
  • shifts
    • superior colliculus - integrate visual, auditory, motor to get X,Y coordinate
    • auditory map - plastic (but only when young)
    • visual map - not plastic
    • if you shift visual map (with a prism), auditory map can shift over to meet the visual
    • optic neuritis - ms optic nerve disease that shifts map
    • only young animals can shift unless they were shifted before and are now unadapting

25 repair and regeneration

  1. full repair - human PNS - skin, muscles
    • 1-2 mm/day growth - speed of slow axonal transport
    • thinnest axons first (thermal receptors and nociceptors)
    • proprioceptors last
    • process
      • perinerium / schwann cells surrounds axons - helps regeneration
      • growth cones that are cut form stumps -> distal axons degenerate = walerian degeneration
      • macrophages come in and eat up the damaged stuff
      • neurotrophins are involved
    • miswiring is common - regrow and may not find right target
      • bell’s palsy - loss of facial nerve - recovers with miswiring (salivary / tear)
    • neuromuscular junctions (NMJ)
      • damaged cells leave synaptic ghost = glia and protein matrix for nerve to regrow into
      • repairs easily after heavy training
  2. no repair / glial scar - human CNS
    • no ghost because so spread out
    • glia cover wound (scar) but can’t develop further
    • has astrocytes and oligodendrocytes (types of glial cells)
      • don’t support regrowth
      • involved in scarring
    • microglia - from immune system
      • control inflammation
      • release cytokines
    • nogo - protein that blocks regrowth (but there are other proteins as well)
    • we try repairing with shunts - piece of sciatic nerve from other part of body with schwann cells from PNS to try to repair a connection in the CNS
  3. stem cell regeneration - put new neurons being formed, 2 places in humans
    • non-human examples
      • floor plate of lizards can make new tail
      • fish retina always making new cells
      • canary brain part has stem cells that learn new song every year
    • small C14 incorporation after early development
      • suggests we don’t regenerate neurons
      • C14 was from nuclear testing
    • human areas that do regenerate
      1. hippocampus
        • memories you store temporarily
      2. subventricular zone makes glomeruli in olfactory bulb cells
        • turnover daily
        • sensory neurons and their targets constantly die and regenerate
      3. niche - places where stem cells stay alive
        • ex. places in CNS with WINT molecular signals
          • damage control - remove these signals for apoptosis = cell death
    • glutamate increase - excitotoxicity
      • can stop with NMDA blockers
      • induce a coma by cooling them down or GABA drugs
    • cytokines increase - immune system (like neurotrophins), inflammation
    • hypoxia/stress
    • neurotrophin withdrawal
      • in stress times neurotrophin goes down